Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[C:24]5=[N:25][CH:26]=[CH:27][CH:28]=[C:29]5[N:30]=[CH:31]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC(OC)OC
Solvent: O=CO
Product: c1cnc2c(c1)ncn2CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 71 %

Procedure:
N*2*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-2,3-diamine (350 mg, 0.85 mmol), trimethylorthoformate (5 mL) and formic acid (0.5 mL) were stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated NaHCO3 solution (40 mL) and DCM (2×40 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 93:7:0.7 by volume) to provide the title compound as a brown oil (255 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H), 1.99-2.10 (m, 6H), 2.57 (m, 4H), 2.64 (t, 2H), 3.56 (m, 2H), 3.92 (m, 2H), 4.03 (t, 2H), 4.40 (s, 2H), 6.82 (s, 1H), 6.90 (d, 2H), 7.02 (d, 2H), 7.20 (m, 1H), 7.99 (d, 1H), 8.38 (d, 1H). HRMS ESI+ m/z 421.2586 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(S(F)(F)[F:47])CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:36]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([F:47])[CH2:18][CH2:19]2)[C:10]1=[O:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Treat a 0° C. solution of 1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-3-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.090 g, 0.15 mmol) in CH2Cl2 (5 mL) with (diethylamino)sulfur trifluoride (0.049 g, 0.305 mmol) and stir for 1 hour at 0° C. under N2. Quench the reaction with saturated NaHCO3, dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.019 g (85%) of the titled product. Rf=0.56 (9/1 CH2Cl2/methanol). ES MS (m/z): 600 (M+).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1ccccc1Cl
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3Cl)c(=O)n12
Temperature: 105 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2-chlorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 105° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexanes) to give the desired product (0.062 g). LCMS calculated for C15H13ClN5OS (M+H)+: m/z=346.1. Found: 346.0.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH2:16]([NH:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+]>CN(C)C=O>[ClH:1].[ClH:1].[CH2:16]([N:23]([CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)CC1CN(Cc2ccccc2)CCO1
Product: Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 58 g of 2-chloromethyl-4-benzylmorpholine, 62.3 g of N-benzyl-N-methylamine and 38.6 g of sodium iodide in 220 ml of dimethylformamide is refluxed under stirring at 140° C. for 6 hours. After completion of the reaction, the dimethylformamide is distilled off under reduced pressure, water is added to the residue and the mixture is subjected to extraction with ethyl acetate. After washing with water, the resultant mixture is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is treated in 37% hydrochloric acid-ethanol to give 2-(N-benzyl-N-methylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. The obtained hydrochloride compound (29.7 g) is subjected to catalytic reduction with 50 ml of ethanol, 80 ml of water and 3 g of 10% palladium-carbon. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the solvent of the filtrate is distilled off to give 2-(methylaminomethyl)morpholine dihydrochloride monohydrate as white crystals, melting at 122°-124° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]=[N+:12]=[N-:13])=[N:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:5])C.O1CCCC1.O.[OH-].[Li+]>O.C(OCC)C>[N:11]([C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:8]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a mixture of 3.0 g (8.76 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 54 mL of tetrahydrofuran was added 3.71 g (88.3 mmole) of lithium hydroxide monohydrate in 36 mL of water. The mixture was stirred at room temperature for 3 hours, and then diluted with 350 mL of diethyl ether. The mixture was extracted three times with 100 mL of water. The combined aqueous layers were acidified by addition of 1M hydrochloric acid, and extracted three times with 100 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.20 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid as a yellow-orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[OH2:25]>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[CH:9][C:7]([O:8][CH2:4][CH3:3])=[O:25]
Reactant: O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Sodium hydride (oily, 60%, 2.40 g) was added little by little to a solution of triethyl phosphonoacetate (12.3 g) in tetrahydrofuran (200 ml) at 0° C., and the mixture was stirred at 10 minutes. Then, 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (14.7 g) was added, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:3, v/v) gave crystals of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.8 g, 81%). The crystals were recrystallized from ethanol. Colorless prisms, mp: 94-95° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8](SC(C)C)=[C:7]([O:20][CH3:21])[CH:6]=2.Cl[C:33]1[CH:34]=C(C=C[CH:42]=1)C(OO)=O.C([O-])(O)=O.[Na+].[O-:48][S:49]([O-:52])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:49]([CH:33]([CH3:34])[CH3:42])(=[O:52])=[O:48])=[C:7]([O:20][CH3:21])[CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(SC(C)C)cc12
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 4.04 mmol) and 3-chloroperoxybenzoic acid (1.819 g, 8.12 mmol) in dichloromethane (50 mL) was stirred overnight. Saturated aqueous NaHCO3 and Na2S2O3 were added slowly, and the mixture was stirred for 30 min before it was extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-15% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.76 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.78 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+).
Reaction SMILES: C[Si](C)(C)[N:3]1[N:7]=[CH:6][CH:5]=[N:4]1.[N+](C1C=CC(S(O[CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)(=O)=O)=CC=1)([O-])=O>CN(C=O)C>[N:4]1([CH:27]2[CH2:28][CH2:23][CH2:24][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH:5]=[CH:6][N:7]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: C[Si](C)(C)n1nccn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ccnn2)C1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A 1000-mL 4-necked round-bottomed flask was charged with a solution of 2H-1,2,3-triazole (30 g, 434.78 mmol, 1.00 equiv) in benzene (500 mL). To this solution was added chlorotrimethylsilane (49.3 g, 456.48 mmol, 1.05 equiv) drop wise 0° C. followed by addition of triethylamine (48.3 g, 478.22 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140-150° C. affording 2-(trimethylsilyl)-2H-1,2,3-triazole as colorless oil (11 g, 18%). To a solution of 2-(trimethylsilyl)-2H-1,2,3-triazole (6.2 g, 43.97 mmol, 2.74 equiv) in DMF (100 mL) was added tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate (6.2 g, 16.06 mmol, 1.00 equiv). The resulting solution was refluxed for 3 hours. Upon completion, the mixture was cooled down to room temperature and concentrated on a rotary evaporator affording tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as brown solid (2.3 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][O:15][CH2:16][CH2:17][CH:18]=1)(=O)=O.[F:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>COCCOC.CCOC(C)=O.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>[O:15]1[CH2:16][CH2:17][CH:18]=[C:13]([C:27]2[C:22]([F:21])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:14]1
Reactant: O=S(=O)(OC1=CCCOC1)C(F)(F)F
Reactant: OB(O)c1cccnc1F
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Fc1ncccc1C1=CCCOC1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
Sodium carbonate (29.0 mL, 58.0 mmol, 2.0 M in water) was added via syringe to a stirred mixture of 5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate (4.49 g, 19.3 mmol), 2-fluoropyridine-3-boronic acid (2.72 g, 19.3 mmol), and tetrakis(triphenylphosphine)palladium (1.12 g, 0.97 mmol) in DME (82 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 17 h. The reaction mixture was then cooled to room temperature before being diluted with EtOAc and water. The organic layer was separated, washed with sat. aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 3-(5,6-dihydro-2H-pyran-3-yl)-2-fluoropyridine. MS (ESI, pos. ion) m/z: 180.0.
Reaction SMILES: Cl.C([C@@H]1C(OC)=[N:9][C@@H:8]([CH2:13][C@@H:14]([CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]([O:29]C)=N1)(C)C.[C:31]([O-])(O)=[O:32].[Na+]>C(#N)C>[CH3:31][O:32][C:7](=[O:29])[C@@H:8]([NH2:9])[CH2:13][C@@H:14]([CH:26]([CH3:27])[CH3:28])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:20][CH:21]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Temperature: 25 °C

Procedure:
With stirring at room temperature, 36 ml of 1N hydrochloric acid am added to a solution of 3.55 g of 2(R)-isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butylphenyl)-propyl]-2,5-dihydro-3,6-dimethoxy-pyrazine in 35 ml of acetonitrile and the mixture is then stirred for a further 3 hours. The reaction solution is then poured onto a mixture of 45 ml of saturated NaHCO3 solution and ice and the suspension is extracted with dichloromethane. The extracts arc concentrated by evaporation and purified by FC (700 g of silica gel, eluant: dichloromethane/methanol/NH3 =200:10:1), yielding the title compound: Rf (dichloromethane/methanol/conc. ammonia=200:10:1)=0.70.
Reaction SMILES: [CH2:1]([C:4]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO.C(O)(=O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:4]1[CH:19]=[C:18]([CH2:20][NH:25][CH3:24])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3]
Reactant: [BH3-]C#N
Reactant: C=CCc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCc1cc(CNC)ccc1Oc1cc(Cl)ccc1C#N
Yield: 80.8 %

Procedure:
2-(2-Allyl-4-formyl-phenoxy)-4-chlorobenzonitrile (0.09 g, 0.30 mmol), methylamine (33% in ethanol, 0.3 mL, 2.4 mmol) and sodium cyanoborohydride (40 mg, 0.64 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (0.5 mL) in methanol (25 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (36 mg, 0.30 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-allyl-4-methylaminomethyl-phenoxy)-4-chlorobenzonitrile fumarate (104 mg, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.O.O[N:15]1C2C=CC=CC=2N=N1.Cl.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>CN(C)C=O>[NH3:15].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: On1nnc2ccccc21
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(F)cc3)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
To a solution of 3-(4-fluorophenyl)propanoic acid (104 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (100 mg, 36%).
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=[O:27])=[O:26])[CH:24]=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:37]N1C(=O)CCC1=O>O1CCCC1.C(OCC)C>[Br:37][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])(=[O:27])=[O:26])[CH:24]=3)=[O:18])=[CH:13][CH:12]=2)[N:8]([Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3ccn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reaction time: 6 h

Procedure:
A solution of 1.7 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide in tetrahydrofuran (110 mL) at −78° C. is treated with 0.564 g of N-bromosuccinimide. After 6 h at −78° C. the temperature is allowed to reach room temperature. The reaction mixture is taken up in diethyl ether, washed with water and dried (magnesium sulfate). The solvent is evaporated and the residue is triturated under sonication with diisopropylether to give 5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide as a tan powder. MS (m/z): 643 (M+1); Rf 0.90 (95:5 methylene chloride/methanol).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19](I)=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](B1OC(C)(C)C(C)(C)O1)([CH3:31])=[CH2:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:29]([CH3:31])=[CH2:30])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2nc(NC(=O)NC3CCCCC3)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
1-Cyclohexyl-3-[7-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (300 mg, 0.582 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.33 mL, 1.75 mmol), Cs2CO3 (948 mg, 2.91 mmol), and Pd(dppf)Cl2 DCM complex (47 mg, 0.058 mmol) were dissolved in THF (2.3 mL) and H2O (0.7 mL). The mixture was irradiated at 100° C. using microwave for 1 hr, cooled to RT, partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, DCM/MeOH 0 to 5% MeOH) to give 131 mg of impure 1-cyclohexyl-3-[7-isopropenyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (52% yield).
Reaction SMILES: [Cl:1]C1C=CC2OC3C=CC=CC=3[C@H]3C(=[O:13])N(C)C[C@@H]3C=2C=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C@@H:29]3[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C@@H:28]3[C:27]=2[CH:42]=1.[OH-]>C(O)C>[ClH:1].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C@@H:29]([C:30]([OH:34])=[O:13])[C@H:28]([CH2:32][NH:31][CH3:33])[C:27]=2[CH:42]=1
Reactant: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@@H]2C1=O
Reactant: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@H]2C1=O
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C(=O)O
Product: Cl
Yield: 22 %

Procedure:
The mixture of lactams (VII) and (VIII) (13.6 grams, 45 mmol, trans/cis ratio 1:2.3), obtained as described under E, was dissolved in ethanol (140 ml). To the solution postassium hydroxide was added (43 grams, 811 mmol), whereupon the mixture was heated to reflux for 18 hours. Part of the ethanol (60 ml) was evaporated and water was added (200 mL). The aqueous phase was extracted twice with toluene (100 ml ). Subsequently toluene (100 ml) was added to the water phase, followed by concentrated hydrochloric acid to adjust the pH to 1. During the addition of hydrochloric acid the temperature rises to 75° C. The water layer was separated and upon cooling the product crystallized. The crystals were collected by filtration and dried to provide trans-2-chloro-10,11-dihydro-11[(methylamino)methy]-dibenz[b,f]oxepin-10-carboxylic acid hydrochloride (11)(3.75 grams, 10.6 mmol, 22%).