Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[NH:10]2)=[C:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:4]=1)#[N:2].[Br:36]Br>C(Cl)(Cl)Cl>[Br:36][CH2:20][C:13]1[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:11](=[O:31])[NH:10][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrBr
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(rac)-Ethyl 4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 115; 3.00 g, 5.62 mmol) was dissolved in chloroform (49.9 ml), and the solution was cooled to 0° C. on an ice bath. Bromine (987 mg, 6.18 mmol) was then added dropwise. Subsequently, the ice bath was removed and the reaction mixture was stirred at RT for 1 h. Sodium thiosulfate solution (50 ml) was then added, and the organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the solid was filtered off with suction and washed with diethyl ether. This gave 2.96 g (90% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: [CH:1]1([C:6]2[C:10]([C:11](OCC)=[O:12])=[C:9]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH:1]1([C:6]2[C:10]([CH2:11][OH:12])=[C:9]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C2CCCC2)noc1C1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1c(C2CCCC2)noc1C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of ethyl 3,5-dicyclopentyl-4-isoxazolecarboxylate (1.57 g, 5.67 mmol) in THF (15.7 mL) was stirred in an ice bath as a 1.5 M solution of diisobutylaluminum hydride in toluene (8.1 mL, 12.1 mmol) was added dropwise. The solution was allowed to stir at 0° C. for 30 minutes then at room temperature for 5.5 hours. An additional portion of diisobutylaluminum hydride (1.6 mL, 2.4 mmol) was added and the solution was allowed to stir for 45 minutes. The solution was cooled in ice bath before the addition of a 10% aqueous solution of Rochelle's salt. The resulting solution was allowed to stir overnight. The solution was extracted with ethyl acetate and the organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 3:7 ethyl acetate:hexanes) to provide (3,5-dicyclopentyl-4-isoxazolyl)methanol (0.80 g, 57% as 0.15 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 4.84 (s, 1H), 4.26 (d, J=4 Hz, 2H), 3.30-3.22 (m, overlapping H2O), 3.13-3.06 (m, 1H), 1.98-1.87 (m, 4H), 1.74-1.56 (m, 12H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH:6]=[C:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.Cl.N1C=CC=CC=1.Cl>>[CH:19]1[C:20]2[C:7](=[CH:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:23]=[CH:22][CH:21]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C=C2c3ccccc3Cc3ccccc32)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(C=C2c3ccccc3Cc3ccccc32)c1
Temperature: 220 °C
Yield: 84.4 %

Procedure:
Mix 9-(3-methoxy-benzylidene)-9,10-dihydro-anthracene (900 mg, 3.0 mmol) and pyridine hydrochloride (4 g) and heat at 220° C. for 30 minutes. Cool to 115° C. and carefully add 5N HCl. Extract the product into EtOAc, dry (MgSO4) the organic solution and concentrate to give 720 mg dark oil. Purify by ISCO using EtOAc/hexanes to give title compound, mp 195.8° C., HPLC>99% purify. MS (es) 283 (M−1). 1H NMR (DMSO -d6) □3.74 (br s, 1H), 6.79-7.45 (m, 13H), 9.46 (s, 1H); 13C NMR (DMSO-d6) δ 40.22, 114.59, 115.81, 119.51, 125.53, 125.85, 127.02, 127.30, 128.05, 128.27, 128.56, 129.77, 129.06, 129.39, 134.75, 135.83, 138.98, 139.92, 142.87, 144.63, 157.27
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1(=[O:32])[N:20]([CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])[C:19](=[O:27])[C:18]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:17]12>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:20]4[C:16](=[O:32])[C:17]5=[CH:31][CH:30]=[CH:29][CH:28]=[C:18]5[C:19]4=[O:27])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: O=C(CCCN1C(=O)c2ccccc2C1=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
31.4 g (0.143 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline dissolved in 300 ml of methylene chloride are added at 0° to a solution of 36.0 g (0.143 mol) of 4-phthalimidobutyryl chloride in 360 ml of methylene chloride and the mixture is stirred at room temperature for 1 hour. The solution is concentrated, extracted with methylene chloride and aqueous sodium hydrogen carbonate solution, dried with magnesium sulfate and the solvent is distilled in a vacuum. Extractive crystallization with acetone gives 8-chloro-1,2,3,4,5,6-hexahydro-4-(4-phthalimidobutyryl)benzo[f]quinoline as white crystals with melting point 182°-183°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:23]([CH3:29])([CH3:28])[C:24](C#N)=[O:25]>C1COCC1>[CH3:28][C:23]1([CH3:29])[C:24](=[O:25])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=2)[O:19]1
Reactant: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1C
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
437 mg of 1-{3-methyl-4-(methylthio)phenyl}-2-(3-fluorophenyl)-ethanone in 50 ml dry THF was stirred with 67 mg of 60% oil dispersion of sodium hydride for an hour at 0° C., which was followed by dropwise addition of 0.8 ml α-bromoisobutyryl cyanide diluted with 25 ml THF. The reaction solution was slowly warmed to room temperature and was stirred overnight. Then the solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 312 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{3-methyl-4-(methylthio)phenyl}-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.27 (s, 3H), 2.48 (s, 3H), 7.36 (m, 4H), 7.32 (m, 1H), 7.45 (m, 2H). IR 1694, 1601, 1385, 1260, 1192.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[Br:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Br)c2C(=O)N2CCC[C@@H]12

Procedure:
9.2 g (0.038 mol) of 6-bromoisatoic acid anhydride and 4.6 g (0.040 mol) of L-proline in 55 ml of dimethyl sulphoxide are heated at 70° for 1 hour, the solvent is removed in a high vacuum and the oil obtained is heated at 170° for 15 minutes. The crude product is purified by chromatography on silica gel using a mixture of chloroform and methanol (20:1) as the elution agent. There is obtained (S)-6-bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which melts at 221°-224° after recrystallization from chloroform/hexane.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-].[NH4+:19].Cl>[OH-].[NH4+].O>[NH2:19][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2
Reactant: [NH4+]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 76 %

Procedure:
To a solution of 20 mg (0.082 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione in 0.5 mL of DMSO-d6 was added 2 drops of 30% ammonium hydroxide and the solution was heated at 80° C. for 24 h. To the mixture was added one more drop of 30% ammonium hydroxide and it was heated at 80° C. for 10 h. The mixture was added to 4 mL of water and then acidified with 2N HCl to pH=1. The precipitate was filtered, washed with water, and dried to leave a yellow solid (15 mg, 76%); mp 250° C. (dec.); 1H NMR (DMSO-d6), 7.202 (1, d, J=11.5), 7.232 (sb, 2), 11.15 (mb, 1), 12.0 (mb, 1). 19F NMR, -133.84 (d, J=11.6). MS, 240 (M+, 100), 212 (10), 177 (10), 166 (20). HRMS, Calcd for C8H5FN4O4 240.0290, found 240.0294.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(C(F)(F)F)ccc2N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 80 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (326 mg) and (S)-tert-butyl 3-(2-amino-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (485 mg) was dissolved in dioxane (4 ml), p-toluenesulfonic acid (26 mg) was added. The reaction mixture was heated at 80° C. for about 5 h. The mixture was diluted with dichloromethane and 10% aq. K2CO3 solution. The organic layer was separated, passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica gel; solvent:100% iso hexane→4:1 H:E).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]([CH3:24])=[C:8]([CH3:25])[N:7]=1>CO>[CH3:3][O:2][N:4]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]([CH3:24])=[C:8]([CH3:25])[N:7]=[C:6]([NH2:5])[C:11]=2[N:12]=[C:13]1[CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CON
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCC(C)=O
Agent: Cl
Solvent: CO
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCC(C)=NOC
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
Methoxylamine hydrochloride (0.57 g, 6.8 mmol) was added to a solution of 5-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridine-1-yl)pentan-2-one (1.31 g, 4.5 mmol) in methanol (30 mL) and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (150 mL), washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure to afford 1.33 g of crude material. The crude material was purified by HPFC (silca gel, CMA 0-40% in chloroform) and dried overnight at 70° C. at 28 psi (1.9×105 Pa) to afford 0.75 g of 5-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridine-1-yl)pentan-2-one O-methyloxime as an off-white powder, mp 144.0-145.5° C. 1H NMR (300 MHz, DMSO-d6) δ 5.58 (s, 2H), 4.23 (t, J=8.1 Hz, 2H), 3.74 (s, H), 3.71 (s, H), 2.77 (t, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.25 (t, J=7.5 Hz, 2H), 1.80 (m, J=7.5 Hz, 8H), 1.00 (t, J=6.9 Hz, 3H; MS (APCI) m/z 318 (M+H)+; Anal. calcd for C20H26N6O2: C, 64.32; H, 8.57; N, 22.06. Found: C, 64.19; H, 8.86; N, 22.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (76.6 mg, 64%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:17].[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CS(C)=O>[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:17])[CH2:40][CH2:39]1
Reactant: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCCl
Reactant: COCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: COCCN1CCN(CCCc2sc(-c3ccccc3)nc2C(=O)Nc2ccccc2-c2nc3cccnc3s2)CC1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A solution of 5-(3-chloropropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (316 mg, 0.67 mmol) and 1-(2-methoxyethyl)-piperazine (964 mg, 6.7 mmol) in DMSO (12 mL) was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature and poured into H2O. The resulting solid was collected by filtration and rinsed with H2O. The crude product was purified by MPLC eluting with DCM/MeOH+1% TEA(0-10% gradient) to give the title compound (374 mg, 96% yield). MS Calcd for C32H34N6O2S2: 598.22. Found (M+H)+ m/z=599.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 140 mL of water, and 29.2 g (0.3 mol) of cyclohexylamine was warmed with stirring and allowed to react at a reflux temperature for 1 hour. Further, an aqueous solution of 12 g of sodium hydroxide in 40 mL of water was dropwise added thereto over 1 hour and the mixture was aged for 1 hour. To the reaction mixture thus obtained was added 200 mL of toluene, and the resulting mixture was cooled down to room temperature. The crystals obtained were collected by filtration, washed with 100 mL of toluene and then with 100 mL of water, followed by drying under reduced pressure to obtain 17.9 g (yield 86%) of the titled compound. Melting point: 151° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccncc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 77%), MS (ISP) m/z=312.5 [(M+H)+], mp 295° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:9]=1.ClCCl.[OH-].[NH4+:36]>C(OCC)(=O)C.CN(C)C=O>[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([NH2:36])=[O:13])=[C:10]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:9]=1
Reactant: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C(=O)O
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to a suspension of Example 324d (214 mg, 0.49 mmol) and dichloromethane (2.2 mL). 1 Drop dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated and the residue was dried (in-vacuo). The resulting acid chloride was suspended in tetrahydrofuran (1.0 mL) and was cooled to 0° C. as ammonium hydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. Ethyl acetate was added and the solution was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-8% methanol/dichloromethane gradient) to afford the title compound (176 mg, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.2 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.16 g, 0.53 mmol) in methanol (10 mL) was added ammonia (7N in methanol, 15 mL, 105 mmol), and the reaction mixture stirred for 4 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (60 mg, 0.52 mmol) in methanol (3 mL) was added. After thc solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-ethyl-phenoxy)-4-chloro-benzonitrile hemifumarate (174 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:54][C:53]4[CH:55]=[CH:56][C:50]([CH:47]([CH3:49])[CH3:48])=[CH:51][CH:52]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)c1ccc(N)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C(C)C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-isopropylaniline (Aldrich) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@H:9]([C:11](=[O:32])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][N:29]=[N+]=[N-])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:33])[N:7]([C@H:9]([C:11](=[O:32])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH2:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A mixture of {(S)-1-[(S)-1-((S)-2-azidomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (550 mg) and 10% palladium on carbon in methanol (4 mL) was stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction mixture was filtered through a Celite pad and the filtrate was evaporated to dryness to give {(S)-1-[(S)-1-((S)-2-aminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (470 mg), m/z=434 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.O.C(=O)(O)[O-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2)(=[O:21])[CH3:20]
Reactant: Nc1c(Cl)ccc2ccncc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1c(Cl)ccc2ccncc12

Procedure:
8-Amino-7-chloroisoquinoline is refluxed in excess acetic anhydride for two hours or until the reaction is complete. The mixture is then poured into water, neutralized with 10% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and concentrated to give 8-acetamido-7-chloroisoquinoline.