Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[NH:44](C(OCC1C=CC=CC=1)=O)[C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.[Pd]>[NH2:44][C@@H:45]([CH:46]([CH3:48])[CH3:47])[C:49]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[NH:11][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:37])[C@@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:2]([CH3:43])[CH3:1])=[N:14][CH:13]=4)=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[CH:28][N:29]=1)=[O:50]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](N)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-12) (1.16 g, 1.99 mmol), Z-Val-OH (0.712 g, 2.83 mmol) and iPr2NEt (0.70 mL, 5.42 mmol) in DMF (40 mL) was added HATU (1.10 g, 2.89 mmol) portionwise. The mixture was allowed to stir at room temperature for 1 h and was then poured into ice-water (400 mL) and allowed to stand for 20 min. The mixture was filtered and the solid washed with cold water and allowed to air dry overnight to give the Z-protected intermediate. LCMS: Anal. Calcd. for C46H54N8O6: 814. found: 815 (M+H)+. The obtained solid was dissolved in MeOH (80 mL), 10% Pd—C (1.0 g) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 h. The mixture was then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2/5-20% MeOH—CH2Cl2) to afford the title compound (1.05 g, 77%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.75-7.79 (m, 3H), 7.61-7.67 (m, 5H), 7.49 (s, 1H), 7.26-7.28 (m, 1H), 5.05-5.09 (m, 2H), 4.03-4.09 (m, 2H), 3.77-3.80 (m, 1H), 3.66-3.70 (m, 1H), 3.52 (s, 3H), 3.40-3.47 (m, 2H), 2.21-2.26 (m, 1H), 2.10-2.17 (m, 3H), 1.81-2.02 (m, 6H), 0.77-0.92 (m, 12H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N].C(=O)([O-])[O-].[K+].[K+].IC.[NH:16]1[CH:21]=[CH:20][CH:19]=NC1=O.ClC1C=CC(CNC(C(=COC)C(OC)=O)=O)=CC=1>CC(C)=O>[N:1]1[C:2]2[C:3](=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=c1nccc[nH]1
Reactant: [N]c1ccccn1
Agent: COC=C(C(=O)NCc1ccc(Cl)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: c1cnc2ncccc2c1

Procedure:
4,7-Dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide. The preparation of specific examples of heterocycle W16.1 is described in Chart BE. 2-Amino-4-bromopyridine BE.1 is reacted with Boc-anhydride in dichloromethane toafford BE.2. The resulting Boc-protected amine is then oxidized with peroxybenzoic acid (Justus Liebigs Ann. Chem. 1972, 758, 111) to afford hydroxypyridine BE.3. The pyridyl nitrogen is then alkylated in the presence of potassium carbonate and iodomethane with acetone as solvent to afford BE.4. The Boc group is then removed under standard deprotection condition to afford BE.5. The pyrimidone BE.5 is then cyclized with methyl 2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to afford naphthyridine BE.6. Reaction of BE.6 with an alkylating agent (e.g. iodomethane) in the presence of potassium carbonate with acetone as solvent affords compounds such as BE.7. Compound BE.7 is then coupled through a modified Sonogashira coupling (Linstrumelle, G.; et. al, Tetrahedron Lett, 1993, 34 6403) with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) to afford the alkyne derivative BE.8. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BE.9 (Z=CH2OH).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[CH:16][C:15]=1[O:21][CH3:22]>CCO>[Br:13][C:14]1[CH:20]=[CH:19][C:17](/[N:12]=[C:5](/[O:4][CH2:2][CH3:3])\[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][C:15]=1[O:21][CH3:22]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C/C(=N\c1ccc(Br)c(OC)c1)OCC
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (54.2 g, 277 mmol) and 4-bromo-3-methoxyaniline (56.0 g, 277 mmol) in EtOH (500 mL) was stirred under nitrogen, at 22° C., for 20 hours. The mixture was filtered and concentrated, then stirred in ether (100 mL), filtered and concentrated. The residue was chromatographed on silica gel 60 (gradient elution, 0-50% EtOAc in hexane) to give the title product. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 1H); 6.43 (d, J=2.0 Hz, 1H); 6.30 (dd, J=8.4 & 2.4 Hz, 1H); 4.28 (q, J=7.1 Hz, 2H); 4.15 (q, J=7.1 Hz, 2H); 3.85 (s, 2H); 3.21 (s, 2H); 1.34 (t, J=7.2 Hz, 3H); 1.26 (t, J=7.0 Hz, 3H) ppm. LRMS (ESI) m/z 344.0 [(M+H)+; calcd for C14H19BrNO4: 344.0].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15]O)=[N:8][CH:7]=[CH:6]2.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:15][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccnc(CO)c2cc1OC
Solvent: ClCCl
Product: COc1cc2ccnc(CCl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 147.6 %

Procedure:
To 306.3 mg of 6, 7-dimethoxyisoquinolin-1-ylmethanol (1.397 mmol) were added 20 ml of dry CH2Cl2 and 665 mg of thionyl chloride (5.95 mmol) and the mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated to give 490mg of 1-chloro-(6,7-dimethoxyisoquinolin-1-yl)methane (III-1) as brown crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[C:20]([O:32][CH3:33])[CH:19]=3)=[CH:16][N:15]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]=2[N:12]=[CH:13][N:14]=1>ClCCl>[Cl:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:32][CH3:33])[CH:19]=3)=[CH:16][N:15]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 ml) was added dropwise to a solution of tert-butyl N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (0.58 g, 1.31 mmol) in dichloromethane (20 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. Most of trifluoroacetic acid and dichloromethane were removed under reduced pressure. The residue was redissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyaniline as white solids (0.45 g, 1.31 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 7.78 (s, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 6.67 (d, 1H), 5.20 (m, 1H), 4.78 (broad, 2H), 3.81 (s, 3H), 2.18 (m, 2H), 1.88-2.00 (m, 4H), 1.72 (m, 2H); MH+343.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12].Cl.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl>>[CH2:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:7]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Reactant: ClCCNCCCl
Agent: Cl
Product: O=c1c2cccc(N3CCNCC3)c2ccn1Cc1ccccc1

Procedure:
5-Amino-2-benzyl-2H-isoquinolin-1-one (0.687 g, 2.75 mmol)) from step 4 was combined with excess bis-(2-chloroethyl)-amine hydrochloride and heated to a melt for 5 minutes. TLC analysis showed one major product and several minor side products. The reaction mixture was chromatographed over silica gel (CH2Cl2/MeOH, 95:5) to afford 2-benzyl-5-piperazin-1-yl-2H-isoquinolin-1-one (0.103 mg, 0.32 mmol); M+H=320.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:21])[CH2:19][CH:18]([CH2:22][CH:23]=[O:24])[CH2:17][C:16]3=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:26](O)[CH2:27][CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:16](=[O:25])[CH2:17][CH:18]([CH2:22][CH:23]4[O:29][CH2:28][CH2:27][CH2:26][O:24]4)[CH2:19][C:20]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC=O)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2OCCCO2)CC1=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of [4-(4′-chloro-4-methylbiphenyl-3-yl)-3,5-dioxocyclohexyl]-acetaldehyde (0.080 g, 0.23 mmol) and propane-1,3-diol (0.021 g, 0.27 mmol) in anhydrous toluene (4 ml) is added a single crystal of para-toluenesulfonic acid and the mixture is stirred at 80° C. for 45 minutes. After cooling to room temperature the solution is concentrated in vacuo to afford a crude product which is purified by flash column chromatography on silica (ethyl acetate eluant) to afford 2-(4′-chloro-4-methylbiphenyl-3-yl)-5-[1,3]dioxan-2-ylmethylcyclohexane-1,3-dione as a white foam.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1)#[N:29]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[C:34]([F:36])[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 3-Cyano-5-Fluorophenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.383 min, UPLC-MS (Condition 11) m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.81-1.93 (m, 1H) 2.86 (d, J=10.95 Hz, 1H) 3.14-3.29 (m, 2H) 3.35-3.49 (m, 1H) 4.21 (br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.67 (d, J=9.38 Hz, 1H) 7.79 (s, 1H) 7.83-7.91 (m, J=8.99 Hz, 3H) 8.06 (d, J=1.96 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:29]([CH:36]=[CH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:38]([CH:37]=[CH:36][CH2:29][C:30]12[O:8][CH:31]1[CH:32]=[CH:33][CH:34]=[CH:35]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(OO)c1ccccc1
Reactant: C(=CCc1ccccc1)Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=CCc2ccccc2)C=C1
Reaction time: 72 h

Procedure:
To perbenzoic acid in chloroform prepared from 15 g of benzoylperoxide was added 6.0 g of o-benzylallylbenzene and the mixture was allowed to stand at 5° C for 3 days. The mixture was washed with 2% sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was chromatographed over a silica gel, and as eluted with benzene/n-hexane (1/1), there was obtained 1.5 g of o-benzylallylbenzene oxide as an oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]([CH3:39])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>>[ClH:42].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]([CH3:39])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([O:34][C:35]([F:37])([F:36])[F:38])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:12][CH2:13]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide hydrochloride (15 mg) was prepared by following General Procedure L using 4-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (30 mg), and hydrochloric acid (0.1 ml, 4.0 N solution in dioxane). LC/MS: m/z 492. 1H NMR (DMSO-d6, 400 MHz): δ 9.21 (br, 1H), 9.00 (br, 1H), 8.42 (m, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.72 (br, 1H), 7.45 (d, 1H), 7.36 (d, 1H), 3.52 (s, 3H), 3.32 (m, 4H), 2.92 (q, 4H), and 1.79 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](Cl)=[O:13])[C:3]1=[O:15].CN1C2C(=CC=CC=2)C=C(C(O)=O)C1=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)Cl)cc2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: Cn1c(=O)c(C(=O)O)cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl chloride, prepared from 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (Archiv der Pharmazie (1990), 323(2), 67-72) and oxalyl chloride, was added dropwise to a solution of tert-butyl 2-aminoacetate hydrochloride (0.041 g, 0.25 mmol), diisopropylethyl amine (0.086 ml, 0.49 mmol), in dichloromethane (1.00 ml), stirred at room temperature for 1 hr. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4 to afford tert-butyl 2-(1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate in a 27% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[NH:13][C@H:12]([C:14]([NH2:16])=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]1[C@@H:9]([CH3:8])[CH2:10][CH2:11][C@H:12]1[C:14]([NH2:16])=[O:15])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: C[C@H]1CC[C@@H](C(N)=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2S,5S)-5-Methyl-pyrrolidine-2-carboxylic acid amide trifluoroacetate (2.0 g, 8.2 mmol, Example 84D) and triethyl amine (1.9 mL, 24.6 mmol) were dissolved in CH2Cl2 (6 mL), and the mixture was cooled to 0° C. Chloroacetyl chloride (0.39 mL, 9.0 mmol) was added slowly via syringe. After 2 h, saturated NaHCO3 was added, and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (10% MeOH/EtOAc) to give the title compound. MS (DCI) m/z 205 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])=O)C1C=CC=CC=1.Br.C(OCC)C>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCCC2)c2ccccc21
Agent: Br
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3(R,S)-[(Benzyloxycarbonyl)amino]-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (435 mg) was treated with a solution of 30% hydrogen bromide in glacial acetic add (10 ml) and stirred for 20 min at room temperature. The mixture was then added dropwise onto cold (0° C.) diethyl ether (50 ml). A white solid precipitated which was filtered off. The solid was treated with 10% sodium hydroxide solution (50 ml), then extracted with ethyl acetate (80 ml). The organic layer was separated, dried (Na2SO4) and evaporated to give crude 3(R,S)-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].[CH3:27][NH2:28]>CN(C=O)C.C(OC(=O)C)C.CCCCCC>[CH3:27][NH:28][C:1]1[C:3]([C:8]([NH:7][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([S:25][CH3:26])[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)[N:2]=1
Reactant: CN
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1nc(-c2ccc(SC)cc2)nc(SC)c1C(=O)Nc1ccc(C)cc1
Temperature: 45 °C
Yield: 37 %

Procedure:
To a solution of 5-Cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2 g, 5.3 mmol, prepared according to the procedure disclosed in our US patent 2004/0259891) in DMF was added methylamine (0.32 g, 10.5 mmol) under stirring. The solution was slowly warmed to 45° C., and maintained at this temperature for 1 hour. The completion of the reaction confirmed by TLC using ethylacetate:hexane (1:1) as a solvent system. The resulted reaction mass was poured onto ice and filtered, the crude solid thus obtained was purified by column chromatography using ethylacetate:hexane to give the title compound, 0.8 g, yield 37%, purity 99.5% by HPLC, m.p.: 228-230° C. 1H-NMR (CDCl3) δ (ppm): 2.35 (s, 3H), 2.54 (s, 3H), 2.73 (s, 3H), 3.1-3.13 (d, 3H), 7.17-7.20 (d, 2H), 7.30-7.32 (d, 2H), 7.48-7.5 (d, 2H), 7.9 (bs, 1H), 8.35 (bs, 1H), and 8.4-8.42 (d, 2H). IR (KBr) cm−1: 3358, 3270, and 1625. MS m/z: 411.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:23][CH:24]=[CH:25][CH2:26]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH:23]=[CH:24][CH2:25][CH3:26])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCC=CCBr
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Product: CCC=CCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-pentene by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]=[C:5]1[CH2:20][CH2:19][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]=[C:5]1[CH2:20][CH2:19][C:8]2([S:12][C:11](=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC=C1CCC2(CC1)SC(=Cc1ccccc1)C(=O)N2CCC(=O)O

Procedure:
In 5 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.25 ml of benzaldehyde and 0.45 g of potassium tert-butoxide at ambient temperature, the resulting mixture was heated under reflux for 6 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue and the deposited crystal was collected by filtration. Thus, 0.32 g of 3-[8-(3-methylbutylidene)-3-oxo-2-(1-phenylmethylidene)-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid was obtained as a colorless crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][CH2:52][C@H:53]2[NH:57][CH2:56][C@H:55]([OH:58])[CH2:54]2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:48]1([NH:51][CH2:52][C@@H:53]2[CH2:54][C@@H:55]([OH:58])[CH2:56][N:57]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:50][CH2:49]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O[C@H]1CN[C@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1C[C@H](O)C[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (81 mg, 1.2 eq.), EDC (115 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R, 5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight, followed by heating at 45° C. for 5 hours. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.