Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-pentyloxyethoxy)phenyl borate (180 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-pentyloxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 106) (188 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-toluidine (52 μl, 0.486 mmol) similar to Example 13 and isolated as a pale yellow oil (132 mg, 99%). 1H NMR (CDCl3): 8.76–8.74 (m, 1H), 8.43–8.40 (m, 1H), 7.78–7.72 (m, 1H), 7.55 (s, 1H), 7.31–7.08 (m, 4H), 6.92 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 2.41 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1C(O)=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].ClC1C=C(C=CC=1Cl)CN1CCNCC1>C(Cl)Cl>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Clc1ccc(CN2CCNCC2)cc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(1.03 g, 7 mmol) was added to a solution of N-BOC-D-Proline (1.51 g, 7 mmol) in methylene chloride (12 ml) and the reaction mixture was stirred at room temperature. After 0.5 h, 3,4-dichlorobenzylpiperazine (1.32 g, 5.4 mmol) [prepared as described in Example 1] was added and the stirring was continued for 16 h. The reaction mixture was then quenched with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography with 30% acetone in dichloromethane as the eluant gave 2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]}-N-(tert-butoxycarbonyl) pyrrolidine (1.2 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[NH:16][CH2:15][C@H:14]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:13]12>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:16]2[C:12](=[O:11])[C@@H:13]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@@H:14]3[CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CNC(=O)[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc([N+](=O)[O-])nc3)C(=O)[C@@H]2C1
Yield: 81.8 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (4.71 g, 23.2 mmol, 1.05 eq) was combined with cis-tert-butyl 4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5 g, 22.1 mmol, 1.0 eq), which after silica gel purification gave cis-tert-butyl 5-(6-nitropyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6.3 g) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (m, 2H), 8.34 (d, J=9.09 Hz, 1H), 4.20 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 4.02-3.85 (m, 2H), 3.80 (d, J=10.11 Hz, 1H), 3.68 (m, 1H), 1.52-1.43 (m, 3H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:8]([O:10]CCCCCCCC)=[O:9].[OH-].[K+]>C(O)C.O>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)[C:8]([OH:10])=[O:9]
Reactant: CCCCCCCCOC(=O)C(=C1SCCCS1)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=C1SCCCS1)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of n-octyl (1,3-dithian-2-ylidene)-(3-trifluoromethylphenyl)-acetate (15 g) in ethanol (375 ml), a 30% solution of potassium hydroxide in water (375 ml) is added. The mixture is refluxed for 2 hours. The solvents are removed in vacuo. Water (500 ml) and ether (500 ml) are added. The water solution is acidified to pH 4 with 5N sulphuric acid. The phases are separated and the water solution is extracted with ether (3×350 ml). The combined organic solutions are dried over magnesium sulphate and the solvent is evaporated in vacuo. The residue is triturated in petrol ether (b.p. 40°-65°) and dried in vacuo to constant weight to give (1,3-dithian-2-ylidene)-(3-trifluoromethylphenyl)-acetic acid, m.p. 165°-166° C.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:2].[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([Br:28])=[CH:22][CH:23]=3)[C:18](=[O:29])[C:17]=2[CH:16]=1.OO.NC(N)=O>ClCCl>[Br:28][C:21]1[CH:20]=[C:19]2[C:24]([C:25]3[CH:26]=[CH:27][C:15]([Br:14])=[CH:16][C:17]=3[C:18](=[O:29])[O:2]2)=[CH:23][CH:22]=1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: O=c1oc2cc(Br)ccc2c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 134.5 %

Procedure:
A solution of TFAA (2.1 mL, 3.15 mmol) in dichloromethane (5 mL) was added dropwise to a suspension of 2,7-dibromo-fluoren-9-one (3.3 g, 10 mmol) and H2O2-urea (1.4 g, 15 mL) in dichloromethane (50 mL). The mixture was stirred at room temperature for 48 hours, a second portion of H2O2-urea was added, and stirring was continued at room temperature for a further 72 hours. The mixture was filtered, the organic phase was extracted with water (50 mL), and dried over Na2SO4. After removal of solvent, the residue was heated with 2N NaOH at 80° C. for 10 minutes, filtered, the cooled filtrate extracted with ether. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (200 mL). HCl (2 mL 4M solution) was added to the ethyl acetate and heated for 2 hours. The solvent was removed under vacuum, the residue was recrystallized from ethyl acetate/ethanol to give the final product 3,8-Dibromo-benzo[c]chromen-6-one as a white solid (1.5 g, 40%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][Cl:21])=[CH:10][CH:9]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[ClH:21].[Cl:21][CH2:20][CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH2:7])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCCl)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ccc(OCCCl)c2ccccc12

Procedure:
To a stirred solution of [4-(2-chloro-ethoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.387 g, 4.3 mmol) in anhydrous dioxane (10 ml) at room temperature is added a solution of 4M HCl in dioxane (15 ml). After 18 hours diethyl ether (150 ml) is added and 4-(2-chloroethoxy)-naphthalen-1-ylamine hydrochloride salt filtered off as a pink solid (1.081 g).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])(=O)C([O-])=O>>[OH:1][CH:2]([CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2
Reactant: C1CCNC1
Reactant: c1cc2c(s1)CCC/C2=N\OCC1CO1
Agent: O=C([O-])C(=O)[O-]
Product: OC(CO/N=C1\CCCc2sccc21)CN1CCCC1
Yield: 77.5 %

Procedure:
This compound is prepared by the procedure described in Example 1 by condensing E-4-(2,3-epoxypropoxy)imino-4,5,6,7-tetrahydrobenzo[b]thiophene with pyrrolidine. Oxalate: white crystals; m.p. 136° C. (recrystallised from isopropyl alcohol); yield: 77.5% of theory.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:6]2[N:5]=1)=O.COCC(O)C.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=2)[CH2:34][CH2:33]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>>[CH3:18][N:16]1[CH:17]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([N:32]4[CH2:33][CH2:34][CH:35]([O:38][C:39]5[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=5)[CH2:36][CH2:37]4)=[N:5]3)=[CH:10][CH:11]=2)[CH:14]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: Cn1cc(-c2ccc3cnc(N4CCC(Oc5cccc(N)c5)CC4)nn23)cn1
Yield: 2.7 %

Procedure:
2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.3827 mmol) was dissolved in 1-Methoxy-2-propanol (374.1 uL, 3.827 mmol) and added to 4-(3-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (223.8 mg, 0.7654 mmol) and N,N-Diisopropylethylamine (200.0 uL, 1.148 mmol). The substance was microwaved at 200 C for 15 min. The reaction was concentrated, dissolved in 1 mL of DMSO and placed onto the Gilson. Lyophilized overnight to give 3-{1-[7-(1-Methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-piperidin-4-yloxy}-phenylamine as a yellow solid (4 mg, 3%). LCMS (E/I+) 417 (M+H). NMR 1H (DMSO-d6)-8.82 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 7.24 (t, 1H, J=8.05 Hz), 7.05 (d, 1H, J=4.71 Hz), 6.87 (d, 1H, J=4.76 Hz), 6.77 (d, 1H, J=8.04 Hz), 6.69 (s, 1H), 6.65 (d, 1H, J=8.04 Hz), 4.62-4.68 (m, 1H), 4.08-4.16 (m, 2H), 3.93 (s, 3H), 3.50-3.6 (m, 2H), 2.04-2.12 (m, 2H), 1.66-1.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][C:9](=[CH:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1
Reactant: Cc1[nH]cnc1C=C1CCc2[nH]c3c(F)cccc3c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2[nH]c3c(F)cccc3c2C1=O
Yield: 46.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methylene]-4H-carbazol-4-one (728 mg) in absolute ethanol (30 ml) was added to a suspension of 5% palladium on charcoal (100 mg) in ethanol (30 ml), and the resulting mixture was hydrogenated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to leave an oil which was purified by FCC eluting with ethanol:ethyl acetate (1:5) to give the title compound (342 mg), m.p. 135°-140°, t.l.c. (ethanol:ethyl acetate, 1:5) Rf 0.175.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:18]P(Br)Br>C(OCC)C>[Br:18][CH2:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCC#Cc1cccc(F)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1cccc(C#CCBr)c1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 126 %

Procedure:
3-(3-Fluoro-phenyl)-prop-2-yn-1-ol (0.750 g, 0.005 mol) was taken in diethyl ether (10 ml) containing catalytic amount of pyridine (0.05 ml). The reaction mixture was then cooled to −5-0° C. Tribromo phosphine (0.26 ml, 0.003 mol) was added slowly at −5-0° C. and stirred at the same temperature for 3 hrs. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over Na2SO4, and evaporated under vacuum to get 1-(3-bromo-prop-1-ynyl)-3-fluoro benzene (0.805 gm, 76%).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[F:11][C:12]([F:19])([F:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([F:19])([F:18])[F:11])=[N:9]2)[CH:3]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: Cc1cccc(NN)c1
Agent: Cl
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 21.5 %

Procedure:
Following the procedure in Example 161A Step 3, m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and 4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted to give 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57 mmol, 22%). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.20 (m, 4H), 5.82-5.61 (m, 3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])[C:19]4[CH2:25][CH2:24][NH:23][CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:33].CN(C)C=O.N1C=CC=CC=1.[S:45]1[CH:49]=[CH:48][N:47]=[C:46]1[C:50](Cl)=[O:51]>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])[C:19]4[CH2:25][CH2:24][N:23]([C:50]([C:46]5[S:45][CH:49]=[CH:48][N:47]=5)=[O:51])[CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:33]
Reactant: O=C(Cl)c1nccs1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCNC2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCN(C(=O)c1nccs1)C2
Reaction time: 8 h

Procedure:
(S)-3-methyl-6-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylamino)pyrimidine-2,4(1H,3H)-dione (0.0325 g, 0.0000723 mol) in dry N,N-Dimethylformamide (2.00 mL, 0.0258 mol) was added dry Pyridine (0.030 mL, 0.00037 mol) followed by 1,3-thiazole-2-carbonyl chloride (0.0300 g, 0.000203 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated, chromatographed through silica gel (4 g, 0-10% MeOH in dichloromethane), and then purifed by HPLC. 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.69 (s, 1H), 8.32 (t, J=7.8, 2H), 8.13-8.04 (m, 2H), 7.31 (dd, J=8.3, 4.7, 2H), 5.50 (dd, J=75.0, 18.3, 1H), 5.04 (d, J=2.8, 1H), 4.79 (dd, J=47.1, 18.7, 1H), 4.67-4.28 (m, 1H), 4.17 (d, J=6.1, 1H), 4.05-3.73 (m, 2H), 3.73-3.55 (m, 4H), 3.45 (dd, J=17.5, 7.1, 1H), 3.09 (s, 3H), 2.82 (d, J=22.7, 2H), 1.28 (d, J=6.7, 3H). LC/MS-m/z+561.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[Cl:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:27]([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: COC(=O)Cc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-Aminophenylacetic acid methyl ester (10.2 g, 39.45 mmol) was dissolved in DCM (200 ml). There were then added first pyridine (12.4 ml, 151.71 mmol) and 3,4-dichlorobenzenesulfonyl chloride (11.8 ml, 75.87 mmol) in DCM (50 ml). The reaction solution was stirred overnight and then diluted with DCM and washed in succession with 0.5 M KHSO4 solution, saturated NaHCO3 solution and saturated NaCl solution, dried over sodium sulfate and concentrated. Purification was carried out by column chromatography on silica gel (DCM).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:5][C:4]=1[Cl:28].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:24]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:4]([Cl:28])[N:5]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: CCCCc1nc(Cl)c(CNC(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(ethoxycarbonylaminomethyl)imidazole was prepared from 5-aminomethyl-2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole using ethyl chloroformate and the Schotten-Baumann procedure described in Example 209, Part B: m.p. 144.0°-147.0°. NMR (200 MHz, DMSO-d6) δ12.74 (s, 1H); 7.73 (d, 1H, J=7 Hz); 7.63-7.27 (m, 5H); 7.03 (d, 2H, J=10 Hz); 5.27 (s, 2H); 4.60 (bd, 2H, J=7 Hz); 3.90 (q, 2H, J=7 Hz); 3.34 (s, 2H); 2.47 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.24 (t of q, 2H, J=7,7 Hz); 1.06 (t, 3H, J=7 Hz); 0.78 (t, 3H, J=7 Hz). Anal. Calcd. for C25H28ClN3O4.(H2O)0.33 : C, 63.17; H, 6.06; N, 8.83. Found: C, 63.30; H, 6.35; N, 8.44.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OC1CCOC1
Reactant: N#Cc1cnc(N)cc1Cl
Product: N#Cc1cnc(N)cc1OC1CCOC1

Procedure:
From intermediate 16 and racemic tetrahydrofuran-3-ol, reacted in an analogous manner to the preparation of intermediate 20. (UPLC-MS 3) tR 0.48 min, ESI-MS 206.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[NH2:36][OH:37].Cl.CC([O-])=O.[Na+]>CCCCO>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=[N:36][OH:37])[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=NO)c1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-acetyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.15 g) in n-BuOH (5 mL) were added NH2OH HCl salt (23 mg) and NaOAc (40 mg). The mixture was refluxed for 6 hour, then evaporated. The residue was diluted with CH2Cl2, washed with 1N HCl, dried and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1:1) to give N-(2,6-dichlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 490 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([CH2:9][CH2:10][C:11](Cl)=[O:12])([O:7][CH3:8])=[O:6].[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O.Cl[CH2:21]Cl>>[CH2:8]([O:7][C:5](=[O:6])[CH2:9][CH2:10][C:11](=[O:12])[C:16]1[CH:17]=[CH:18][NH:14][CH:15]=1)[CH3:21]
Reactant: c1cc[nH]c1
Reactant: ClCCl
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)CCC(=O)c1cc[nH]c1
Reaction time: 8 h

Procedure:
A mixture of AlCl3 (24.02 g) and dichloromethane (400 mL) was treated with (carbomethoxy)propionyl chloride (27.05 g). A solution of pyrrole (10.01 g) in dichloromethane (150 mL) was then added dropwise. After stirring overnight, the reaction mixture was poured over ice and water (500 mL). The resulting mixture was then extracted with dichloromethane (500 mL). The combined organic layers were washed with brine (500 mL), dried (MgSO4) and concentrated to afford γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (5.14 g).
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:19]2[CH:20]=[C:21]([CH:34]=[CH:35][CH:36]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])=[O:23])=[N:15][C:16]=1[C:17]#[N:18].[NH:37]([C:39]([C@H:41]1[CH2:46][CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1)=O)[NH2:38]>O>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:19]2[CH:20]=[C:21]([CH:34]=[CH:35][CH:36]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])=[O:23])=[N:15][C:16]=1[C:17]1[NH:38][N:37]=[C:39]([CH:41]2[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]2)[N:18]=1
Reactant: N#Cc1nc(-c2cccc(C(=O)NCc3ccc(Cl)cc3F)c2)cnc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NN)C1
Agent: NC(=O)c1ccccc1
Solvent: O
Product: Nc1ncc(-c2cccc(C(=O)NCc3ccc(Cl)cc3F)c2)nc1-c1nc(C2CCCNC2)n[nH]1
Temperature: 180 °C
Yield: 64.5 %

Procedure:
3-(5-anmino-6{3-[(3S)-piperidin-3-yl]-1H-1,2,4-traiazol-5-yl}pyrazine-2-yl)-N[4-chloro-2-fluorophenyl)methyl]benzamide: 3-(5-Amino-6-cyano-pyrazin-2-yl)-N-(4-chloro-2-fluoro-benzyl)-benzamide (238.0 mg, 0.63 mmol) and 1,1-dimethylethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (460 mg, 1.89 mmol) was combined together and it was heated to 180° C. for 1 or 2 hrs. The reaction mixture was poured into water (575 mL), and extracted with ethyl acetate (2×35 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by MPLC to give 3-[5-amino-6-(5-piperidin-3-yl-2H-[1,2,4]triazol-3-yl)-pyrazin-2-yl]-N-(4-chloro-2-fluoro-benzyl)-benzamide (206.0 mg, 65.0% yield): 1H NMR (400 MHz, d4-MeOH): δ 8.60 (d, 2H), 8.20 (d, 1H), 7.82 (d, 1H), 7.58 (t, 1H), 7.38 (t, 1H), 7.15 (m, 2H), 4.60(s, 2H), 3.62 (m, 1H), 3.40(m, 3H), 2.99 (m, 1H), 2.37 (m, 1H), 1.98 (m, 3H); MS (EI) for C25H24N8OFCl: 507.03 (MH+).