Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:25])[C:18]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:19][C:13]=3[N:12]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:25])[C:18]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:19][C:13]=3[N:12]=2)=[O:34])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc(-n4ccnc4)c(F)cc3[nH]2)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(-n4ccnc4)c(F)cc3[nH]2)c1
Yield: 57.4 %

Procedure:
The title compound (0.32 g, 58%) was prepared by the above general procedure using 2-[[(4-methoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(imidazol-1-yl)-1H-benzimidazole (0.53 g, 1.5 mmol) (obtained in example 5), m-chloroperbenzoic acid (50%, 0.62 g, 1.8 mmol) and dichloromethane (20 mL). IR (KBr) 3500, 1048 cm-1 ; 1H NMR (CD3OD) δ 3.86 (s, 3H, OCH3), 4.72 (ABq,J=10.8 Hz, Δv=15.6 Hz, 2H, SOCH2), 6.94 (m, 2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.68 (d,J=10.8 Hz, 1H), 7.88 (d,J=7.6 Hz, 1H), 8.08 (s, 1H), 8.26 (d,J=5.6 Hz, 1H); Mass (m/z) 371 (M+.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(N(CC)CC)C>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[C:15]3[C:10](=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1)=[O:37]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from {3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: mp 192-195° C.; MS (ES) m/z 515.8.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>CN(C=O)C>[Br:7][CH2:8][CH2:9][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a suspension of K2CO3 (4.52 g, 32.7 mmol), 1,2-dibromoethane (10.6 ml, 122.8 mmol) in DMF (12 mL) was added a solution of 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) in DMF (3 mL) at 0° C. The mixture was stirred at room temperature for 18 h., filtered and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc-hexane (increasing percentage of EtOAc from 20 to 25%) to afford the title compound (1.21 g, 64% yield). 1H NMR: (CDCl3) δ (ppm): 9.88 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 4.38 (t, J=6 Hz, 2H), 3.67 (t, J=6 Hz, 2H). LRMS (ESI): (calc.) 227.9, 229.9; (found) 229.1, 231.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66 g, 1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). The reaction was stirred at room temperature until complete. The reaction was quenched with H2O, and the aqueous mixture was extracted with CH2Cl2. The organic phase was washed with H2O and brine and dried over Na2SO4. After filtration and concentration, the residue was dried under vacuum to give tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which and used directly in the next step. To a mixture of tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol), 8-hydroxyquilinine (34 mg, 0.23 mmol), K2CO3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture was degassed and back-filled with N2. The reaction was stirred at 130° C. overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH2Cl2, washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound as a yellow oil (0.12 g, 13%): 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H), 7.09 (m, 1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H), 2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J=8.0 Hz, 2H), −0.04 (s, 9H); ESI MS m/z 602 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[N:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:36][CH2:35][CH2:34][N:28]1[CH2:33][CH2:32][N:31]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:26])([F:1])[F:27])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Reactant: OCCN1CCNCC1
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2)N1CCN(CCO)CC1

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(piperazin-1-yl)ethanol gave 122. MS: (ESI+)=492.2. 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.4 Hz, 2H), 7.38 (dd, J=8.4, 2.1 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 5.89 (q, J=8.7 Hz, 2H), 4.57 (s, 4H), 4.40 (t, J=5.4 Hz, 1H), 4.06 (q, J=5.3 Hz, 1H), 3.51 (dd, J=11.6, 6.0 Hz, 4H), 3.17 (d, J=5.2 Hz, 1H), 2.46-2.39 (m, 5H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][C:38]1[C:42](B(O)O)=[C:41]([CH3:46])[O:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:46])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4c(C)noc4C)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
To a solution (15 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.54 g) synthesized in Example A174(3) in toluene were added (3,5-dimethylisoxazol-4-yl)boronic acid (0.41 g) and 2N aqueous sodium carbonate solution (1.46 mL), and the mixture was stirred at room temperature for 10 min under argon atmosphere. To the reaction mixture were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.05 g) and tris(dibenzylideneacetone)dipalladium (0) (0.03 g), and the mixture was heated under reflux under argon atmosphere overnight. The reaction mixture was cooled to room temperature and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[5-(3,5-dimethylisoxazol-4-yl)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.13 g, 23%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.12 g, 96%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([CH3:18])=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([CH:16]([OH:17])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4.17 g (17.1 mmol) of methyl (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2yl) ketone (Compound 16) in methanol at 0° C. was portionwise added 0.77 g (20.4 mmol) of sodium borohydride and the resulting suspension stirred at 0° C. for 4 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted three times with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo and resulting residue purified using flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give a single isomer: the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCCCN1CCOCC1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCCN1CCOCC1
Yield: 92 %

Procedure:
The compound prepared in Example 3 was reacted with 4-(3-aminopropyl)morpholine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 92%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][C:14]([O:30]C)=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.B(Br)(Br)Br>ClCCl>[OH:30][C:14]1[CH:13]=[C:12]2[C:17]([N:18]=[C:19]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH3:25])[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)=[N:11]2)=[CH:16][C:15]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1O
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a solution of (S)-methyl 2-(1H-indazol-5-yl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (208 mg, 0.50 mmol) in dichloromethane (20 ml) was added BBr3 (0.37 g, 0.75 mmol) at −60° C. The resulting solution was stirred for 0.5 h at −60° C. The reaction was then quenched by the addition of water/ice (200 ml), extracted with dichloromethane (4×50 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under vacuum to give the residue, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to afford (S)-methyl 7-hydroxy-2-(1H-indazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (180 mg, 90%).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:25]=[O:26])[C:18]([SH:21])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Sc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=Cc1cc(Cl)ccc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
Tetramethylethylenediamine (TMEDA) (10.44 mL, 8.035 g, 69.15 mmol) was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol) and the solution was chilled to 0° C. A solution of 4-chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 mL) was added with stirring over 1 hour. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (2.94 mL, 2.78 g, 38.03 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for hours and became a powdery suspension. A mixture of 2 N HCl and ice was added to the reaction mixture until the pH became acidic (pH=1). During this addition, the mixture warmed and became first red and then pale yellow. This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear red-brown oil. This oil was triturated with hexanes yielding a red-brown semisolid. This semisolid was purified by plug flash chromatography over silica gel, eluting with 1:1, hexanes:dichloromethane to afford 5-chloro-thiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[NH2:18])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cc(N2CCC(F)CC2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N2CCC(F)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
Add Pd/C (10%, 70 mg) to the solution of 4-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)piperidine (300 mg, 1.0 mmol) in methanol (10 mL), stir the mixture under hydrogen atmosphere for 16 hrs at room temperature. Filter and concentrate the filtrate to get the crude product (270 mg, 100%) which is used directly without further purification.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH2:15][CH:16]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:9]1([C:15]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: O=CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(-c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A solution of phenylhydrazine (1 mL, 10.15 mmol) and phenylacetaldehyde (1.32 mL, 10.15 mmol) in acetic acid was refluxed for 6 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium carbonate (100 mL) at 0° C. After extraction with dichloromethane (2×30 mL), the organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired indole (1a) as a pale oil (940 mg, 4.86 mmol, 48%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([Cl:30])[CH:9]=1>>[Cl:30][C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15]
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3Cl)CC2)c(C)c1
Yield: 66.3 %

Procedure:
Using pyrrolidin-2-one (23 mg) and (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 119 and by the reaction and treatment in the same manner as in Example 1, the title compound (67 mg) was obtained.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:8][CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[C:22]1([CH3:28])[CH:27]=CC=[CH:24][CH:23]=1>>[CH:3]12[CH2:28][CH:22]([CH:23]=[CH:24]1)[CH2:27][CH:2]2[C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:4]
Reactant: C=CC(=O)OC1CCC(NS(C)(=O)=O)CC1
Reactant: Cc1ccccc1
Agent: C1=CCC=C1
Product: CS(=O)(=O)NC1CCC(OC(=O)C2CC3C=CC2C3)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a mixture of 26.1 g of 4-[(methylsulfonyl)amino]-cyclohexyl acrylate (synthesized by the procedure of Example 4) and 50 g of toluene was added 8.0 g of cyclopentadiene. The mixture was stirred at 40° C. for 24 hours. The reaction solution was purified directly by silica gel column chromatography, obtaining 32.0 g of 4-[(methylsulfonyl)-amino]cyclohexyl 5-norbornene-2-carboxylate (yield 98%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[S:10][C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)=[CH:6][C:5]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:26])[C@H:22]([OH:27])[C@@H:21]([CH2:28][OH:29])[O:20]2)=[C:4]([OH:30])[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:9]2[S:10][C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)=[CH:6][C:5]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:26])[C@H:22]([OH:27])[C@@H:21]([CH2:28][OH:29])[O:20]2)=[C:4]([O:30][CH2:32][CH2:33][O:34][CH3:35])[CH:3]=1
Reactant: COCCBr
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ncc(-c4ccco4)s3)c(Cl)cc2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cc(Cl)c(Cc2ncc(-c3ccco3)s2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 15 h
Yield: 18.2 %

Procedure:
To a solution of phenol 63 (205 mg, 0.451 mmol) in acetone (10 mL) was added bromoethylmethyl ether (1.6 mL, 15.8 mmol) and K2CO3 (2.3 g, 15.8 mmol) at room temperature. The mixture was stirred at 50° C. for 15 h. The mixture was cooled to room temperature and filtered off through the celite. The filtrate was concentrated in vacuo. The residue was purified by prep HPLC (C18) to provide the titled compound 64 (42 mg, 19%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][CH:45]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:39][C:40]1[CH:45]=[C:44]([CH:43]=[CH:42][CH:41]=1)[O:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1
Reactant: Oc1cccc(F)c1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(O[C@H]2CC[C@@H]3CN(c4cccc(C(F)(F)F)n4)C[C@@H]32)c1
Reaction time: 7 h

Procedure:
To (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-ol (90 mg, 0.331 mmol) from Example 30 and triphenylphosphine (173 mg, 0.661 mmol) was added tetrahydrofuran (1.150 mL) and 3-fluorophenol (0.059 mL, 0.661 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (DIAD, 0.129 mL, 0.661 mmol). The reaction mixture was stirred for 7 hours and then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-6% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.56 (d, J=8.0, 1H), 7.31 (dd, J=15.3, 8.2, 1H), 7.02 (d, J=7.3, 1H), 6.92 (dt, J=11.2, 2.4, 1H), 6.89-6.77 (m, 2H), 6.56 (d, J=8.6, 1H), 4.65 (d, J=2.2, 1H), 3.69 (dd, J=11.0, 8.9, 1H), 3.52 (dd, J=10.7, 7.6, 1H), 3.41 (dd, J=11.3, 4.7, 1H), 3.25 (dd, J=10.7, 3.0, 1H), 2.93-2.78 (m, 2H), 2.10-1.94 (m, 2H), 1.82 (dt, J=13.8, 7.1, 1H), 1.50-1.37 (m, 1H); MS (ESI+) m/z 367 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-Acetyl-4-(4-aminophenyl)piperazine (10.96 g) in ice-cold pyridine (100 ml) was added methanesulphonyl chloride (6.3 g) dropwise. The mixture was then stirred at ambient temperature overnight and the pyridine removed in vacuo. The residue was triturated with aqueous sodium bicarbonate, and the resulting solid was washed (water) and crystallized from methanol/ethyl acetate (charcoal). The yield of the title compound was 9.97 g, m.p. 165°-7°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2N=1)(C)(C)C.Cl.ClCC1N(C)N=NC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:35]([CH3:30])[N:34]=[N:33][CH:31]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Agent: Cn1nncc1CCl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light yellow solid. MS (m/e): 378.3 (MH+).