Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([OH:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[N+]=[N-].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:35][CH2:36][N:37]([C:40]([O:15][C@H:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[C@@H:4]([NH2:1])[C@H:5]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:6][CH2:7]2)=[O:41])[CH2:38][CH2:39]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cc(F)cc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H]1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 100 mL round-bottom flask was suspended (5S,6S,9R)-5-azido-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (46 mg, 0.145 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (66.9 mg, 0.175 mmol) in dimethylformamide (1 mL) under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (0.393 mL, 0.393 mmol) was added dropwise. The resulting tan solution was stirred under nitrogen at −10° C.˜0° C. for 2 h and at room temperature for 2 h. LCMS showed good conversion. The reaction was quenched with sodium bicarbonate solution. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 8% methanol/methylene chloride afforded the desired product (62 mg, 76%) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:23](O)=[O:24])[CH2:22][O:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:49][C:50]1[CH:51]=[C:52]([F:72])[C:53]([C:66]2[N:70]=[C:69]([CH3:71])[O:68][N:67]=2)=[C:54]([C:56]2[CH:57]=[C:58]([F:65])[C:59]([C@H:62]([NH2:64])[CH3:63])=[N:60][CH:61]=2)[CH:55]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3([C:23](=[O:24])[NH:64][C@@H:62]([C:59]4[C:58]([F:65])=[CH:57][C:56]([C:54]5[CH:55]=[C:50]([Cl:49])[CH:51]=[C:52]([F:72])[C:53]=5[C:66]5[N:70]=[C:69]([CH3:71])[O:68][N:67]=5)=[CH:61][N:60]=4)[CH3:63])[CH2:22][O:21][CH2:20]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)N)c(F)c2)no1
Reactant: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)NC(=O)C3(NC(=O)OCC4c5ccccc5-c5ccccc54)COC3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carboxylic acid (77.4 mg, 0.228 mmol, intermediate 8) in dry DMF (2 ml) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (48.1 mg, 0.251 mmol) and 1-hydroxybenzotriazole hydrate (38.4 mg, 0.251 mmol) at room temperature. The resulting colorless solution was stirred for 5 min before a solution of (R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylamine (80.0 mg, 0.228 mmol, step B) in dry DMF (2 ml) was added. This mixture was stirred at room temperature for 1.5 h. Then water was added, the pH was adjusted to 7 with sat. NaHCO3 solution and the mixture was extracted three times with EtOAc. The combined organic layers were washed three times with water and then with brine, dried with Na2SO4 and evaporated. The remaining light brown foam was purified by chromatography (silica gel; DCM/MeOH 98:2-95:5) and the title compound was obtained as off white foam (150 mg, 98%). MS: 672.3 [M+H]+.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CC2CCCC2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:49][CH2:48][N:47](C)[CH2:46][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:45][CH2:46][NH:47][C:48](=[O:19])[CH2:49]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:64][CH2:65][CH2:66][CH2:67]2)=[CH:35][CH:36]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 539.2423, calculated for C29H36N4O4Cl [(M+H)+]539.2420.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride and stirred for 30 minutes at 20° C. 60 mg of 5-bromopentanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:13]([OH:16])[CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.S(Cl)(C)(=O)=O.C(N(CC)CC)C.CO.[OH-].[K+]>CCOC(C)=O.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:13]1[O:16][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](CSc1ccccc1)[C@@H](O)CO)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: CO
Product: O=C(N[C@@H](CSc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reaction time: 5 h

Procedure:
After the crude compound of (2R,3R)-3-benzyloxycarbonylamino-4-phenylthio-1,2-butanediol (13.3 g) from the example 10 was dissolved in 110 ml of EtOAc, 4 ml (1.3 equivalent) of pyridine and 5.3 ml (1.2 equivalent) of benzoyl chloride were added to the solution and it was stirred at 5˜10° C. for 5 hours. 3.6 ml (1.2 equivalent) of Ms-Cl was added to the solution and 12.8 ml (2.4 equivalents) of triethyl amine was drop-added in the temperature of below 15° C. After the addition, it was stirred for 30 minutes. 1.5 ml (1 equivalent) of methanol was added to the solution and stirred at room temperature for 1 hour. The resultant solution was rinsed using 90 ml of 1N HCl, 90 ml of 5% NaHCO3 and 50 ml of H2O and distillated under reduced pressure. To the concentrated solution, 180 ml of 1,4-dioxane was added and the solution of 5.56 g (2.2 equivalent) of 85% KOH in 42 ml of H2O was added. The resultant solution was stirred at room temperature for 2 hours. The solution was diluted with 280 ml of water and extracted using 280 ml of toluene. After the toluene layer was rinsed by 170 ml of H2O, 170 ml of 5% NaHCO3 and 170 ml of brine and treated with Na2SO4 anhydride, it was filtered and concentrated under reduced pressure. A white crystal compound of (2S,3R)-3-benzyloxycarbonylamino-4-phenylthio-1-buteneoxide was obtained by column chromatography using Hexane: EtOAc=2:1. mp 61.7° C.
Reaction SMILES: S([O-])([O-])(=O)=O.C[NH+:7]=[C:8]([NH2:10])S.C[NH+]=C(N)S.O.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][NH:25][C:8]([NH2:10])=[NH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: C[NH+]=C(N)S
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: N=C(N)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 30.0 g. (0.12 moles) of S:methylthiouronium sulfate in 200 ml. of H2O there is added a solution of 24.6 g. (0.20 moles) of benzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72 hours at room temperature. The clear solution is heated at reflux for two hours under a stream of nitrogen. the solvents are removed in vacuo and the residue is treated with 300 ml. of isopropanol. The solid is removed by filtration and dissolved in 300 ml. of water. The solution is made basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to give benzyloxyguanidine, m.p. 105°-50° C.
Reaction SMILES: [OH:1][C@@:2]([C:23]([F:26])([F:25])[F:24])([CH2:16][C:17]#[C:18][Si](C)(C)C)[CH2:3][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])([CH3:6])[CH3:5]>C1COCC1>[OH:1][C@@:2]([C:23]([F:24])([F:25])[F:26])([CH2:16][C:17]#[CH:18])[CH2:3][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])([CH3:5])[CH3:6]
Reactant: CC(C)(C[C@@](O)(CC#C[Si](C)(C)C)C(F)(F)F)c1ccccc1C(N)=O
Solvent: C1CCOC1
Product: C#CC[C@](O)(CC(C)(C)c1ccccc1C(N)=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a stirred, ice-cooled, THF solution (100 mL) of 2-((R)-3-hydroxy-1,1-dimethyl-3-trifluoromethyl-6-trimethylsilanylhex-5-ynyl)benzamide (17.8 g, 46.2 mmol) n-tetrabutylammonium fluoride was added (51 mL of 1 M solution in THF, 51 mmol) dropwise via addition funnel. After 30 minutes, the reaction was quenched with 200 mL of 1 M HCl and further diluted with brine. The mixture was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was redissolved in dichloromethane and the solvent evaporated. The residue was then dissolved in 30 mL of diethyl ether and triturated with hexanes. The precipitated solid was filtered. The filtrate was collected and the solvent evaporated, and the residue treated with diethyl ether/hexanes as before to obtain more solid precipitate. The solids were combined and dried in vacuo to give 2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzamide (10 g, 33% over two steps). This material was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[CH:32][CH:31]=1>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][N:18]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[N:40]=[C:39]([CH3:41])[O:38][N:37]=3)=[CH:34][CH:35]=2)[CH2:17][C@H:16]1[CH3:21]
Reactant: Cc1nc(-c2ccc(CBr)cc2)no1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN3CCN(c4nc(-c5ccncn5)cc(=O)n4C)[C@H](C)C3)cc2)no1
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 0.52 mmol) and potassium carbonate (0.22 g, 1.59 mmol) in N,N-dimethylformamide (1.5 ml) was added 3-[4-(bromomethyl)phenyl]-5-methyl-1,2,4-oxadiazole (0.14 g, 0.55 mmol) at room temperature and the mixture was stirred for 4 hours. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with water, brine, and dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-{(2R)-2-methyl-4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][CH2:23]O>>[Br:20][CH2:21][CH2:22][CH2:23][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: OCCCBr
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Product: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Yield: 61.2 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.49 g, 1.8 mmol) was reacted with 3-bromopropanol (0.31 mL, 3.6 mmol) to afford 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 63%) as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Reactant: BrCCCOC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCOC2CC2)c2cc(Br)ccc21
Temperature: 70 °C

Procedure:
To a suspension of 6-bromo-3,3-dimethylindolin-2-one (example 14a, 300 mg, 1.25 mmol) and Cs2CO3 (814 mg, 2.5 mmol) in DMF (2 ml) was added a solution of (3-bromopropoxy)cyclopropane (447 mg, 2.5 mmol) in DMF (0.5 ml). The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was filtered through sintered glass and concentrated. The crude material was purified by flash chromatography on silica gel using ethyl acetate as eluent. The title compound was obtained as orange viscous oil (360 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][C:3]=1C(OC)=O.[OH-].[K+].C(OCC)(=O)C.Cl>C1COCC1.CO.O>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1=C(O)CCC(C(=O)OC)(c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC(=O)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
Dimethyl 4-hydroxy-1-(4-trifluoromethylphenyl)-3-cyclohexene-1,3-dicarboxylate (1.13 g) was dissolved in a mixed solvent of THF (3 mL) and methanol (3 mL). A 1 N potassium hydroxide solution (1.89 mL) was added and the mixture was stirred at 100° C. for eight hours. After leaving to cool, ethyl acetate and water were added to the reaction solution, followed by neutralization with 1 N hydrochloric acid. The organic layer was separated, washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (272 mg). The property values of the compound are as follows.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][C:17]1[C:30]2[C:29](=O)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([Br:33])=[CH:19][CH:18]=1>>[C:1]([C:9]1[C:10](=[O:12])[N:16]([CH3:15])[C:17]2[CH:18]=[CH:19][C:20]([Br:33])=[C:21]3[C:22](=[O:32])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:29]=1[C:30]=23)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Product: Cn1c(=O)c(C(=O)c2ccccc2)c2c3c(c(Br)ccc31)C(=O)c1ccccc1-2

Procedure:
Ethyl benzoylacetate is reacted with 1-methylamino-4-bromoanthraquinone in a solvent to obtain 1-benzoyl-6-bromo-2,7-dihydro-3-methyl-2,7-dioxo-3H-dibenzo[f,ij]isoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#N)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:5][CH2:4]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(O)[O-:38].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)([CH:23]=[O:38])[CH2:5][CH2:4]1
Reactant: O=S([O-])O
Reactant: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethyl ketal (0.57 g, 1.6 mmol) in toluene (20 mL) at room temperature under an argon atmosphere was treated with a solution of diisobutylaluminum hydride (1.5M in toluene, 2.7 mL, 4 mmol). After 2 h, a solution of saturated aqueous sodium bisulfite was added and the mixture was extracted twice with ethyl acetate. The organic extract was washed with 5% aqueous sodium carbonate, was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.55 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3.Cl.[NH2:28][OH:29]>CCO.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=[N:28][OH:29])[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3
Reactant: COc1cccc2c1-c1ccc(C(C)=O)c(Br)c1C(c1ccccc1)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cccc2c1-c1ccc(C(C)=NO)c(Br)c1C(c1ccccc1)O2

Procedure:
A solution of Example 357C (700 mg, 2.03 mmol) and hydroxylamine hydrochloride (2.45 g, 30.4 mmol) in a mixture of EtOH (70 mL) and pyridine (70 mL) was refluxed for 8 hours, cooled and concentrated. The residue was dissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to provide the desired compound without purifiction.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14])#[N:2].[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.O>[CH3:17][N:18]([CH3:19])[S:13]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C:1]#[N:2])(=[O:15])=[O:14]
Reactant: N#Cc1c(OC(F)F)cccc1S(=O)(=O)Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(OC(F)F)c1C#N

Procedure:
To a solution of 0.65 g (2.4 mmol) of purified 2-cyano-3-difluoromethoxyphenylsulfonyl chloride in 20 ml of tetrahydrofuran a solution of 274 mg (2.4 mmol) of dimethylamine and 510 mg of sodium carbonate in 15 ml of water was added at room temperature. The reaction mixture was stirred at room temperature for 5 minutes before water was added. The aqueous phase was acidified to pH=1 using hydrochloric acid (10% strength by weight, aqueous solution). The aqueous phase was then extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was triturated with methyl tert-butyl ether. Yield: 0.53 g (79% of theory) of the title compound having a melting point of 100-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:22]([CH3:23])[CH3:21])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CNc1nc(NS(=O)(=O)c2ccc(N)cc2)cc(N(C)C)n1
Yield: 93.1 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 18 ml (0.1 mol) of dimethylamine in ethanol (5.6M) were stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.30 g (78%) of 4-amino-N-(6-dimethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >300° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1c2ccc(C=O)cc2CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C1c2ccc(CO)cc2CCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (430 mg, 1.29 mmol) in MeOH (10 mL) was added sodium borohydride (24.40 mg, 0.64 mmol) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-ethyl 2-tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg, 1.163 mmol, 90%) as a colorless oil.