Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:16][C:17]1[NH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1CCNCC1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc[nH]1
Temperature: 25 °C
Yield: 442.1 %

Procedure:
A mixture of 5-chlorooxindole (6.98 g, 41.6 mmol), 3,5-dimethyl-1H-pyrrole-2-carhoxaldehyde (5.12 g, 41.6 mmol) and piperidine (410 μL, 4.16 mmol) in 200 mL of EtOH was heated at reflux for 8 h. The reaction mixture was cooled to room temperature and filtered to give the title compound (4.50 g, 40%) as a red/orange solid.
Reaction SMILES: [CH2:1]1[O:14][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[CH2:21]([NH:22][CH2:1][CH:2]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:1][CH:2]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCC

Procedure:
Condensation of 1-tridecene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxytridecylamine] (I: R = CH3 (CH2)10, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C(=O)N2CCN[C@@H](C)C2)n1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((S)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.450 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[CH2:14]([O:21][C:22]([N:24]([CH2:26][CH2:27][OH:28])[CH3:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([O:21][C:22]([N:24]([CH2:26][CH:27]=[O:28])[CH3:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC=O)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, 100% yield).
Reaction SMILES: CO[C:3]1[C:4](=O)[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:12][C:13]([NH2:15])=[S:14].C[O-].[Na+].CO.CO>C(O)(=O)C>[SH:14][C:13]1[N:12]=[C:4]2[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=[C:3]2[N:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C)ccc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2nc(S)nc-2cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
165 g of 2-methoxy-5-methyl-2,4,6-cycloheptatrien-1-one and 84 g of thiourea were added to 255 g of 28% sodium methoxide/methanol solution and everything was stirred for 30 minutes at room temperature. Next, 60 ml of methanol was added, and then acetic acid was added until the pH value of the resulting solution became 5 or so. The crystals thus precipitated were separated by filtration, fully washed with methanol and then dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([SH:14])=[N:11][C:10]=2[CH:15]=1)=[O:5])[CH3:2].[H-].[Na+].[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C=O)C>[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][S:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:10]=2[N:11]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CNCCCCl
Reactant: CCOC(=O)c1ccc2oc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2oc(SCCCNCC(=O)OC(C)(C)C)nc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 5-ethoxycarbonyl-2-mercaptobenzoxazole (670 mg) in DMF was added 60% sodium hydride (126 mg) in oil under ice-cooling, and the mixture was stirred for 30 minutes. A solution of 3-tert-butoxycarbonylmethylaminopropyl chloride (623 mg) in DMF was added to the reaction mixture, and the mixture was stirred with heating at 60° C. for 18 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (594 mg, yield 50%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].ClCC1ON=C(CC2C=CC([I:41])=CC=2)N=1.OC1C(C)=C(O)C=CC=1C(=O)C>>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([I:41])=[CH:19][CH:18]=3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Reactant: ClCc1nc(Cc2ccc(I)cc2)no1
Agent: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone, employing 5-chloromethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole and 1-(2,4-Dihydroxy-3-methyl-phenyl)-ethanone. LC-MS (m/e): 463 (M−1).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:40]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:40])[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 194, 1.48 g, 2.89 mmol) following the procedure described for Intermediate 20. Silica gel chromatography (0%-80% ethyl acetate/hexanes) afforded the desired product as a light yellow foamy solid (1.41 g, 95%).
Reaction SMILES: [C:1](NNP(OCC)(OCC)=O)(=[O:3])[CH3:2].[CH:14]([O:17][P:18]([NH:24][NH2:25])(=[O:23])[O:19][CH:20]([CH3:22])[CH3:21])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:25][NH:24][P:18]([O:17][CH:14]([CH3:15])[CH3:16])([O:19][CH:20]([CH3:21])[CH3:22])=[O:23])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(NNC(C)=O)OCC
Reactant: CC(C)OP(=O)(NN)OC(C)C
Solvent: c1ccncc1
Product: CC(=O)NNP(=O)(OC(C)C)OC(C)C

Procedure:
This compound was prepared in a similar manner to the compound of Example 1, but using diisopropylphosphorohydrazidate instead of diethylphosphorohydrazidate, and pyridine in place of triethylamine. The product distilled at 130°-140° C./0.07 mm.
Reaction SMILES: CN(C)C=O.[CH2:6]1[CH:11]([CH2:12][C:13]([OH:15])=O)[CH2:10][CH2:9][O:8][CH2:7]1.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>C(Cl)Cl.[Cl-].[NH4+]>[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13](=[O:15])[CH2:12][CH:11]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:32][CH:31]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: Nc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCOCC1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-dimethylformamide (0.27 mL, 3.47 mmol) was added to a solution of tetrahydropyranyl-4-acetic acid (5.0 g, 34.7 mmol) and thionyl chloride (2.53 mL, 34.7 mmol) in DCM (200 mL) at 0° C. After stirring 1 h at RT the solution was cooled to 0° C. N-Ethyl-N-isopropylpropan-2-amine (15.14 mL, 87 mmol) was added, followed by 4-bromoaniline (5.97 g, 34.7 mmol) in 20 mL DCM were added slowly and the solution was stirred at 0° C. After 1 h the reaction was diluted with saturated ammonium chloride and the organics were removed. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material N-(4-bromophenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide as a tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[NH2:11])=[CH:6][C:5]=1[S:13](=[O:20])(=[O:19])[NH:14]C(C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH3:22])[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[NH2:11])=[CH:6][C:5]=1[S:13](=[O:19])(=[O:20])[NH2:14]
Reactant: CN(C)C(=O)c1ccc(C(N)=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(C(N)=O)cc1S(N)(=O)=O

Procedure:
At room temperature, 1.0 g (3.1 mmol) of N,N-dimethyl-2-tert-butylsulfamoyl-4-carbamoylbenzamide in 10 ml of trifluoroacetic acid was stirred for 2.5 h. The mixture was concentrated and the residue was triturated with diethyl ether, filtered off with suction and dried. This gave 0.53 g (63% of theory) of N,N-dimethyl-4-carbamoyl-2- sulfamoylbenzamide of m.p. 202-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([O:17][C:18](=O)[C:10]=12)=[O:16].C(OC(C)C)(C)C>C(OC(=O)C)(=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:15](=[O:16])[C:11]3[C:10](=[N:9][CH:14]=[CH:13][N:12]=3)[C:18]2=[O:17])=[N:3][CH:4]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: Cc1ccc(N)nc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(N2C(=O)c3nccnc3C2=O)nc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
2-Amino-5-methylpyridine (21.6 g.) is added to a suspension of pyrazine-2,3-dicarboxylic anhydride (30 g.) in acetic anhydride (300 cc.) at a temperature of about 25° C. The reaction mixture is stirred for 10 minutes at this temperature and then heated at a temperature of about 100° C. for 15 minutes. After cooling to a temperature of about 50° C., diisopropyl ether (600 cc.) is added and cooling is continued to 5° C. After stirring for one hour at this temperature, the insoluble product is filtered off and washed with diisopropyl ether (3×50 cc.). After drying, 6-(5-methylpyrid-2-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[3,4-b]pyrazine (32 g.), which melts at 240° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[NH:31]([C:32]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)Nc3ccccc3)c3ccccc23)CC1
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0399 g, 0.121 mmol) was dissolved in THF (2 mL) at rt under N2. Phenyl isocyanate (0.016 g mL, 0.0173 g, 0.145 mmol, 1.20equiv.) was added, then the reaction mixture was stirred for 2.5 h. The reaction mixture was concentrated and the crude product (0.0598 g) was chromatographed (SiO2 25 g, eluted with 3:2 hexane:EtOAc) to give tert-butyl 6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0390 g) in 72% yield. 1H NMR (300 MHz, CDCl3) δ 1.36, 1.44, 2.96-3.08, 3.42-3.51, 3.65-3.72, 4.17, 4.23, 5.14, 5.23, 6.94-7.30, 7.43-7.49; MS (ESI+) for C26H32N4O3 m/z 449.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([NH:13][C:14](=O)[CH3:15])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]2[N:13]=[C:14]([CH3:15])[NH:17][C:5]=2[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)c2nc(C)[nH]c2c1
Reaction time: 5 h

Procedure:
A mixture of 0.55 g (1.98 mmol) N-(4-methoxy-2-nitro-6-trifluoromethyl-phenyl)-acetamide and 100 mg Pd/C in 30 mL acetic acid was hydrogenated for 5 h under a hydrogen atmosphere at 80° C. until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>C(Cl)Cl.[Cl-].[Na+].O>[CH3:13][C:4]1[N:3]=[C:2]([N:1]2[CH2:22][CH2:23][CH2:24][C:25]2=[O:26])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(N)nc1C
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(N2CCCC2=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 6-amino-2-methylnicotinate (450 mg) and triethylamine (0.42 mL) were dissolved in methylene chloride (5 mL), 4-chlorobutyryl chloride (0.31 mL) was added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated brine, and the mixture was extracted with methylene chloride. The solvent was evaporated, and the obtained residue was purified by column chromatography (ethyl acetate:hexane). The solvent was evaporated, and to the obtained residue were added N,N-dimethylformamide (3 mL) and sodium hydrogen carbonate (420 mg), and the mixture was stirred at 80° C. After completion of the reaction, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The solvent was evaporated, ethanol (2 mL) and 1N aqueous sodium hydroxide solution (2 mL) were added to the obtained crude product (300 mg) of ethyl 2-methyl-6-(2-oxopyrrolidin-1-yl)nicotinate, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give a crude product of 2-methyl-6-(2-oxopyrrolidin-1-yl)nicotinic acid. Using the obtained crude product (0.605 mmol) of 2-methyl-6-(2-oxopyrrolidin-1-yl)nicotinic acid and 1-(3,5-dimethylpyridin-2-yl)piperazine (116 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 93, the title compound (9 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:50][C:51]1[CH:60]=[C:59]2[C:54]([C:55]([N:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)=[CH:56][C:57]([NH2:61])=[N:58]2)=[CH:53][CH:52]=1>>[NH2:61][C:57]1[CH:56]=[C:55]([N:62]2[CH2:63][CH2:64][N:65]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17](=[O:25])[CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]3=[O:1])=[O:16])[CH2:66][CH2:67]2)[C:54]2[C:59](=[CH:60][C:51]([Cl:50])=[CH:52][CH:53]=2)[N:58]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(C(=O)Cc2ccccc2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Cc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3S)-hexahydro-2-oxo-1-(phenylacetyl)-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 535 (M++1). 1H NMR (CDCl3, 400 MHz): δ 1.20˜1.50 (m, 2H), 1.80˜2.20 (m, 4H), 3.10˜3.20 (m, 5H), 3.60˜3.70 (m, 4H), 4.28 (AB, 2H), 4.75 (dd, 1H), 4.80˜4.95 (m, 3H), 5.85 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.22˜7.36 (m, 5H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CN[C:11](NC)=[O:12]>ClC1C=CC=CC=1Cl>[N:7]1[C:11](=[O:12])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: Nc1ccccc1N
Reactant: CNC(=O)NC
Solvent: Clc1ccccc1Cl
Product: O=C1N=c2ccccc2=N1
Temperature: 172 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
216 Parts of o-phenylenediamine and 193.6 parts of N,N'-dimethyl urea are heated in 1000 parts of o-dichlorobenzene for 2 hours to 172° C. Methylanine evolves at 130° C. The suspension is stirred for a further 4 hours at 172° C, then cooled to room temperature and filtered by suction. The filter cake is washed with 800 parts by volume of ethanol and suspended in 1000 parts of water. This suspension is filtered by suction, washed with 100 parts of water and the filter cake is dried at 100° C, giving 250.8 parts (93.6% of theory) of benzimidazolone. The melting point of the product is between 312° and 315° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([C:11]([O:13]CC)=[O:12])=[O:10])[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([C:11]([OH:13])=[O:12])=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C(=O)Nc1nc(C)c(C)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NC(=O)C(=O)O)sc1C

Procedure:
Ethyl 4,5-dimethylthiazol-2-ylcarbamoylcarboxylate (1.2 g., 5.26 mmole) was slurried in 40 ml. of water. Potassium carbonate (1 N, 5.3 ml., 2.65 mmoles) was added and the mixture heated on a steam bath for 5 minutes, yielding a clear solution. The reaction mixture was cooled in an ice-water bath and 6 ml. of 1 N hydrochloric acid added. The precipitated crude product was recovered by filtration (933 mg.). Recrystallization from acetic acid gave purified 4,5-dimethylthiazol-2-ylcarbamoylcarboxylic acid [652 mg.; m.p. 235°-236° C. (dec.)].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH3:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH3:20])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CCI
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 37 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.40 g, 1.3 mmol) was reacted with iodoethane to afford 0. 16 g (37%) of the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]2[CH:2]=[C:3]([CH2:4][C@@H:5]3[CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:26]=[C:22]2[N:21]=1
Reactant: Cc1ccnc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2cc(C[C@@H]3CCCCN3C(=O)OC(C)(C)C)nc2n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.300 g, 0.94 mmol) in DMF (2 ml) was added 4-methyl-2-pyrimidinamine (0.153 g, 1.41 mmol) and the mixture was stirred at 80° C. for 1.5 h. To the reaction mixture was added brine and a saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash cromatography on silica gel (Biotage 25+M, DCM/MeOH from 100/0 to 90/10). Collected fractions gave the title compound (0.350 g slightly contaminated with residual 4-methyl-2-pyrimidinamine). UPLC: rt=0.53, peak observed: 331 (M+1). C18H26N4O2 requires 330.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][S:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C[O-].[Na+].CN(C)C=O>O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:5]2[S:4][C:3]3[CH:8]=[CH:9][C:10]4[C:15]([C:2]=3[NH:1][C:6]2=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CSc2ccc3ccccc3c2N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2c(ccc3ccccc23)SC1=Cc1ccc(Cl)cc1
Yield: 52.8 %

Procedure:
A mixture of 1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (5.17 g), 4-chlorobenzaldehyde (5.62 g), sodium methoxide (1.73 g) and dimethylformamide (80 ml) is refluxed for 4.5 hours. After cooling, the reaction mixture is poured into water and the resulting precipitate is separated by filtration, washed and dried and then is recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorobenzylidene)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (4.28 g). M.p. 277°-279° C.