Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23]>C(O)C>[CH3:22][NH:23][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc2[nH]c(-c3ccnc(Cl)n3)cc2c1
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c(-c3ccnc(NC)n3)cc2c1
Yield: 105.1 %

Procedure:
30 g (95.4 mmol) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were initially charged and suspended in 150 ml of ethanol. 53.9 g of methylamine solution in ethanol (8 M) were added to this suspension which was heated to from 75° C. to 80° C. in an autoclave for 4 h. After concentration and washing with ethanol, 29.7 g of ethyl 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (97.6 HPLC area %).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cnc2ccccc2n1
Yield: 76 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloroquinoxaline instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 118 mg, 76%) which was obtained as a light yellow solid. MS: m/e=312.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Cl.[CH3:16]O>>[CH3:16][O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Through a solution of 6-hydroxynaphthalene-2-carboxylic acid (4.87 g, 26 mmol, Aldrich) in MeOH (100 mL, Aldrich) was bubbled HCl gas for 1 h. The resulting mixture was stirred for 10 h at RT. The solution was concentrated in vacuo to give the title compound as a pink powder. MS (ESI, pos. ion) m/z: 203 (M+1). Mass Calc'd for C12H10O3: 202.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: NCc1cccnc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4cccnc4)cc3F)cn2)cc1
Yield: 167.8 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 3-(aminomethyl)pyridine (24.0 μl, 0.237 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-pyridin-3-ylmethyl-benzamide as a yellow solid (152 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-305) as a yellow powder (47.9 mg, 77%).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:18][Sn](C)(C)C>CN(C)P(=O)(N(C)C)N(C)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([CH3:18])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(CC)c1ccc(C)c2[nH]c(=O)n(C)c12
Yield: 57.1 %

Procedure:
A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 0.168 mmol), tetramethyltin (1.16 mL, 8.4 mmol) in hexamethylphosphoric triamide (5 mL) was refluxed for 18 h. After cooling, the mixture was diluted with water and extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (n-hexane/ethyl acetate=90:10-50:50) to give the title compound (111 mg, 0.48 mmol, 57%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH2:17]2)#[N:13].[H-].[Na+].[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([C:65](=O)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:61][CH:60]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:60]=[CH:61][C:62]([C:65](=[CH:24][CH:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[N:13])[CH:15]=4)[CH2:20]3)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:63][CH:64]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: N#Cc1ccc2c(c1)CCC(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCc2cc(C#N)ccc2C1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
9.0 g of (6-cyano-1,2,3,4-tetrahydro-2-naphthyl)methyltriphenylphosphonium p-toluenesulfonate was suspended in 150 ml of tetrahydrofuran, followed by gradual addition of 600 mg of 60% sodium hydride. The thus prepared mixture was refluxed under heating for 20 minutes. After cooling down to room temperature, to the resulting reaction solution was added 10 ml of a tetrahydrofuran solution containing 4.16 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. The resulting reaction mixture was stirred for 10 minutes, and then refluxed under heating for 2 hours. After cooling down to room temperature, the reaction product thus obtained was dissolved in ethyl acetate, and washed with water and saturated sodium chloride aqueous solution in that order. After drying the resulting organic layer to distill off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 3.90 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]3-(6-cyano-1,2,3,4-tetrahydro-2-naphthyl)acrylate in a yellow oily form as a mixture of E and Z forms. 2.58 g of the thus obtained E/Z mixture was dissolved in 40 ml of ethanol, and the resulting solution was mixed with 650 mg of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure for 5 hours. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent. In this way, 1.69 g of the title compound was obtained in a yellow oily form.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:28](=[O:29])[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N(C(=O)Cl)c2ccccc2)c1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(N(C(=O)N2CCN(C(=O)OCc3ccccc3)C[C@H]2C(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.2 %

Procedure:
A mixture of 264 mg (1 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid, 265 mg (1.1 mmole) of N-(3-methylphenyl)-N-phenylcarbamoyl chloride, 390 mg (3 mmole) of DIEA in 5 mL of DMF was stirred for 16 hr at room temperature. The solution was concentrated in vacuo and the residure was taken up in 50 mL of CH2CL2 and washed with 2×25 mL of 1N HCl. Concentration in vacuo gave 0.55 g of an oil, which was carried on in Step C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]=[C:29]([C:31](O)=[O:32])[O:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[O:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:30]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1nc(-c2cccnc2)no1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.2 g, 0.72 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.137 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.375 mL, 2.15 mmol) and EDCI (0.2 g, 1.07 mmol) using DMF as solvent using the method of Example 34(d). Yield 33.4 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.41 (m, 2H), 4.52 (m, 1H), 6.79 (m, 1H), 7.65 (m, 1H), 7.78 (m, 1H), 7.95 (d, 1H), 8.03 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.51 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([CH3:22])[CH2:19][NH:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: CC(C)CN
Reactant: FC(F)(F)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Product: CC(C)CNc1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)pyrimidine (548 mg, 3 mmol) and triethylamine (0.460 mL, 3.30 mmol) in isobutylamine (1.5 mL) was stirred at room temperature for 11 hours and 30 minutes (Care: exotherm). The mixture was evaporated, then dichloromethane (DCM) (5 mL) and water (5 mL) added. The organic layer was separated and purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient). The relevant fractions were combined and concentrated to yield the title compound, 548 mg. LCMS (2 min, formic) Rt 1.08 min, m/z (ES+) 220 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:26])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(C)(=O)=O)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
To a solution of [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (51 mg, 0.13 mmol) in THF (6.0 mL) was added a solution of lithium hydroxide monohydrate (62.1 mg, 2.6 mmol) in water (1.5 mL). The resulting solution was stirred for 15 hours at room temperature. The solvent was removed under vacuum. The residue was diluted with water (˜20 mL) and neutralized with 1.0 N aqueous HCl to form a suspension. The product was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude solid which was triturated with dichloromethane and hexanes. The solids were collected by filtration and washed with hexanes. After air drying, [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid (48 mg, 94%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.4 (br. s, 1H), 7.91 (dd, J=8.91, 6.65 Hz, 2H), 7.70 (s, 1H), 7.36 (t, J=8.41 Hz, 1H), 3.78 (br. s, 6H), 2.95 (s, 3H), 2.26-2.47 (m, 6H), 1.75 (d, J=12.05 Hz, 2H). MS cald. for C19H23FNO4S [(M+H)+] 380, obsd. 380.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:19]1
Reactant: O=C(Cl)c1ccoc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)nc23)CC1
Yield: 60.9 %

Procedure:
Beginning with 1.0 gm (4.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.68 gm (5.2 mMol) 3-furoyl chloride, 0.85 gm (61%) of the title compound were prepared as an ivory crystalline solid essentially by procedure described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)=[CH:19][CH:20]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C=CC(=O)c2ccc(OCC3CO3)cc2)cc1OC
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(OCC(O)CN3CCN(c4ccccc4)CC3)cc2)cc1OC

Procedure:
A solution of 3,4-dimethoxy-4′-(2,3-epoxy-propoxy)-chalcone, 16 (1 g, 2.9 mmol) and 1-phenyl piperazine (0.45 mL, 3 mmol) in dry methanol (90 mL) was stirred at reflux for 6 h. Reaction mixture was concentrated on rotavapor and crude product purified by column chromatography to afford 18. Yield 870 mg (60%); mp 126-127° C.; MS (FAB) 503 (M++1); IR (KBr) 3426, 1652; 1H NMR (200 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 2H), 7.76 (d, J=15.5 Hz, 1H), 7.39 (d, J=15.5 Hz, 1H), 7.31-7.20 (m, 3H), 7.16 (d, J=1.3 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.95-6.87 (m, 3H), 4.19-4.08 (m, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.23 (t, J=4.7 Hz, 4H), 2.90-2.85 (m, 2H), 2.69-2.61 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 189.2, 162.8, 151.8, 151.6, 149.7, 144.6, 132.1, 131.1, 129.6, 128.5, 123.4, 120.3, 116.6, 114.8, 111.7, 110.7, 70.9, 65.9, 60.8, 56.5, 53.8, 49.7. Analyses calculated for C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.18; H, 6.93; N, 5.32.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH2:12][CH2:11]1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCNc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.30 ml, 2.58 mmol) is added dropwise to a solution of 2,3-dihydro-1H-quinolin-4-one (260 mg, 1.77 mmol), triethylamine (0.32 ml, 2.30 mmol) and DMAP (10 mg) in CH2Cl2 at 0° C. The resulting mixture is stirred at room temperature for overnight. Water is added and the mixture is extracted with CH2Cl2 and washed with brine, dried over anhydrous sodium sulfate. After concentration, a residue is yielded, which is used “as is” for the next reaction without further purification.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([O:14][NH2:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].C1COCC1.CO.O.Cl>O>[C:6]([C:8]1[CH:9]=[C:10]([O:14][NH2:15])[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cccc(ON)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NOc1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
LiOH.H2O (91.0 mg, 2.17 mmol) was added to a solution of O-(3-methoxycarbonyl-phenyl)hydroxylamine 14 (90.4 mg, 0.541 mmol) in a 3/1/1 mL mixture of THF/MeOH/H2O and the reaction was stirred at room temperature. After 24 h the reaction was diluted with H2O (50 mL), acidified to pH-3-4 with 0.5 N HCl, and extracted with EtOAc (3×25 mL). The combined organics were washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated to afford 3 as a white solid (78.7 mg, 95%). 1H-NMR (500 MHz, d6-DMSO) δ 7.01 (s, 2H), 7.24 (ddd, J=1.4, 2.8, 8.3 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.46 (dt, J=1.4, 7.3 Hz, 1H), 7.68 (dd, J=1.4, 2.8 Hz, 1H); 13C-NMR (125 MHz, d6-DMSO) δ 113.5, 117.8, 121.3, 129.2, 131.8, 161.7, 167.3; ESI-MS 162 m/z [M-H+]−, C7H6NO3 requires 162.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23]C(=O)C)=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CCO>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Temperature: 120 °C

Procedure:
N-{2-tert-Butyl-1′-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}acetamide (500 mg, 1.37 mmol) was dissolved in 10 mL of 1:1/EtOH:2M HCl. The solution was divided into two sealed tubes (5 mL/tube). Each tube was heated at 120° C. in a Personal Chemistry microwaves instrument for 1 h. The fractions were pooled and the solvent was evaporated. The residue was diluted with 2M NaOH and extracted (3×) with EtOAc. The organic phase washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The solvent was evaporated. Yield: 440 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40-1.52 (m, 2H), 1.52-1.54 (m, 9H), 1.56-1.66 (m, 4H), 1.68-1.75 (m, 2H), 2.07-2.17 (m, 3H), 4.14 (d, J=7.62 Hz, 2H), 6.65 (dd, J=8.50, 2.25 Hz, 1H), 7.04-7.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:3][C:4]([O:6][CH3:7])=[O:5].[ClH:14]>[Pd].C(O)(=O)C>[ClH:14].[ClH:14].[NH2:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C=C(N)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CC(N)c1cccnc1
Temperature: 2.5 °C
Reaction time: 1.75 h
Yield: 78.4 %

Procedure:
Dry palladium on charcoal (0.54 g, manufactured by Degussa, 5% Pd/C) was added to a solution of methyl 3-Amino-3-(3-pyridyl)-2-propenoate (5.4 g, 30 mmol) in dry acetic acid (13 g) in a 450 ml Pyrex high-pressure bottle. The reaction mixture was hydrogenated at 3-3.2 bar. After 1.5-2 h, the catalyst was filtered and washed with 20 g of isopropyl alcohol until the wash solvent was no longer yellow. Gaseous HCl (10.6 g, 0.3 mol) was bubbled through the stirred filtrate at 5-15° C. The suspension was cooled to 0-5° C. and stirred for two hours. The resulting white precipitate was filtered, washed with 5 g of isopropyl alcohol, and dried at 45° C. to yield 5.95 g (78.4%,) of methyl 3-Amino-3-(3-pyridyl)propanoate dihydrochloride.
Reaction SMILES: ClC(OCC(C)C)=O.O.[C:10]([NH:17][C@H:18]([C:23]([OH:25])=O)[CH2:19][CH:20]([CH3:22])[CH3:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38]>C1COCC1>[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH:38][C:23](=[O:25])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:17][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCCN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: COCCCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (520 μL, 4.0 mmol) was added to a solution of N-Boc leucine monohydrate (1.0 g, 4.0 mmol) and N-methyl morpholine (440 μL, 1.73 mmol) in THF at 0° C. After two minutes, 3-methoxypropylamine (410 μL, 4.0 mmol) was added and the mixture was allowed to warm to rt. After thirty minutes, the reaction mixture was filtered through a bed of celite and all volatiles were removed under reduced pressure to yield N-Boc-L-leucine-3-methoxypropyl amide (1.10 g, 92%) as a white solid. 1H NMR: (CDCl3) δ 0.93, 6H, d; 1.42, 9H, s; 3.35, 3H, s; 3.38, 2H, d; 3.43 m 2H, t; 4.03m 1H, m; 4.39, s, 1H; 4.91, 1H, m; 6.60, 1H, m,
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].[CH2:26]1COCC1.C[Mg]Br.[NH4+].[Cl-]>CCOCC>[OH:2][CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)[CH3:26]
Reactant: C1CCOC1
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CSc1ncc(C(C)O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Temperature: 0.5 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A 3-necked 2 L RBF equipped with an addition funnel, temperature probe and nitrogen inlet was charged with tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (25.0 g, 69.4 mmol) and THF (400 mL). The mixture was cooled to 0.5° C. using an ice water bath. Methylmagnesium bromide (3.0 M in Et2O, 74.0 mL, 222 mmol) was added dropwise via an addition funnel over 35 min. The temperature was kept below 8° C. during the addition. The reaction mixture was stirred for 90 min at 0.5° C. and then saturated NH4Cl (aq.) was added slowly via an addition funnel while cooling in ice. The mixture was stirred for 1 h then extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated furnishing a yellow solid. The yellow solid was suspended in Et2O (ca. 200 mL), filtered, washed with additional Et2O (2×50 mL), and dried under vacuum overnight affording tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (23.17 g, 61.5 mmol, 89% yield) as a light yellow solid. m/z (ESI, +ve ion) 377.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (1H, s), 8.86 (1H, s), 8.07 (1H, s), 7.80 (1H, s), 7.32 (1H, dd, J=8.1, 1.1 Hz), 7.19 (1H, t, J=8.1 Hz), 6.95-7.07 (1H, m), 5.87 (1H, d, J=4.1 Hz), 4.93 (1H, dd, J=6.5, 4.3 Hz), 2.43 (3H, s), 1.47 (9H, s), 1.40 (3H, d, J=6.5 Hz).