Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(S(N)(=O)=O)c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-benzenesulfonamide as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.91 (s, 1H), 8.17 (d, 1H), 8.11 (s, 1H), 7.70 (d, 1H), 7.54 (t, 1H), 7.48 (d, 1H), 7.39 (br, 2H), 7.05-6.98 (2H), 6.37 (s, 1H), 4.00 (t, 2H), 3.85 (s, 3H) and 2.98 (t, 2H); MS (ESI) (M+H)+ 399.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(F)cc3)c3ccc(F)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-fluorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%. Amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][CH:9]2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][C:9]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1

Procedure:
3-(p-Chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2-a]-benzimidazole-2-acetic acid, (5.0 g.) is suspended in a solution of 100 ml. of a 6 N NCl and 200 ml. of dioxane. The mixture is heated at reflux for 18 hours. The solution is concentrated in vacuo to 50 ml. To the concentrate is added 200 ml. of water, and sufficient 4 N NaOH solution to dissolve all the solids. The alkaline solution is made acidic with acetic acid. The solid is collected, washed well with water and air-dried. The crude material is recrystallized from dimethoxyethane. The product (2.0 g.) melts at 242°-243° C.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][C@H:6]1[OH:21].[H][H].C(OCC)C>CO.[Pd]>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(O[C@@H]2CCNC[C@H]2O)c1C
Yield: 46.6 %

Procedure:
A solution of trans-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (3.5 g, 9.8 mmol) in methanol (50 ml) was added to 5% palladium on charcoal (350 mg) under an atmosphere of nitrogen. The vessel was placed under an atmosphere of hydrogen and stirred vigorously until hydrogen uptake ceased. The resulting suspension was filtered over a short pad of celite (pre-washed with methanol) and the pad washed with a further portion of methanol (100 ml). Concentration of the methanolic solution in vacuo gave a yellow oil. Dilution with diethyl ether (100 ml) yielded trans-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine as a white solid (1.01 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C:11](=O)[C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]=23)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]=23)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)C(=O)c2c3n(c4ccccc24)CCNCC3)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(NC(=O)Cc2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
(Chart C, Step 1): A solution of N-(4-methoxyphenyl)-2-oxo-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide (355 mg, 0.98 mmol) in 1,2-dichloroethane (20 mL) is treated with TFA (2.5 mL) and triethylsilane (2.5 mL). The resulting clear golden solution is heated to reflux. After 18 hrs, the reaction is cooled to rt, washed twice with saturated sodium bicarbonate (50 mL), once with brine (50 mL), dried over MgSO4, filtered, and concentrated to give a golden oil. This material is purified by LC (230-400 silica gel) eluting with 5:0.5:94.5 methanol/NH4OH/dichloromethane to afford 275 mg of N-(4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide as a white foam. IR (drift) 1662, 1602, 1535, 1512, 1467, 1411, 1372, 1358, 1323, 1297, 1243, 1180, 1032, 830, 740 cm−1; OAMS supporting ions at: ESI+350.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([OH:27])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>C(Cl)Cl.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:22][CH2:21][C:20]([C:25]([NH2:30])=[O:27])([CH2:19][CH2:18]1)[CH2:23][CH2:24]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)O)(CC1)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=O)(CC1)CC2
Reaction time: 2 h

Procedure:
A portion of carboxylic acid 1-D (0.67 g, 1.77 mmol) was suspended in methylene chloride (15 ml) and treated with 1,1′-carbonyldiimidazole (0.57 g, 3.52 mmol) at room temperature and under a nitrogen atmosphere. After 2 h, concentrated ammonium hydroxide was added (40 ml) and the reaction was stirred for 18 h. The crude mixture was diluted with water (150 ml) and extracted with 3 portions of methylene chloride (70 ml). The organic washes were combined, washed with brine, dried (Na2SO4), and stripped to yield 1-E as a white powder. MS (ESI+)=379.3 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.88-7.86 (m, 1 H), 7.75-7.71 (m, 2 H), 7.54 (t, 1 H), 5.75 (s, 1 H), 5.47 (s, 1 H), 3.50 (s, 3 H), 2.22 (t, 6 H), 2.00 (t, 6 H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[NH:6][C:7]=1[I:8])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([N:6]1[C:7]([I:8])=[C:3]([CH:1]=[O:2])[CH:4]=[C:5]1[C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C=O)c(I)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C=O)c(I)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a stirred solution of 4 (0.72 g, 2.6 mmol) in acetone (20 mL) was added K2CO3 (0.71 g, 5.1 mmol). The resulting mixture was stirred for 30 minutes at room temperature. Benzyl bromide (0.46 mL, 3.8 mmol) was added dropwise to the reaction mixture and was then refluxed for 16 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate and water. The combined organic layer was dried over anhydrous MgSO4, filtered and then concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 5 as a white solid (0.85 g, 90%). 1H NMR (CDCl3) δ 9.66 (s, 1H), 7.50 (s, 1H), 7.24-7.25 (m, 3H), 6.98 (d, J=7.6 Hz, 2H), 5.75 (s, 2H), and 3.72 (s, 3H); 13C NMR (CDCl3) δ 186.98, 160.33, 136.43, 128.97, 128.22, 127.84, 127.10, 126.59, 119.32, 92.81, 52.81, and 52.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1>>[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1
Reactant: CC1NCCc2c(Cl)csc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2scc(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-chloro-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CNC>C1COCC1>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][C:3]2[O:7][C:6]3[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=3[C:4]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: CNC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(CN3CCN(C)CC3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxybenzo[b]furan (Example 33) (50 mg, 0.10 mmol) in dry THF (2 mL) at room temperature was added N-methylpiprazine (24 μL, 0.22 mmol) and the mixture was stirred for 2 hours and then added solution of dimethylamine (0.2 mL, 2M solution in THF, excess) and stirred for 4 hours. The solvent was distilled and the crude was purified over silica gel column and the product was crystallized from acetonitrile to afford the title compound as a light yellow crystalline solid (22 mg, 46%). 1H NMR (300 MHz, CDCl3) δ 7.12 (s, 2H, benzoyl Hs), 6.89 (d, J=8.58 Hz, 1H), 6.85 (d, J=8.58 Hz, 1H), 3.93 (s, 6H, 2×OMe), 3.82 (s, 6H, 2×OMe), 2.57 (b, 4H), 2.39 (b, 4H), 2.23 (s, 3H, NMe).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12]2[S:13][CH:14]=[N:15][N:16]=2)[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3].[Br:31]N1C(=O)CCC1=O>C(#N)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12]2[S:13][C:14]([Br:31])=[N:15][N:16]=2)[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nncs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazole (0.020 g, 0.0451 mmol) was dissolved in 0.25 mL ACN, followed by addition of N-Bromosuccinimide (0.00883 g, 0.0496 mmol), and the reaction mixture was heated at 60° C. for 14 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was then purified by flash column chromatography, eluting with 5.3:1 (hexanes/ethyl acetate), to afford the desired product as a thick golden oil (22 mg, 93%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23](ON3C(=O)CCC3=O)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>O.C1COCC1>[C:23]([N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4])([O:22][CH2:21][CH:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:24]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: OC[C@@H]1CCCN1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC[C@H]1CO
Reaction time: 1 h
Yield: 74 %

Procedure:
L-prolinol (Compound 1) (0.61 g, 6.0 mmol) was dissolved in 70 ml of pure water, thus preparing an L-prolinol aqueous solution. N-(9-Fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (2.0 g, 6.0 mmol) was dissolved in 10 ml of THF. This THF solution was added to the L-prolinol aqueous solution, and this was stirred for 1 hour so as to react the L-prolinol and the Fmoc-OSu. The reaction solution was separated into a liquid fraction and a precipitate fraction. These fractions respectively were subjected to extraction with ethyl acetate, and organic layers respectively were collected therefrom. The thus-obtained organic layers were mixed together, and anhydrous sodium sulfate was added thereto to absorb moisture (hereinafter, this process is referred to as a “drying” process). The organic layers were filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by silica gel column chromatography (the eluent: hexane:ethyl acetate=1:1). Thus, Compound 2 was obtained (1.4 g, yield: 74%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=O)[CH2:29][C:30]([O:32]CC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 24 h
Yield: 88.5 %

Procedure:
The intermediate (S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (117 mg, 0.25 mmol) was dissolved in THF (4 mL) and treated with LiOH (12 mg, 0.5 mmol) in water (1 mL) and stirred for 24 h. The reaction mixture was evaporated to half-volume, diluted with water (5 mL) and the pH adjusted to pH ˜7 with a 1 N solution of hydrochloric acid. The resulting precipitate was filtered with the aid of water and air dried to afford the title compound as a solid (97 mg, 88%). LC/MS (Method A) 5.31 min, [M+1]+ 439.
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26](O)=[O:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]([N:5]([CH2:25][C:26](=[O:27])[N:31]([CH3:32])[CH3:30])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with dimethylamine hydrochloride (CAN 506-59-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=425.5 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH3:15])[CH:6]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH:14][CH3:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N)c(NC)c1
Yield: 86.6 %

Procedure:
4-Amino-3-methylamino-benzoic acid ethyl ester (2.1 g) was prepared by following General Procedure B starting from 3-methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) and Pd—C (560 mg) in methanol (25 mL).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][O:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:10])[CH3:11])=[N:6][CH:7]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1c(O)cnc(OC(C)C)c1C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(OCCNC(=O)OC(C)(C)C)cnc(OC(C)C)c1C
Yield: 64.8 %

Procedure:
A mixture of methyl 5-hydroxy-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131c, 0.70 g, 3.1 mmol), tert-butyl (2-bromoethyl)carbamate (0.76 g, 3.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in CH3CN (24 mL) was degassed with N2 and refluxed for 15 hours. To the reaction mixture was added brine (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5-{2-[(tert-butoxycarbonyl)amino]ethoxy}-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131d, 0.74 g, 65%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]=[C:19]2[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][C:23]=3[NH:22][C:21](=[O:29])[N:20]2[CH:30]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[CH2:27][CH2:28][C:23]2[NH:22][C:21](=[O:29])[N:20]3[CH:30]=[C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[N:18]=[C:19]3[C:24]=2[CH2:25]1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: Fc1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reaction time: 0.75 h

Procedure:
2-Fluorobenzyl bromide (54 uL, 0.45 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (128 mg, 0.45 mmol) and triethylamine (76 uL, 0.54 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 45 minutes, and then concentrated. Aqueous sodium bicarbonate was added, the aqueous layer extracted twice with 10% methanol/ethyl acetate, and the combined organic layers dried over magnesium sulfate, filtered, concentrated, and triturated with methanol/ether to give 9-(2-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 13) as an off-white solid, m.p. 270°-273° C. Treatment with ethanolic HCl affords the corresponding HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(F)cc1
Reactant: Nc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Nc1ccc(Cl)cc1
Yield: 81.7 %

Procedure:
A solution of (E)-4-fluorostyrylsulfonyl chloride (10 mmol) and 4-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 126-128° C, was obtained in 81.7% yield.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]([CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24]CC1C=CC=CC=1)=[O:16])([O:3][CH3:4])=[O:2].[H][H]>CO.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]([CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1O

Procedure:
A solution of (28) (0.11 g., 0.25 mM) in methanol (11 mL) containing 10% palladium on carbon (30 mg.) is shaken in a 40 p.s.i. hydrogen atmosphere until no (V) remained (TLC analysis). The filtered solution was then concentrated in vacuo to give the title compound (29), used immediately in step P.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[F:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([N:27]=[C:28]=[S:29])=[O:26])=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][C:28](=[S:29])[NH:1][C:2]2[S:12][C:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=3[C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccc(F)cc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Yield: 71.7 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 4-fluorobenzoyl isothiocyanate (0.18 g, 0.99 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl 2-(3-(4-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.330 g, 0.71 mmol, 71% yield) was isolated as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.70 (s, 1H), 9.01 (s, 1H), 8.00-7.94 (m, 2H), 7.25-7.18 (m, 2H), 4.74 (apparent t, J=1.5 Hz, 2H), 2.76 (apparent t, J=1.5 Hz, 2H), 1.64 (s, 9H), 1.31 (s, 6H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=[O:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:2][C:1]1[O:3][C:6]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[N:5][N:4]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(C)=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCc3nnc(C)o3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of N′-acetyl-2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetohydrazide (0.42 g), 4-methylbenzenesulfonyl chloride (0.16 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. 4-Methylbenzenesulfonyl chloride (0.083 g) was added, and the mixture was stirred at 110° C. for 8 hr. Ethyl acetate and 1 M hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 60%).