Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O1CCOCC1>[C:6]([O:5][C:1](=[O:4])[NH:2][N:3]1[CH:12]=[CH:16][CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nn1cccc1
Yield: 12.5 %

Procedure:
A mixture of tert-butyl carbazate (5.51 g, 41.7 mmol), 2,5-dimethoxytetrahydrofuran (6.5 mL, 50.0 mmol) and acetic acid (33.6 mL) in dioxane (80 mL) was refluxed for 3 h; then cooled, the dark brown reaction mixture was concentrated, the resulting residue was directly silica gel column purified (eluents: 10% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product (951 mg) as white solid. 1H NMR (CDCl3, δ in ppm): 7.17 (s, br, 1H), 6.66 (m, 2H), 6.11 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[N:6][N:5]=2)[CH2:3][CH2:2]1.[O:9]=[S:10]1(=[O:36])[CH2:15][CH:14]=[C:13]([C:16]2[C:21]([F:22])=[CH:20][C:19]([N:23]3[CH2:27][C@H:26]([CH2:28]OS(C)(=O)=O)[O:25][C:24]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:12][CH2:11]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[O:36]=[S:10]1(=[O:9])[CH2:11][CH:12]=[C:13]([C:16]2[C:21]([F:22])=[CH:20][C:19]([N:23]3[CH2:27][CH:26]([CH2:28][N:6]4[N:7]=[N:8][C:4]([CH:1]5[CH2:3][CH2:2]5)=[N:5]4)[O:25][C:24]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:14][CH2:15]1
Reactant: C1CC1c1nnn[nH]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Product: O=C1OC(Cn2nnc(C3CC3)n2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Yield: 73.8 %

Procedure:
Cyclopropylcarbonitrile (2 ml, 27 mmol) was added to a solution of trimethylsilylazide (4.3 ml, 32.5 mmol) and trimethylaluminum (16 ml of a 2M toluene solution, 32 mmol) at 0° C. The cold bath was removed, the mixture was stirred at room temperature for 15 minutes, then warmed to 80° C. for 16 hours. The solution was carefully added to a slurry of ice and 1N HCl, followed by acidification with concentrated HCl and extraction twice with ethyl acetate. The combined organic phases were washed with saturated NaCl, dried over sodium sulfate, and evaporated to yield a solid residue. Trituration with 1:1 hexane:ethyl acetate gave 5-cyclopropyl-1H-tetrazole (CAS# 27943–07–3) as a white crystalline solid (1.5 g, 51%). 5-cyclopropyl-1H-tetrazole (0.183 g, 1.66 mmol), (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol), polystyrene-triphenylphosphine (1.73 mmol/g loading: Argonaut Technologies, Inc. Foster City, Calif. USA, 1.46 g, 2.53 mmol) and diisopropylazodicarboxylate (0.33 ml, 1.68 mmol) were reacted as described for Example 58. Purification was carried out by chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane solution with ether to yield the title compound as a white powder (0.28 g, 74%).
Reaction SMILES: [N+:1]([C:4]1[S:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]=1[NH2:13])([O-])=O.[ClH:14].CCOC(C)=O>CCO.[Ni]>[ClH:14].[S:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([NH2:13])=[C:4]1[NH2:1]
Reactant: Nc1c([N+](=O)[O-])sc2ncccc12
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-nitrothieno[2,3-b]pyridin-3-amine (1.1 g, 5.6 mmol) in EtOH (60 mL) was added Raney Ni (1 g), followed by slow addition of N2H4.H2O (1.4 g, 22 mmol). The mixture was stirred at room temperature for 2 h. A solution of HCl in EtOAc (1 M, 18 mL, 18 mmol) was added to the reaction mixture slowly, and the mixture was filtered. The filter cake was washed with EtOAc (20 mL×3), then dried under reduced pressure to give the crude product as a yellow solid (2.7 g). ESI MS: m/z 166 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[CH3:33])=[CH:4][CH:3]=1.[CH2:34]1COC[CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:34][CH3:35])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[CH:21][CH:20]=3)[C:9]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (compound 1d, 2.3 g, 4.55 mmol) in anhydrous THF (40 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 3.04 g, 22.8 ml, 22.77 mmol) was added dropwise and the reaction mixture was heated at 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by adding a solution of saturated ammonium chloride (40 ml) and the resulting mixture was extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 30-35% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 1.1 g of the compound in dichloromethane (10 ml) and precipitating it by slow addition of diisopropyl ether. (0.89 g, 47%)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=O)[C:5](F)=[CH:6][CH:7]=1.O.[NH2:24][NH2:25].O>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:25][N:24]=[C:9]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: NN
Reactant: COc1c(Br)ccc(F)c1C(=O)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: COc1c(Br)ccc2[nH]nc(-c3ccc4ccccc4c3)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A total of 1.63 g of (3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanone was dissolved in 15 ml of pyridine, 2.2 ml of hydrazine monohydrate was added, followed by stirring at 100° C. for 6 hours. Water was added to the reaction mixture, and then it was extracted with ethyl acetate for two times. The organic layer was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation. Then, the resulting crystals were washed with hexane once and dried in vacuo, to give 0.923 g of the title compound as brown crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([O:31]C)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>O1CCOCC1>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([OH:31])=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 80.5 %

Procedure:
A mixture of methyl 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylate (298 mg, 0.694 mmol) and 1.0 M NaOH (3.5 mL, 3.5 mmol) in 8.0 mL dioxane was rapidly stirred at rt for 1.8 hours. The pH of the mixture was adjusted to pH 4 using 10% aqueous HCl, and then water added to form a yellow precipitant. The precipitant was filtered, washed with H2O then 30% EtOAc/hexane to give the title compound as a yellow solid (232 mg, 81%). 1H NMR (DMSO-d6 plus D2O) δ: 10.10 (s, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.56-7.65 (m, 2H), 7.54 (s, 1H), 7.33-7.41 (m, 2H), 7.22-7.29 (m, 2H), 6.98 (d, J=7.3 Hz, 1H), 4.55 (s, 2H), 3.60-3.65 (m, 2H), 3.27 (t, J=5.4 Hz, 2H), 2.79-2.94 (m, 1H), 1.21 (d, J=6.7 Hz, 6H)
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]([O:21]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[C:10]([CH:19]=[O:21])=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN)ccc21
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: CC(C)(C)OC(=O)n1cc(C=O)c2cc(CN)ccc21
Yield: 73 %

Procedure:
This compound was prepared from 416 (297 mg, 1.21 mmol) in a manner similar to that for 409a to yield a cream-colored solid (243 mg, 73%): mp 126-128° C. TLC Rf 0.50 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 12.10 (s, 1H), 9.91 (s, 1H), 8.27 (m, 1H), 8.00 (s, 1H), 7.45-7.43 (m, 2H), 7.17-7.15 (d, 1H, J=8.4 Hz), 4.22-4.20 (d, 2H, J=6 Hz), 1.40 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 184.7, 155.7, 138.6, 136.0, 134.0, 124.0, 123.1, 119.2, 118.0, 112.0, 77.6, 43.7, 28.2. Elemental analysis calculated for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.75; H, 6.61; N, 10.20.
Reaction SMILES: Cl[C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(Cl)nc3cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NCc4ccccc4)nc3cc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 10.6 %

Procedure:
A mixture of F1 (100 mg) and benzylamine (1.5 ml; 13.6 mmol) is stirred in a microwave apparatus at 200° C. for 8 min. After re-cooling the mixture is concentrated in vacuo and purified by RP-MPLC (Polygoprep 100-50 C18) eluting with a water/MeCN gradient to give the desired compound (13 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccc(Cl)c(Cl)c2)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc(Cl)c(Cl)c2)OC1c1ccccc1
Yield: 63.5 %

Procedure:
Phenyl isocyanate (1.7 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(3,4-dichlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (4.7 g) in 1,2-dichloroethane (50 cc). The solution obtained is heated to reflux for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (7:3 by volume)], collecting 20-cc fractions. Fractions 2 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-2-(3,4-dichlorophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (4 g), m.p. 130° C., is obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8]2=[O:24])=[CH:5][C:4](=[O:25])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:24])=[CH:5][C:4](=[O:25])[O:3]1
Reactant: CC1OC(=O)C=C1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1OC(=O)C=C1N1CCC2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (127 mg, 0.362 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.396 mL, 18.12 mmol), the resulting solution was stirred at rt for 1 h. After concentration, the residue was treated with methylene chloride (1 mL) and hydrogen chloride (1 mL, 4 N in dioxane). The resulting mixture was concentrated to give the title compound as hydrogen chloride salt. LC/MS: (M+1)+: 251.19.
Reaction SMILES: CO[C:3](=[NH:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:34])(=[O:33])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[CH2:36](N)[CH2:37][NH2:38]>C(O)C>[NH:38]1[CH2:37][CH2:36][N:35]=[C:3]1[C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:27][CH:28]=3)(=[O:33])=[O:34])=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NCCN
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(CNS(=O)(=O)c2ccc(NC(=O)Nc3cccc(C4=NCCN4)c3)cc2)cc1

Procedure:
3-{3-[4-(4-Sulfamoylbenzylsulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (130 mg, 1 eq.) was suspended in anhydrous ethanol (10 ml), ethylenediamine (0.1 ml, 5.7 eq.) was added and the mixture was refluxed for 16 h. The precipitate was filtered off, washed with diethylether and dried in vacuo. Yield: 60 mg (45%) of 4-{3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ureido}-N-(4-sulfamoylbenzyl)-benzenesulfonamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([N:20]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([NH:29][O:30]C5CCCCO5)=[O:28])=[CH:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Cl>CO>[OH:30][NH:29][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][N:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1
Reactant: Cn1ccc2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccc21
Agent: Cl
Solvent: CO
Product: Cn1ccc2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NO)c4)cc3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.346 g (E)-3-{1-[4-(1-methyl-1H-indol-5-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 20 ml methanol and 13.9 ml 0.5M aqueous HCl is stirred at ambient temperature for 24 h. The crude product is isolated and in case of incomplete deprotection the resulted mixture is treated again with 1 N aqueous HCl until the reaction is at completion. The crude product is isolated by evaporation and the title compound is isolated by prep-HPLC chromatography using an ammonium formiate gradient. By this method 0.047 g of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1I.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[C:20]#[N:21]
Reactant: CN(C)C=O
Reactant: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(I)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of (4S,5S)-1-(3-chloro-4-iodophenyl)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (113 mg) in DMF (3.5 mL) were added zinc cyanide (12 mg) and tetrakis(triphenylphosphine)palladium(0) (34 mg), and the mixture was stirred at 100° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 75 mg, 90%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(C)nc3)CCC2)CCN(C)C1
Temperature: 90 °C
Yield: 25.1 %

Procedure:
5-(2-Bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (127 mg, 0.58 mmol) and K2CO3 (120 mg, 0.87 mmol) were mixed in 1,2-dimethoxyethane (4 mL) and water (2 mL). The reaction mixture was purged with nitrogen, Pd(PPh3)4 (17 mg, 0.0147 mmol) was added and the reaction mixture was heated at 90° C. for 45 min. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 26 mg of 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (dd, 1H), 7.61 (d, 1H), 7.31 (s, 1H), 6.95-7.10 (m, 2H), 4.7 (d, 1H), 4.38 (d, 1H), 3.8 (m, 1H), 3.55 (m, 1H), 2.82-3.2 (m, 9H), 2.61 (s, 3H), 2.4 (s, 3H), 2.3 (m, 2H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]1([O-])[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[N:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:7]1[CH:8]=[N:9][C:10]2[C:15](=[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]3=[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]3=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccnc2c3ccccc3c3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1cnc2c3ccccc3c3ccccc3c2n1
Yield: 93 %

Procedure:
Next, 18 mL of phosphoryl chloride was dripped into 2.91 g of dibenzo[f,h]quinoxaline-1-oxide obtained in the above Step 1. This mixed solution was stirred while being heated under reflux for 1 hour. This mixed solution was poured into iced water, followed by addition of potassium carbonate so that the mixture was alkaline. This solution was filtered, and the obtained residue was washed with water and then methanol to give the object of the synthesis (as a pale yellow powder in a yield of 93%). The synthesis scheme of Step 2 is illustrated in the following (a″′-2-2).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([CH:13]3[C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH:12]3[CH:14]([CH:13]3[C:16]3[CH:17]=[C:18]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:19]=[CH:20][CH:21]=3)[CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of 3-[3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 25, 34 mg, 0.11 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then methanesulfonylchloride (13 mg, 10 μl, 0.11 mmol). The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (29 mg, 71%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][NH:10]2)(=[O:3])[CH3:2].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:18][C:19]#[N:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2
Reactant: N#CCBr
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CC#N

Procedure:
The compound prepared in (1) above (1.95 gm) was dissolved into 40 ml of DMF, and 6 ml of bromoacetonitrile was added to the solution. After heating under reflux for 3 hours, the reaction mixture was concentrated, and chloroform was added to the residue. The residue, after washing with saturated brine, was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a chloroform-methanol (100:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 605 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>COCCOC.FC(F)(F)C([O-])=O.[Ag+]>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)Nc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Silver trifluoroacetate (1.3 g) was added in two portions over 20 minutes to a stirred solution of 3-amino-4-chlorophenol (0.5 g) and 2-(4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester (0.8 g) in 1,2-dimethoxyethane (10 mL) at room temperature. The mixture was stirred at room temperature for 15 hours and then filtered through hyflo, washing with 1,2-dimethoxyethane. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) gave title compound as a pale peach solid, 0.75 g.