Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-4-fluorobiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 87%).
Reaction SMILES: [CH3:1][Si:2]([O:15][CH:16](C)C)([O:11][CH:12](C)C)[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][Si:2]([O:11][CH3:12])([O:15][CH3:16])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc([Si](C)(OC(C)C)OC(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=Cc1ccc([Si](C)(OC)OC)cc1
Reaction time: 4 h
Yield: 64.5 %

Procedure:
Compound 4-(methyldiisopropyloxysilyl)styrene (8.23 g, 31 mmol) was dissolved in dry methanol (10 ml,). 1% molar of p-toluene sulfonic acid (17 mg) was added all at once. The yellow suspension was stirred for 4 hours. The organic solvent was pumped off and the corresponding crude oil was distilled under vacuum (B.p. 70-80° C., 5.10−2 mbar) to afford 4-(methyldimethoxysilyl)styrene as a yellow oil (4 g, 20 mmol) in 65% yield. 1H NMR (CDCl3, δ, ppm) 7.64 (2H, d); 7.49 (2H, d); 6.77 (1H, dd), 5.84 (1H, d), 5.33 (1H, d), 3.60 (6H, s); 0.39 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH3:24])[C:19]([CH:22]=O)=[N:20][CH:21]=1>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:22][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([Cl:15])=[CH:21][N:20]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)cnc1C=O
Product: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C

Procedure:
Yellow oil prepared from (4-amino-butyl)-methyl-carbamic acid tert-butyl ester and 5-chloro-3-methyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.60 (m, 4H), 2.27 (s, 3H), 2.30-2.36 (m, 2H), 2.83 (s, 3H), 3.20-3.26 (m, 2H), 3.83 (s, 2H), 8.34 (d, 1H, J=1.5 Hz), 7.4 (d, 1H, J=1.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3'-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177-178° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 6.94 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.58 (t, 1H), 7.63 (t, 1H), 7.83 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([F:17])([C:14](=[O:16])[NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 68.9 %

Procedure:
In analogy to example 1 from 4-fluoro-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.565 g), synthesis described in WO2008/98977, and 4-trifluoromethoxy-aniline (0.405 g) there as obtained 4-fluoro-4-(4-trifluoromethoxy-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) as an off white solid. MS (ESI): 405.1 ([M-H]−).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]Br.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
12.1 g of methyl 2-chloro-4-methanesulfonyl-3-methylbenzoate was dissolved in 250 ml of carbon tetrachloride, and the solution was refluxed under stirring. Then, 7.5 g of bromine and 1 g of benzoyl peroxide were gradually added thereto over a period of 30 minutes, and the solution was further refluxed for 4 hours under heating. After cooling, 200 ml of chloroform was added thereto, and the mixture was washed with a 5% sodium hydrogensulfite aqueous solution. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with ethyl ether to obtain 13.2 g of crystals of the desired product. Melting point: 77°-78° C.
Reaction SMILES: Br.[N:2]1[C:3](=[O:11])[CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.Br[CH2:13][C:14]1[C:15]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1>C1COCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][CH:4]3[N:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]4=[N:2][C:3]3=[O:11])[C:15]=2[CH:22]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: O=C1CN2C=CC=CC2=N1
Agent: Br
Solvent: C1CCOC1
Product: O=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
A mixture of 100 mg (0.47 mmol) of imidazo[1,2-a]pyridin-2-one hydrobromide salt and 122 mg (0.47 mmol) 3-bromomethyl-5-chloro-benzo[b]thiophene in 5 mL of THF is treated with 1 mL (1.0 mmol) of 1M lithium bis(trimethylsilyl)amide THF solution at −78° C. The resulting mixture is stirred this temperature for 1 h and the mixture is quenched with saturated ammonium chloride solution. The product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[CH2:33]1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@H:32]4[CH2:37][CH2:36][CH2:35][C@@H:34]([N:38]5[CH2:42][CH2:41][CH2:40][C:39]5=[O:43])[CH2:33]4)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: N[C@H]1CCC[C@@H](N2CCCC2=O)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N5CCCC5=O)C4)n3)c3cc(Cl)cnc32)cc1

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 1a, (0.14 g, 0.29 mmol) and 1-((1R,3S)-3-aminocyclohexyl)pyrrolidin-2-one, 45c, (0.10 g, 0.53 mmol) and Na2CO3 (0.09 g, 0.88 mmol) freshly ground, in THF (2.25 mL) and CH3CN (0.45 mL) and heat to 135° C. for 30 min. The mixture was slowly poured into 15 mL 1M HCl and extracted with EtOAc (5×). The combined organic layers were washed with brine, dried over Na2SO4 and filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% MeOH—CH2Cl2 gradient) provided the final product as a sticky residue. Trituration with CH3CN provided an off white powder (105 mg) which was impure, but which was taken directly to the final deprotection step.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[H][H]>[Pd].C(O)C>[CH:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)=[CH2:2]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C=CC1(O)CN2CCC1CC2
Yield: 98.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (5.0g), palladium on calcium carbonate (5% w/w, 0.5 g) and ethanol (200 ml) was stirred under an atmosphere of hydrogen until 900 ml of hydrogen has been consumed. The mixture was filtered and evaporated to give 3-ethenyl-3-hydroxyquinuclidine (5.0 g) as an oil which gave a solid on standing and was used without further purification, m.p. 76°-80° C.; NMR(DMSO-d6): 1.2(1H, m), 1.4-1.6(3H, m), 2.0(1H, m), 2.45-2.85(6H, m), 4.55(1H, s), 5.0(1H, d of d), 5.25(1H, d of d), 6.1(1H, d of d); m/z 154 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:35]5[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)([C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH:34]=5)[CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)C1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 90.3 %

Procedure:
92 mg 1-(6-bromoquinolin-4-yl)piperidine-4-carboxylic acid (4-fluorophenyl)methylamide (compound in Production Example 458) and 114 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 139 mg 1-[6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)quinolin-4-yl]-piperidine-4-carboxylic acid (4-fluorophenyl)methylamide. This product was reacted in the same manner as in Example 67, to give 80 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N=C=NC(C)C)(C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([O:9][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Compound I can be prepared according to the procedures described in U.S. Provisional Patent Application No. 61/243,596, filed Sep. 18, 2009. To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29 g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5° C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5° C. for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50° C. to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3×20 ml) and dried to give (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate as a white solid (23.2 g, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[NH:6][N:5]=1)[CH3:2].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[NH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=3[CH3:9])=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CCOc1n[nH]c(C(=O)O)c1C
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CCOc1n[nH]c(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1C
Yield: 4.21 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-ethoxy-4-methyl-1H-pyrazole-5-carboxylic acid (0.117 g, 0.690 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.15 g, 0.575 mmol). The product was purified with reverse phase flash-chromatography. Yield 4.21%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 1.28 (t, 3H), 1.94 (s, 3H), 4.10-4.17 (m, 2H), 4.28-4.33 (m, 2H), 4.37-4.46 (m, 1H), 6.96 (d, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 12.08 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: C=Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: C=Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 44 %

Procedure:
2-Chloro-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 2-(piperazin-1-yl)-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde (44% yield) as a yellow solid. ESI/MS 332 (M+H), RT 2.57 min; NMR (CDCl3) 10.29 (1H, s); 8.28 (1H, d, J=6 Hz); 7.62 (2H, d, J=6 Hz); 7.38 (4H, m); 7.00 (1H, d, J=9 Hz); 6.85 (1H, dd); 5.89 (1H, d, J=15 Hz); 5.42 (1H, d, J=18 Hz); 3.38 (4H, m); 2.77 (4H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[N:10]([CH2:21][CH2:22][OH:23])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH2:1]([O:8][C:9]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[CH2:21][CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1cccc2cc[nH]c12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 8.61 mmol) in dichloromethane (50 mL) was added triethylamine (1.56 mL, 11.2 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.74 mL, 9.47 mmol) added in a dropwise manner. The mixture was warmed to room temperature and allowed to stir for 2 hours. The mixture was then quenched with water (30 mL) and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined extracts were washed with 1.0 M hydrochloric acid (20 mL), water (30 mL), dried over anhydrous sodium sulfate and evaporated to dryness. Methanesulfonic acid 2-[benzyloxycarbonyl-(1H-indol-7-ylmethyl)-amino]-ethyl ester (3.46 g) was obtained as an oil
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:5]([N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)[CH3:8])=[O:6].[CH2:40]([Zn]CC)[CH3:41]>C1COCC1.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:39][C:38]1[CH:37]=[CH:36][C:4]([C:5]([N:7]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:10]2)[CH3:8])=[O:6])=[CH:3][C:2]=1[CH2:40][CH3:41]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC[Zn]CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)ccc1Cl
Temperature: 65 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution of 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide (50 mg; 0.076 mmol) in THF (0.5 mL) was added under an argon atmosphere tetrakis(triphenylphosphine)palladium (0) (5 mg; 0.04 mmol) and diethylzinc (1 M in hexane, 762 μL; 0.762 mmol). The resulting solution was stirred for 5 h at 65° C. before it was diluted with ethyl acetatec (30 mL) and washed with aqueous sodium carbonate (saturated, 20 mL), water (20 mL) and aqueous sodium carbonate. (saturated, 20 mL). The aqueous phases were extracted with ethyl acetate (30 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 90:10) afforded the title compound (37 mg, 47%) as a light brown foam. MS m/e: 604.2 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:59]1[CH2:64][CH2:63][CH:62]([C:65]2[C:66](=[O:75])[NH:67][C:68]3[C:73]([CH:74]=2)=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:61][CH2:60]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:59]4[CH2:60][CH2:61][CH:62]([C:65]5[C:66](=[O:75])[NH:67][C:68]6[C:73]([CH:74]=5)=[CH:72][CH:71]=[CH:70][CH:69]=6)[CH2:63][CH2:64]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (44 mg, 0.088 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (31.5 mg, 0.098 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (25.7 mg, 0.097 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Reaction was quenched with 50% acetonitrile-water. Mixture was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as light tan solid in 51% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.91 (s, 1H) 11.78 (s, 1H) 7.71 (s, 1H) 7.62 (d, J=7.93 Hz, 1H) 7.48 (s, 1H) 7.44 (t, J=7.63 Hz, 1H) 7.28 (d, J=8.24 Hz, 1H)7.15 (t, J=7.48 Hz, 1H) 5.58 (d, J=17.70 Hz, 1H) 5.40 (d, J=17.40 Hz, 1H) 4.55 (d, J=11.90 Hz, 1H) 4.29-4.46 (m, 1H) 4.07-4.23 (m, 2H) 3.91-4.05 (m, 1H) 3.11-3.24 (m, 2H) 2.95-3.09 (m, 2H) 2.82-2.95 (m, 1H) 2.64 (t, J=13.12 Hz, 1H) 2.43 (dd, J=16.48, 4.27 Hz, 1H) 1.89-1.96 (m, 1H) 1.78-1.88 (m, 1H) 1.47-1.64 (m, 1H) 1.30-1.46 (m, 1H). High resolution MS m/e (M+H)+=708.0445.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:41]4[CH:40]=[CH:39][C:38](C=O)=[CH:37][C:36]=4[S:35][C:34]4[C:29]3=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:13]3[C:18]([S:19][C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[S:35][C:36]4[C:41]3=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:19][C:20]=2[CH:21]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1N2CCCCCCN1c2ccccc2Sc2cc(C=O)ccc21
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)Sc1ccccc1N2CCCCCCN1c2ccccc2Sc2ccccc21

Procedure:
Phosphorus oxychloride was added dropwise to dry dimethylformamide (1:1.2 molar ratio) at 0° C. under nitrogen. A solution of 1,6-di(10H-10-phenothiazinyl)hexane (obtained in the previous step) in dry DMF was added stepwise to the reaction flask. The reaction mixture was stirred at 70° C. until the starting compound reacted completely as indicated by TLC. The reaction mixture was cooled to room temperature, poured into ice water, and neutralized with a dilute KOH solution until the pH reached 7-8. The aqueous solution was extracted several times with chloroform. The combined chloroform solutions were washed with water, dried with anhydrous sodium sulfate, and filtered. The solvent was removed by distillation. The crude product was purified by column chromatography using a mixture of ethyl acetate and hexane in a volume ratio of 1:8 as the eluent. The yield of 10-[6-(3-formyl-10H-10-phenothiazinyl)hexyl]-10H-3-phenothiazine carbaldehyde was 56%. The 1H-NMR spectrum of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.35-1.50 (m, 4H), 1.55-1.90 (m, 4H), 3.82 (t, 4H), 6.73-7.19 (m, 14H), and 9.80 (s, 2H).