Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.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>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccccc4)cc23)c1F
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To 5-bromo-3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (32, 55.0 mg, 0.10 mmol) in tetrahydrofuran (10 mL) were added 1.0 M potassium carbonate in water (3.5 mL), phenylboronic acid (18.8 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) under an atmosphere of nitrogen. The reaction was stirred at 65° C. for 3 hours, and then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude compound 33 that was used in the next step.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[O:8]>>[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])([OH:8])[C:1]#[CH:2]
Reactant: C#C[Mg]Br
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: C#CC(O)(C(F)(F)F)C(F)(F)F

Procedure:
To a 100 ml solution of ethynyl magnesium bromide (0.5 M in THF) in an acetone-ethanol dry ice bath was bubbled hexafluoro acetone gas (6.1 g, 36.7 mmol) over 2 h. The reaction mixture was warmed to r.t and then refluxed for 0.5 h. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ether. The combined organic phases were washed with brine, and dried over MgSO4. A liquid mixture of 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol with THF at b.p. 100-103° C. (4.7 g, contained about 68 mol % THF) was obtained by distillation (12 inch Vigreux column).
Reaction SMILES: [Cl:1][CH:2]([F:19])[C:3]([F:18])([F:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[OH:16])=[O:5].[H][H]>[Ni].C(O)C>[Cl:1][CH:2]([F:19])[C:3]([F:17])([F:18])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[OH:16])=[O:5]
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)C(F)(F)C(F)Cl
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1

Procedure:
In an autoclave 267 g (0.895 mole) of compound (b), 18 ml of Raney-nickel suspension, and 1.3 l of ethanol were placed. The nitro group was reduced with hydrogen at a temperature of 65°-70° C. and an initial pressure of 100-105 bar. After 90 min the required amount of hydrogen had been taken up. The solution was let off and after filtering of the Raney nickel concentrated by evaporation. The dry residue was dissolved in 310 ml of boiling methanol, filtered, and diluted with 360 ml of water.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:10]1[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1O)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1O)C2
Yield: 82.4 %

Procedure:
A mixture of 7-(2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g), concentrated hydrochloric acid (0.048 ml), water (0.048 ml) and ethanol (10 ml) was refluxed for 4 hours and cooled. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure. The resulting crystals were washed with ethanol, while heating, to give 5-guanidinoimino-7-(2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 68) (0.09 g) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]1[S:37]([CH3:40])(=[O:39])=[O:38])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[CH2:30]([C:10]1[C:11]2[C:16](=[C:15]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:43]([OH:45])([C:42]([F:47])([F:46])[F:41])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(S(C)(=O)=O)n(C(=O)OC(C)(C)C)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1[nH]c2c(N3CCNCC3)cccc2c1Cc1ccccc1

Procedure:
To a solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester (277 mg) in CH2Cl2 (10 ml) was added MCPBA (296 mg) at 0° C. The reaction was allowed to warm up to room temperature overnight. After adding 150 mg of PPh3, the reaction was stirred for another 30 minutes and was then poured into a mixture of EtOAc/H2O. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting residue was purified by flash chromatography to give 3-Benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methanesulfonyl-indole-1-carboxylic acid tert-butyl ester as yellow solid. MS: (M+H)+ 570.4. 3-Benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methanesulfonyl-indole-1-carboxylic acid tert-butyl ester was then dissolved in dichloromethane and treated with trifluoroacetic acid to give 3-benzyl-2-methanesulfonyl-7-piperazin-1-yl-1H-indole as a TFA salt, MS: (M+H)+ 370.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[Br:10]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:10][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cc2cn[nH]c2cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1n[nH]c2cnccc12
Yield: 66.7 %

Procedure:
1H-pyrazolo[3,4-c]pyridine (1 g), bromine (1.33 g), and water (40 mL) were stirred for 1 h. Basification with 20% sodium hydroxide solution, and adjustment to pH 7 by addition of acetic acid, yielded 3-Bromo-1H-pyrazolo[3,4-c]pyridine (1.1 g, 67%). ESI MS m/z=275 (M+1)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2occc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4occc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzofuran-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.20 (dd, J=2.0, 1.0 Hz, 1 H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 7.91 (dt, J=8.6, 1.0, 0.8 Hz, 1 H), 8.14-8.24 (m, 2 H), 8.47 (dt, J=7.9, 2.0 Hz, 1 H), 8.60 (d, J=1.4 Hz, 1 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.28 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH3:25])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:2]1([CH3:25])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]3[CH:12]([CH2:13][N:14]([C:40](=[O:41])[CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CNCC32)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(C(=O)Cc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.2 %

Procedure:
A suspension of (3aRS,7aRS)-7,7-bis-(3-tolyl)-4-perhydroisoindolone hydrochloride (1.5 g) in dichloromethane (30 cc) cooled to +4° C. is treated with triethylamine (1.15 cc) and then with phenylacetyl chloride (0.63 g). The reaction mixture is stirred for 5 hours at 25° C. and then washed with water (3×100 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized twice from acetonitrile to give (3aRS,7aRS)-7,7-bis-(3-tolyl)-2-(phenylacetyl)-4-perhydroisoindolone (0.36 g). m.p.=207° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][C@H:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14](C(=O)C)[C:15]=2[CH:16]=1)[CH3:2].N>C1COCC1.CO>[CH2:1]([C:3]12[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@]12CCC3(C[C@H]1CCOc1cc4c(cnn4C(C)=O)cc12)OCCO3
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCC12CCC3(CC1CCOc1cc4[nH]ncc4cc12)OCCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of rac-1-((4aR,12bS)-12b-ethyl-1,4,4a,5,6,12b-hexahydro spiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolan]-9(2H)-yl)ethanone (89, R2=Ethyl) (3.02 g, 8.15 mmol) in a mixture of THF (54 mL) and MeOH (27 mL) was treated with ammonia (7 M in MeOH, 3.49 mL, 24.5 mmol) and stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to give rac-(4aR,12bS)-12b-ethyl-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (90, R2=Ethyl) (2.68 g, 100%). The material was used without further purification. LC/MS, method 3, 2.09 min, MS m/z 329 (M+1)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.33-4.24 (m, 1H), 4.00-3.84 (m, 4H), 3.75-3.64 (m, 1H), 2.79-2.66 (m, 1H), 2.51-2.40 (m, 1H), 2.33-2.19 (m, 2H), 2.09-1.98 (m, 1H), 1.88-1.78 (m, 1H), 1.76-1.29 (m, 5H), (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([NH2:30])=[O:29]>CN(C)C=O.ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: NC(=O)CBr
Reactant: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 216 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.28 g, Example 30), potassium carbonate (0.16 g) and 2-bromoacetamide (0.16 g) was stirred together at ambient temperature in dry dimethyl formamide (5 ml) for 4 days and then allowed to stand at ambient temperature for 9 days. The mixture was diluted with dichloromethane (50 ml) and washed with 1M aqueous sodium hydroxide solution and then with water. Some insoluble material which remained throughout the extractions was collected by filtration. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 2-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]acetamide, m.p. 247-248° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][O:15][CH2:16][CH:9]2[CH2:10][O:11][CH2:12]3)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][O:24][CH2:25][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH:22]12[N:17]([C:4]3[N:5]=[C:6]([N:8]4[CH:13]5[CH2:14][O:15][CH2:16][CH:9]4[CH2:10][O:11][CH2:12]5)[N:7]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=4)[N:3]=3)[CH:18]([CH2:25][O:24][CH2:23]1)[CH2:19][O:20][CH2:21]2
Reactant: Clc1nc(N2C3COCC2COC3)nc(N2C3COCC2COC3)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nc(N3C4COCC3COC4)nc(N3C4COCC3COC4)n2)cc1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
To a 10 mL vial were added 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg, 0.61 mmol), Pd(PPh3)4 (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na2CO3 aqueous solution (0.305 mL). The resulting mixture was heated at 120° C. for 20 minutes in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline as a white solid (120 mg).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[Br:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 27 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.62 g, 4.16 mol) in methanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The reaction mixture was stirred at 25° C. for 27 h. The reaction mixture was concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×400 mL). The organic layer was washed with water (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.39 g, 89%) as a white solid which was used without further purification: mp 149-150° C.; FAB-HRMS m/e calcd for C15H19BrO4S (M+H)+ 375.0266, found 375.0274.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20]>CC#N>[CH2:17]([O:18][CH2:19][CH2:20][O:14][C:6]1[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:16]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Reactant: CCOCCBr
Solvent: CC#N
Product: CCOCCOc1cc(N)ccc1C(C)(C)C

Procedure:
3-(2-Ethoxyethoxy)-4-tert-butylbenzenamine (C-3) was synthesized following the general scheme above starting from 2-tert-butyl-5-nitrophenol (C-1-a) and 1-bromo-2-ethoxyethane. 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=7.9 Hz, 1H), 6.17 (s, 1H), 6.14 (d, J=2.3 Hz, 1H), 4.00 (t, J=5.2 Hz, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.53 (q, J=7.0 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J=7.0 Hz, 3H); HPLC ret. time 2.55 min, 10-99% CH3CN, 5 min run; ESI-MS 238.3 m/z (MH+).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([O-:19])=[O:18])=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of 5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylbenzoate 103 (7.13 mmol, 2.5 g) in THF (30 mL), lithium hydroxide (28.5 mmol, 0.683 g) in (20 mL) water was added and the reaction was stirred overnight at 40° C. The reaction mixture was acidified with 2N HCl solution and extracted with ethyl acetate (2×). Organic layer was washed with 2N NaOH (3×), aqueous layer was acidified with 2N HCl solution and the milky mixture was extracted with ethyl acetate (3×), dried and concentrated under reduced pressure. Crude product was triturated with ACN to give 5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylbenzoic acid 104 (550 mg, 23%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.50 (s, 3H), 7.30 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.90 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 10.40 (s, 1H). (m/z)=323 (M+H)+.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-])=O)=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=1>C(O)C>[Br:4][C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([NH2:17])=[CH:7][CH:6]=1
Reactant: COCCCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COCCCNc1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
78.57 g of tin(II) chloride are added to a solution of 21.01 g of (5-bromo-2-nitrophenyl)-(3-methoxypropyl)amine in 950 ml of ethanol. The reaction mixture is heated to reflux for 12 hours. The mixture is cooled to room temperature and concentrated by evaporation. The residue is treated with 2M NaOH until a pH of 11 has been attained. The mixture is extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue. Rf=0.31 (1:1 EtOAc-heptane). Rt=3.06 (gradient I).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C)C=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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:20]=[CH2:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (3.0 g, 8.9 mmol), tributyl-vinyl-stannane (3.9 mL, 13.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (514 mg, 0.445 mmol) in N,N-dimethylformamide (10 mL) was stirred at 85° C. for 15 h. The mixture was cooled to 25° C., extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, hexanes to 15% ethyl acetate/hexanes) to afford 1-benzenesulfonyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine (2.2 g, 87%) as a white solid: LC/MS m/e calcd for C15H13N2SO2 [M+H]+ 285.34, observed 285.2; 1H NMR (400 MHz, CDCl3) δ ppm 5.32 (d, J=11.0 Hz, 1H), 5.78 (d, J=17.6 Hz, 1H), 6.59 (d, J=4.0 Hz, 1H), 6.77 (dd, J=11.0 Hz, J=17.6 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.74 (d, J=4.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 8.19 (m, 2H), 8.46 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(O)CS
Reactant: N#Cc1ccc(F)cc1Cl
Product: CC(O)CSc1ccc(C#N)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 2-chloro-4-(2-hydroxypropylthio)benzonitrile. 2.5 g of 2-chloro-4-(2-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxypropylthio)benzoic acid. 2.1 g of 2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.2 (M)+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=[C:44]([S:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56](=[O:67])[NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=O)[CH:51]=4)(=[O:49])=[O:48])[CH:45]=3)[N:40]=[CH:39][C:38]=2[C:69]([NH2:71])=[O:70])[CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:9]([O:8][C@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH2:6][NH:5][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][NH:57][C:56]([C:52]1[CH:51]=[C:50]([S:47]([C:44]2[CH:45]=[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=2)[N:40]=[CH:39][C:38]([C:69]([NH2:71])=[O:70])=[C:37]3[NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)(=[O:48])=[O:49])[CH:55]=[CH:54][CH:53]=1)=[O:67])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Glacial acetic acid (0.005 mL, 0.089 mmol) and Intermediate 2 (50 mg, 0.149 mmol) were added to a stirring solution of Intermediate 112 (55 mg, 0.089 mmol) in DMF (2 mL) at rt. The resulting solution was stirred for 3 h, then NaBH(OAc)3 (57 mg, 0.267 mmol) was added in portions. The reaction mixture was stirred over night then poured into said. NaHCO3 (40 mL). The precipitate was filtered, washed with H2O (50 mL), and dried to give the title compound (76 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C50H63N6O8SSi+ 935.4. Found m/z=935.4 (M+H+).