Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 82 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (0.45 g, 0.84 mmol), 4-(methanesulfonyl)phenylboronic acid (0.50 g, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (59 mg, 0.08 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.3.
Reaction SMILES: [Na+].Cl[CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[CH2:11]([NH2:13])[CH3:12].[Na]>O>[CH2:11]([NH:13][CH2:3][CH:4]([OH:10])[CH2:5][S:6]([OH:9])(=[O:8])=[O:7])[CH3:12]
Reactant: O=S(=O)([O-])CC(O)CCl
Reactant: CCN
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCNCC(O)CS(=O)(=O)O
Temperature: 4.699999809265137 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-hydroxy-1-propanesulfonic acid sodium salt (10 g, 50.9 mmol) in water (total volume: 40 mL) was added over 5 hours, via a syringe pump, to a cold (4.7° C.) solution of ethyl amine in water. The mixture was stirred for an additional 2 hours at 4.7° C. then for 18 hours at room temperature. NMR: quantitative yield. The mixture was concentrated. A solid could not be obtained: the sodium salt was too hygroscopic. The solution was treated with Amberlite IR-120 Plus, acid form, ion-exchange resin to give the free acid. It was still too hygroscopic to be obtained as a solid form. Submitted as a solution: d=1.314 g/mL, 62.5% w/w of the free acid in water. The 1H and 13C NMR and MS were consistent with the structure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH2:11](O)[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:9][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C1CCCC(C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCC(=O)C1
Yield: 100 %

Procedure:
To a round bottom flask was added 3-oxo-1-cyclohexanecarboxylic acid (3.85 g, 27.1 mmol), ethanol (7.91 mL), p-toluenesulfonic acid (0.097 g, 0.56 mmol) and toluene (65.9 mL). The mixture was refluxed with Dean-star trap overnight. The reaction mixture was cooled down and concentrated under reduced pressure to afford 4.61 g (100%) of the title compound, 3-oxo-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18].[C:29](OCC)(=[O:31])[CH3:30]>>[C:29]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18])(=[O:31])[CH3:30]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(2-naphthoyl)indole (step 1). tlc: Rf =0.6 (50% ethyl acetate in hexanes)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7])\[CH3:22])[CH3:17]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(Cl)cc1Cl
Temperature: 23 °C
Yield: 38.5 %

Procedure:
Potassium t-butoxide (7.50 g, 0.067 mol) was added to a stirred solution of 2,4-dichloro-phenol (5.46 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.50 g, 38%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26](Cl)=[O:27].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[N:15]1[CH:24]=[CH:25][C:26]([OH:27])=[N:16]1
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: O=C(Cl)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(-n2ccc(O)n2)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.2 %

Procedure:
12 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 200 mL of tetrahydrofuran, and 100 mL of water was added. To this solution, 16 g of potassium carbonate and 8.1 g of 3-bromopropionyl chloride were added, followed by stirring at room temperature for 5 hours. The aqueous layer was neutralized to the vicinity of pH 2 with 6N hydrochloric acid. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid, which was washed with hexane. Then, this solid was dissolved in 200 mL of toluene, and 100mL of water was added. Then, 3.7 g of potassium permanganate and tetra n-butyl ammonium bromide in a catalytic amount were added, followed by stirring at room temperature for 10 minutes. Then, an insoluble solid was removed by filtration, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the solid was washed with hexane to obtain 8.7 g of pale yellow crystals (melting point: 166-168° C.).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@@H:5]1[C@@H:3]([NH:2][C:49]([C:45]1[CH:44]=[C:43]2[C:48](=[CH:47][CH:46]=1)[N:40]([CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:28]3[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=1)[C:41]([CH3:53])=[C:42]2[CH3:52])=[O:50])[CH3:4])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@H]3CCCN3C(=O)OCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-benzyl 2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[N:12]=[C:11]2[C:13]([C:17]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]4[N:21]=[CH:22][CH:23]=[C:24]([CH:25]=O)[C:19]=4[CH:18]=3)=[CH:14][N:15]([CH3:16])[C:10]2=[CH:9][C:8]=1[O:38][CH3:39].S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.CO>[CH:1]1([NH:4][CH2:25][C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[N:27]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)(=[O:30])=[O:29])[C:17]([C:13]4[C:11]5=[N:12][C:7]([O:6][CH3:5])=[C:8]([O:38][CH3:39])[CH:9]=[C:10]5[N:15]([CH3:16])[CH:14]=4)=[CH:18][C:19]=23)[CH2:3][CH2:2]1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 48 h

Procedure:
To a solution of 0.141 cm3 of cyclopropylamine in 6 cm3 of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C., are added 0.2 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.4 g of sodium sulfate. Stirring is continued for 48 hours at room temperature. 6 cm3 of methanol and 0.031 g of sodium borohydride are added. The reaction medium is stirred at the same temperature for 24 hours. 100 cm3 of dichloromethane are added. The precipitate formed is filtered off and the filtrate is concentrated under reduced pressure and then purified by flash column chromatography (SiO2, dichloromethane/ethyl acetate 80/20 by volume as eluents) to give 0.110 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amine with the following characteristics:
Reaction SMILES: OO.Cl[CH2:4][C:5]([C:7](Cl)(Cl)Cl)=[O:6].[CH:11]1[CH2:18][CH2:17]CCC[CH2:13][CH:12]=1.C(Cl)(Cl)Cl>O>[CH:4]12[O:6][CH:5]1[CH2:7][CH2:13][CH2:12][CH2:11][CH2:18][CH2:17]2
Reactant: C1=CCCCCCC1
Reactant: O=C(CCl)C(Cl)(Cl)Cl
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Product: C1CCCC2OC2CC1
Yield: 83 %

Procedure:
There were added 13.68 parts of a 50% aqueous hydrogen peroxide to a refluxing mixture of 3.92 parts of tetrachloroacetone, 11.58 parts of cyclooctene and 149 parts of chloroform. Water was removed continuously as it was formed, over a period of 4 hours of heating. The removed water was then added to the reaction mixture. The organic phase was then separated from the aqueous phase. Based on VPC analysis there was obtained an 83% yield of cyclooctene oxide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C:12]3([CH3:16])[CH2:15][O:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C(=O)NCc2nccnc2Cl)COC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(c2ncc3c(Cl)nccn23)COC1
Temperature: 25 °C
Yield: 128.7 %

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-3-methyloxetane-3-carboxamide (1.945 mmol, 0.47 g) in dichloromethane (10 ml) cooled in an ice-bath was added pyridine (27.2 mmol, 2.198 ml) and trifluoromethane sulfonic anhydride (11.67 mmol, 1.971 ml). The ice-bath was removed and the reaction was stirred at room temperature. After 2 hours the reaction mixture was cooled in ice-bath, diluted with ethyl acetate (5 mL) and quenched with aqueous sodium hydrogencarbonate. The organic layer separated and the aqueous layer washed four times with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel, ethyl acetate) yielded 8-chloro-3-(3-methyloxetan-3-yl)imidazo[1,5-a]pyrazine (0.56 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[CH3:33]>C1C=CC=CC=1>[Br:1][CH2:33][C:26]1[C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=2)[N:29]=[CH:28][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nccc(C)c2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1ccc2nccc(CBr)c2c1
Reaction time: 5 h
Yield: 19.8 %

Procedure:
N-Bromosuccinimide (0.92 g, 5.2 mmol) and 2,2′-azobisisobutyronitrile (0.095 g, 0.58 mmol) were added to a solution of 6-methoxy-4-methylquinoline (1.0 g, 5.8 mmol) in anhydrous benzene (15 mL) at room temperature, and the mixture was stirred for 5 hours under reflux. Further 2,2′-azobisisobutyronitrile (0.19 g, 1.2 mmol) was added thereto, and the mixture was stirred for 17 hours under reflux. The solvent was evaporated under reduced pressure, and the resulting residue was roughly purified by silica gel chromatography to give 0.26 g of mixture containing the title Reference Compound as green oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=O)=[CH:4][CH:3]=1.[CH2:12]([Mg]Br)[CH3:13]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: OC1(c2ccc(Cl)nc2)CC1
Reaction time: 16 h
Yield: 18.2 %

Procedure:
To a suspension of methyl 6-chloropyridine-3-carboxylate (1 g, 5.83 mmol) in 17 mL anhydrous ether was charged with 3 M ethyl magnesium bromide (8.5 mL, 26 mmol) in ether and stirred for 1 h before the addition of titanium isopropoxide (1.73 mL, 5.84 mmol) to the reaction mixture. The mixture was stirred for 16 h under nitrogen atmosphere. The mixture was quenched with saturated ammonium chloride aqueous solution and aqueous phase was adjusted to pH 3 with 1 N HCl. The mixture was partitioned between DCM and brine. The organic layer was dried over Na2SO4 and concentrated to afford the crude material. The resulting solid was purified by flash chromatography on silica gel, eluting with 10-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a brown greasy solid (180 mg, yield: 18.2%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]([CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n(CC2CCOC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(CC2CCOC2)n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
In a 200 mL round-bottomed flask, to a solution of Example 85C (6.24 g, 13.4 mmol) in ethyl acetate (20 mL) was added hydrogen chloride (4 N in dioxane, 20 mL) and stirred at 20° C. for 2 hour. The reaction was concentrated and triturated with ethyl acetate. The solid was collected and dried to provide the title compound as the hydrogen chloride salt (2.12 g, 61%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (s, 9H) 1.61-1.69 (m, 1H) 1.81-1.89 (m, 1H) 2.73-2.81 (m, 1H) 3.45 (dd, J=8.85, 5.80 Hz, 1H) 3.61-3.67 (m, 3H) 3.78-3.84 (m, 1H) 4.17-4.26 (m, 2H) 5.53 (s, 1H) 7.07 (s, 2H); MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(C(C)=O)C.[CH3:35][O:36][CH2:37][CH2:38]Br>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:21][CH2:22][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:38][CH2:37][O:36][CH3:35])[CH:11]=3)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a suspension of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (519.2 mg, 1.71 mmol), K2CO3, 10 mL of methyl ethyl ketone, and 2 mL of DMF is added 2-bromoethyl methyl ether. The resulting mixture is stirred at 85° C. for 8 h. The mixture is concentrated and the residue is partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase is extracted with additional ethyl acetate (20 mL). The combined organic phases are washed with saturated NaCl, dried over MgSO4, and then the solution is concentrated and the product is washed with diethyl ether to afford 505.0 mg (81.7% yield) of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:17](=O)[CH3:18])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][N+:8]([O-])=O)[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][C:25](N)=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][N:8]([C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)[C:17]=1[CH3:18])=[O:20])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)cn(-c2ccc(F)cc2)c1C
Yield: 52.4 %

Procedure:
A mixture of 2-acetyl-4-nitro-3-phenyl-butyric acid ethyl ester (4.26 g, 14.3 mmol), 4-fluoroaniline (1.75 g, 15.73 mmol), and TsOH monohydrate (136 mg, 0.72 mmol) in toluene (40 mL) was refluxed overnight, while the generated water was collected with a Dean-Stark distillation head; then the reaction was cooled, diluted with EtOAc, washed with diluted sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution respective, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title compound (2.422 g); ESI MS (m/z): 324 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13](Cl)=[O:14])=[CH:12][C:6]=2[N:5]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:4][CH2:3]1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:26]([NH:30][C:13]([C:11]1[CH:10]=[CH:9][C:7]2[S:8][C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][N:5]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:12]=1)=[O:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)Cl)ccc2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CCC(C)(C)S2
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.4 %

Procedure:
To a biphasic mixture of 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carbonyl chloride (30 mg, 0.076 mmol) in DCM (2 mL) and saturated aqueous NaHCO3 (2 mL) was added tert-butylamine (25 μL, 0.236 mmol). The reaction was stirred at room temperature for 72 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The biphasic mixture was extracted with DCM (3×2 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of Hexanes with 5-50% EtOAc to provide N-tert-butyl-2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxamide (26.3 mg, 0.052 mmol, 68.2% yield) as an off white solid. LCMS (+ESI) m/z=432.9 [M+H]+; 1H-NMR (CDCl3) δ 7.73-7.70 (m, 2H), 7.68-7.63 (m, 2H), 7.55 (tt, 1H), 7.49 (d, 1H), 7.47-7.41 (m, 2H), 5.89 (s, 1H), 3.77 (br s, 1H), 1.88 (br s, 2H), 1.46 (s, 9H), 1.12 (br s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3Cl)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)/[CH:3]=[O:4].[CH:13](OC)(OC)OC>ClCCl.C(OCC)C>[CH3:13][O:4][CH:3]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([CH3:12])[CH:8]=2)[CH:5]=[C:2]1[CH3:1]
Reactant: COC(OC)OC
Reactant: C/C(C=O)=C\c1ccc(C)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC1C(C)=Cc2ccc(C)cc21
Reaction time: 1 h
Yield: 59 %

Procedure:
Anhydrous FeCl3 (2.0 g, 12.3 mmol.) was added to a solution of (2E)-2-methyl-3-(4-methylphenyl) -2-propenal (5.0 g, 31.3 mmol.) and trimethyl orthoformate (36.4 g, 34.3 mmol.) in dichloromethane (35 ml). The dark red solution was stirred for one hour, then diluted with 100 ml of diethyl ether and washed with water (3×75 ml). The organic phase was dried (MgSO4), filtered and concentrated. Kugelrohr distillation (65-80° C., 20 mTorr) yielded 3.2 g (18.4 mmol., 59% yield) of the title compound.