Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38](Cl)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>O1CCCC1>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are reacted with 221 mg (0.96 mmol) of quinoline-8-sulfonyl chloride and 0.33 ml (4.08 mmol) of pyridine in 8 ml of tetrahydrofuran overnight.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:27]=1.[Cl-].[NH4+:30]>>[Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([NH2:30])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:27]=1
Reactant: Cc1nn(C)cc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 68 %

Procedure:
10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to the procedure in Example 2. 10-bromo-3((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 134 mg (68% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:19]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(2-aminopyridin-3-yl)phenol (19.8 g), tert-butyldimethylchlorosilane (21.8 mL) and 1H-imidazol (8.69 g) in DMF (200 mL) was stirred at room temperature for 20 hr. To the mixture was added water, and the resulting precipitate was collected by filtration, and then washed with water to give the title compound (30.5 g) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11][C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=3)[CH:16]=2)[NH:11][C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)c2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1CN(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
The title compound was prepared according to the procedure for Example 5 from 4-benzyl-6-bromo-3,4-dihydroquinoxalin-2(1H)-one (1.6 g, 5 mmol), and 3-chlorophenyl boronic acid (0.8 g, 5 mmol). An off-white powder (0.9 g, 51%): m.p. 182-185° C. 1H-NMR (DMSO-d6) δ3.74 (s, 2H), 4.54 (s, 2H), 6.87 (d, J=0.7 Hz), 7.0 (m, 2H), 7.36 (m, 8H), 7.52 (t, J=1.8 Hz, 1H), 10.57 (s, 1H), MS (ESI) m/z 349 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pt]=O>[NH2:1][C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=c1[nH]ccc(NCc2ccccn2)c1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc2[nH]c(-c3c(NCc4ccccn4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 113 %

Procedure:
Platinum oxide (0.146 g, 0.65 mmol) was added to a stirred solution of 3-(4-nitro-1H-benzoimidazol-2-yl)-4-[(pyridin-2-ylmethyl)-amino]-1H-pyridin-2-one in methanol (12 ml) and tetrahydrofuran (12 ml). The reaction was purged with nitrogen three times and the atmosphere replaced with hydrogen and the reaction stirred at room temperature. After 72 hours the reaction was recharged with platinum oxide (0.146 g, 0.65 mmol) and hydrogen and stirred for a further 24 hours. The reaction was filtered through Celite and the filter cake washed with tetrahydrofuran and methanol. The solvent was concentrated under reduced pressure to give the desired crude aniline (0.610 g, 113%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:3]21.[CH3:22][N:23]([CH3:29])[C:24](=[O:28])[C:25](O)=[O:26].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:22][N:23]([C:24](=[O:28])[C:25]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:3]21)=[O:26])[CH3:29]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of ethyl 10-amino-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (250 mg, 0.895 mmol) and 2-(dimethylamino)-2-oxoacetic acid (157 mg, 1.343 mmol) in DMF (6 mL) was added diisopropyl-ethylamine (0.498 mL, 2.86 mmol), 4-(dimethylamino)pyridine (DMAP) (21.87 mg, 0.179 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (511 mg, 1.343 mmol) and the resulting mixture stirred at room temperature for 5 hr. Solvent was removed under reduced pressure. The crude material was diluted with ethyl acetate (50 mL) and washed with 1N HCl (20 mL), dried (Na2SO4) and concentrated to yield the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (76 mg, 74%), MS (ISP) m/z=411.5 [(M+H)+], mp 157° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:9]2[CH2:14][NH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:10]=2[N:24]=1.[CH2:38]([NH2:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:23])[C:16]=1[N:11]1[C:10]2[N:24]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:40][CH2:38][CH3:39])[N:7]=[C:8]([C:25]3[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:9]=2[CH2:14][NH:13][C:12]1=[O:15]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCCl)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNCC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To 3-[2-[(3-chloropropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (265 mg, 0.50 mmol) in DMF (10 mL) was added ethylamine (1.25 mL, 2.0 M in THF, 2.5 mmol) and potassium carbonate (0.276 g, 2.0 mmol). The mixture was heated at 50° C. for about 20 hours, then at 80° C. for about 4 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O (30 mL+15 mL×2) and brine (20 mL). The organic layers were collected and concentrated. Flash chromatograph afforded the title compound (134 mg, 50%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 0.96-1.02 (m, 6H), 1.61-1.72 (m, 2H), 1.85-1.96 (m, 2H), 2.30 (s, 3H), 3.07 (q, J=7.11 Hz, 2H), 3.19-3.29 (m, 3H), 3.33-3.40 (m, 3H), 3.83 (d, 1H), 3.90 (d, 1H), 6.83-6.99 (m, 3H), 7.51 (d, J=8.03 Hz, 1H), 7.69 (d, J=1.76 Hz, 1H), 7.87 (dd, J=7.91, 1.88 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)=[CH:27][N:28]3[C:31]3[N:36]=[CH:35][N:34]=[C:33]([NH:37][CH3:38])[CH:32]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[C:29]4[C:25]([C:26]([C:39]5[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=5)=[CH:27][N:28]4[C:31]4[CH:32]=[C:33]([NH:37][CH3:38])[N:34]=[CH:35][N:36]=4)=[CH:24][CH:23]=3)[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(N)c4)cc32)ncn1
Solvent: C1CCOC1
Product: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)c4)cc32)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (15.8 mg, 0.071 mmol) was added to a mixture solution of 6-(6-(3-aminophenyl)-3-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (20 mg, 0.047 mmol) in THF (1 mL) at room temperature. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, EA:Hx=1:1; DCM:MeOH=100:1; 20:1). The target compound was obtained as yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(CCC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methylpyrimidin-4-yl)acrylic acid (330 mg) in THF (5.0 mL) and ethyl acetate (5.0 mL) was added 10% palladium-activated carbon (30 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (153 mg) as a white solid.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].IC>C1COCC1>[CH3:2][CH:26]([C:12]1([CH2:11][CH:10]([CH3:34])[CH3:9])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)CC1(C(C)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
LDA (1.5 mL, 3.0 mmol, 2.0M in heptane/THF/ethylbenzene) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (967 mg, 2.69 mmol) and THF (11.0 mL) at -78° C. The solution is stirred at -78° C. for 30 minutes and then iodomethane (0.19 mL, 3.1 mmol) is added. The solution is stirred at -78° C. for 2 hours and then allowed to slowly warm to room temperature overnight. Aqueous workup (EtOAc, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) gives 791 mg (79%) of the title compound as an oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[OH:27])=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:27][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24]
Reactant: OC(c1cccc(Cl)c1)c1c(Cl)sc(Cl)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1cccc(C(OC2CCCCO2)c2c(Cl)sc(Cl)c2Br)c1
Reaction time: 3.5 h

Procedure:
Pyridinium p-toluenesulfonate (74.0 mg, 0.293 mmol) was added to (4-bromo-2,5-dichloro-3-thienyl)(3-chlorophenyl)methanol from Example 8, Step 1 (1.09 g, 2.93 mmol) and 3,4-dihydro-2H-pyran (2.67 mL, 29.3 mmol) in CH2Cl2 (12 mL). After 3.5 h, the reaction mixture was diluted with CHCl3 and washed with 5% aq. NaHCO3, water and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (30-50% CHCl3/hexane in 20 min.) to afford the desired product as a colorless gum.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[N:26][CH:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(C)nc1
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ncc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.000438 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.122 g, 0.00021 mol) and al lowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.13 g, 0.00109 mol) was added and stirred for further 3 h. At 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. To get the desired compound as yellow oil (0.036 g, 24% yield). 8-Isopropyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 0.036 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.013 g, 0.000103 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.022 g, 49% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: FC(F)(F)c1n[nH]cc1Br
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cc(Br)c(C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
The mixture of 3.38 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole and 0.66 g of paraformaldehyde was stirred at 140° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.28 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[N+:17]([O-])([OH:19])=[O:18]>ClCCl>[OH:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([N+](=O)[O-])c(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A mixture of ethyl 5-methoxyindole-2-carboxylate (8.15 g, 37.2 mmol), (prepared by the method described in Heterocycles Vol. 43, No. 2, p. 263-266), nitric acid adsorbed on silica gel (24 g) and dichloromethane (150 ml) was stirred at ambient temperature for 18 hours. The dichloromethane was removed in vacuo and the product washed off the silica with acetone. The acetone was evaporated in vacuo. The residue was treated again with nitric acid on silica (1 g) as above and the work up procedure repeated to give ethyl 5-hydroxy-4-nitroindole-2-carboxylate (5.8 g, 59%).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)=[NH:7].[ClH:21]>O>[ClH:21].[NH2:7][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)=[NH:5]
Reactant: COC(=O)c1ccc(NC(=N)N)cc1OC
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc(NC(=N)N)ccc1C(=O)O
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Into a reactor was added 5 (29.8 kg, 104 mol) and water (475 L). The mixture was heated to 75 to 80° C. and concentrated HCl (107 kg, 1051 mol) was added over a minimum of 30 min while maintaining the temperature between 75 and 80° C. The reaction mixture was stirred for 3 h at 75 to 80° C. The reaction mixture was sampled and the % conversion was determined by HPLC analysis. The mixture was heated at 75 to 80° C. until the % conversion reached >97.3% or until at total reaction time of 7 h. The reaction was cooled to 20 to 25° C. over a minimum of 3 h and stirred for an additional 2 h at 20 to 25° C. The reaction was filtered and washed with 16% w/w HCl (2×35 kg), water (82 L) and heptane (2×120 L). The resulting wet cake was dried under vacuum at 35 to 50° C. to provide 23.9 kg (93% yield) of 6. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.72 (s, 4H), 7.69 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.81 (dd, J=2.3, 8.8 Hz, 1H), 3.80 (s, 3H); MS (ESI) m/z 210.4 (M+, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:6].[OH-].[Na+]>O.C(OCC)C>[CH:4]1([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(CCCBr)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C

Procedure:
A stirred mixture of 4-bromo-2'-nitrobutyrophenone (3.44 g, 0.013 mole) and NaOH (0.76 g, 0.019 mole) in water is heated at reflux temperature until reaction is complete by TLC, cooled to room temperature and extracted with diethyl ether. The ether extracts are combined, dried over Na2SO4 and concentrated in vacuo to give a dark brown liquid residue. The residue is taken up in diethyl ether, filtered through silica gel and concentrated in vacuo to give the title product as a yellow oil, identified by 1HNMR.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[F:23][C:10]([F:9])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1n[nH]c(=O)n1N
Solvent: c1ccncc1
Product: Cc1n[nH]c(=O)n1NS(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: -10 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
10.0 g (0.088 mol) of 4-amino-5-methyl-2,4-dihydro-3H-1, 2,4-triazol-3-one are dissolved in 50 ml of dry pyridine, the mixture is cooled to -10° C., and 32.7 g (0.12 mol) of 2-trifluoromethoxy-benzenesulphonyl chloride are added. The reaction mixture is allowed to reach room temperature approximately 20° C.) and stirred for approximately 12 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride and shaken with 1N hydrochloric acid and then with water. The organic phase is dried with sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate under a water pump vacuum. 23.1 g (80% of theory) of 4-(2-trifluoromethoxy-phenylsulphonylamino)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as an oily residue.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:16](O)[CH2:17][OH:18].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:3]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[O:18][CH2:17][CH2:16][O:4]1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(c2ccc(C(=O)O)cc2)OCCO1

Procedure:
A mixture of 63.5 grams (0.31 mole) of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid, 156 ml. of ethylene glycol, and 1 gram of toluenesulfonic acid in 600 ml of toluene is refluxed for 24 hours using a Dean-Stark trap to remove water. The mixture is then cooled and partially evaporated; and to the residue, 4.5 grams of solid potassium hydroxide are carefully added followed by 225 ml of water. The resulting mixture is refluxed for 11/2 hours, cooled, filtered and the layers separated. The aqueous layer is acidified with 2N hydrochloric acid, and the resulting precipitate is removed by filtration. The precipitate is washed with water, then water/ethanol (5/1), and then petroleum ether. The product is dried in vacuo to yield the title product (m.p. 213.5°-215.5° C.).