Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:22][OH:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:23][CH2:22][C@@H:13]2[CH2:14][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (28.8 g: 77 mmole) in dichloromethane (150 ml) under ice cooling, p-toluenesulfonyl chloride (19.11 g: 1.3 eq.), triethylamine (10.4 ml: 1.3 eq.) and dimethylaminopyridine (0.94 g: 0.1 eq.) are added. The mixture is stirred at 25° C. for 7 hours. The reaction mixture is diluted with ice water. The resultant organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from n-hexane to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (37.7 g). Yield: 93%. NMR δ(CDCl3) ppm: 2.20 to 2.50(m, 1H), 2.44(s, 3H), 3.05(s, 3H), 3.45 to 4.60(m, 5H), 5.18(s, 2H), 5.26(br s, 1H), 7.34(d, J=8 Hz, 2H), 7.50(d, J=8 Hz, 2H), 7.75(d, J=8 Hz, 2H), 8.23(d, J=8 Hz, 2H). IR ν (CHCl3) cm-1 : 1700, 1599.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.[CH3:26][N:27]([CH:29]=O)[CH3:28].P(Cl)(Cl)Cl>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[ClH:10].[CH3:26][N:27]([CH:29]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12)[CH3:28]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)C=N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
To a solution of 12.8 g. (31.5 mmole) of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride in 115 ml. of dry DMF were added with stirring 10.4 g (6.5 ml., 72 mmole) of phosphorus trichloride. The reaction mixture was stirred at room temperature for about 2 days and was then dispersed in a mixture of 5% aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and treated with 1 N hydrochloric acid. The title compound precipitated from solution and was filtered and dried under vacuum. There were obtained 11.3 g. (67% yield) of the salt.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH:24]=[CH:25]1)[CH2:20][CH2:19]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
17β,19-Dihydroxy-4-androsten-3-one dipropionate and dichlorodicyanobenzoquinone are refluxed in anhydrous dioxane for a period of 48 hours. The mixture is cooled and filtered and the filtrate concentrated under vacuum. Methylenechloride is added and the resulting mixture filtered. The filtrate is washed well with water, dried over sodium sulfate and the solvent removed. Chromatography of the residue on silica gel and elution with methylenechloride provides a solid which is crystallized from an acetone-hexane solution to yield the desired 17β,19-dihydroxy-1,4-androstadien-3-one dipropionate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[CH2:40]([CH2:42][NH2:43])[OH:41]>C(OCC)(=O)C>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:43][CH2:42][CH2:40][OH:41])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: NCCO
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
A mixture of 28.6 g (56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 50 ml dimethyl sulfoxide and 50 ml (830 mmol) ethanolamine was stirred at 140° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 200 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The aqueous layers were extracted with two 200-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of 150 ml diisopropyl ether and 150 ml heptane to give 29.1 g (93%) of the title compound as white crystals. M.p. 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2cc(Cl)ccc2n1CCCO
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 6.5 parts of 5-chloro-2-methyl-1H-benzimidazole-1-propanol and 120 parts of trichloromethane are added dropwise 12 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the mixture is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromaethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1-(3-chloropropyl)-2-methyl-1H-benzimidazole.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.O1CCOCC1.[NH:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]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.O>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:41]4[CH:42]=[N:38][NH:39][CH:40]=4)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
Reactant: OB(O)c1cn[nH]c1
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: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]c4)ccc32)c1Br
Yield: 44 %

Procedure:
342 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline are introduced into 13 ml of 1,4-dioxane. 74 mg of 4-pyrazoleboronic acid, 77 mg of Pd(PPh3)4 and 165 mg of sodium carbonate are added. The mixture is heated at reflux for 4 h 30 min. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 136 mg of 3-bromo-5-(2,6-difluorophenyl)-7-(1H-pyrazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white foam), which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[N:30]=[CH:29][C:28]([N:31]([CH2:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])[CH2:36][CH2:35]3)[CH3:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH2:46]=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:20])[CH3:21])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[CH2:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([N:40]4[CH2:41][C:42](=[O:43])[N:44]([CH3:46])[CH2:45]4)[CH2:38][CH2:39]3)=[CH:29][N:30]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)CN[C@H]1CC[C@H](CN(C)c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)nc2)CC1
Reactant: C=O
Solvent: CCO
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(N(C)C[C@H]3CC[C@H](N4CC(=O)N(C)C4)CC3)cn1)C(=O)C2

Procedure:
The mixture of Example 122 (38 mg, 0.061 mmol) and formaldehyde (0.046 ml, 37% solution, 10 eq, 0.612 mmol) was heated for 15 h in EtOH (1 mL) at 80° C. The reaction mixture was concentrated to dryness and the residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH 9: 1] 1:0→0:1) yielding the title compound as a colorless solid (31 mg, 0.048 mmol, 79%). HPLC: FtRet=1.236; LC-MS: m/z 646.4 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].CCO>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN=[N+]=[N-])c3ccccc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
tert-Butyl 6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.174 g, 0.490 mmol) was dissolved in 1:1 EtOAc:EtOH (4 mL). 10% Pd/C (0.0543 g) was added, then the reaction mixture was stirred at rt under H2 for 2 h. The reaction mixture was filtered through celite and the celite pad was carefully washed with EtOAc. The filtrate was concentrated to give tert-butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.153 g) in 95% crude yield. 1H NMR (300 MHz, CDCl3) δ 1.51, 2.99-3.10, 3.67-3.80, 4.17, 7.12, 7.19, 7.32, 7.50.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[O:31])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:38][CH:39]=2)[C:21]2[CH:20]=[CH:19][C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 3-cyanophenylisocyanate dissolved in 500 μL dichloroethane was added to the above resin bound 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg). Shaking the mixture for 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×1 mL THF and 3×1 mL dichloromethane afforded the resin bound title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:11][SiH:12]([CH3:17])N[SiH](C)C>>[C:1]1([C:7]#[C:8][CH2:9][O:10][SiH:12]([CH3:17])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[SiH](C)N[SiH](C)C
Reactant: OCC#CC1=CCCCC1
Product: C[SiH](C)OCC#CC1=CCCCC1
Yield: 176 %

Procedure:
3-Cyclohexenylprop-2-yn-1-ol (2.509 g, 26.10 mmol) and 1,1,3,3-tetramethyldisilazane (1.527 g, 11.45 mmol) were used according to the method mentioned above to produce the title compound as a brown clear liquid (3.916 g, 20.15 mmol, 77.2%). The crude reaction mixture was analyzed by 1H NMR to confirm the product formation and used in KOtBu catalyzed transhydrosilylation reaction.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Li]CCCC.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].Cl>C1COCC1.O>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:25]([O:26][CH2:27][CH3:28])=[O:29])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cnccc32)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2cnccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of compound 6-b (10 g, 367 mmol) in dry THF (150 mL) was cooled to −70° C. and n-BuLi (CAS 109-72-8) (2.5 M in hexane, 16.7 mL, 41.9 mmol) was added dropwise under N2. The mixture was stirred at −78° C. for 1 hour and then ethyl carbonochloridate (CAS 541-41-3) (fresh redistilled, 4.2 mL, 44 mmol) was added dropwise at −70° C. The mixture was warmed to 20° C. naturally and stirred at 20° C. for 1 hour. Then water (800 mL) was added. The mixture was acidified to pH=4 to 5 with a 1N HCl aqueous solution and extracted with ethyl acetate (400 mL×2). Then the pH of the aqueous layer was adjusted to pH=8 by addition of NaHCO3. The resulting mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was washed with tert-butylmethyl ether. The solid was dried under high vacuum. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (3:2). After evaporation of the fractions, 6-c is obtained (6 g, 47%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]2[S:24][C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:17][C:7]=2[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c2c(c1O)Nc1ccccc1S2
Reaction time: 2 h

Procedure:
To a solution of 3,5-di-t-butyl-1,2-benzoquinone (2.2 g) in methanol (15 ml) cooled in an ice bath was added 2-aminothiophenol (1.38 g) and the mixture was stirred for 2 hours. A solid precipitate was filtered off and crystallized from heptane to yield the title compound m.p. 202°-212° (dec.). From the methanol filtrate there was obtained, after chromatography and crystallization, an additional crop of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:46][S:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Yield: 98.3 %

Procedure:
Suspend trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (12.5 g, 24 mmol) in dry methylene chloride (100 ml). Add diisopropylethylamine (8.3 mL, 48 mmol). Slowly add methanesulfonyl chloride (2.7 mL, 36 mmol). Pour reaction into saturated aqueous sodium bicarbonate after 20 minutes and extract with methylene chloride. Wash the organic layer with water, dry with sodium sulfate, filter and concentrate in vacuo to yield 14.2 g (99%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(#N)C>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([O:12][CH3:13])=[O:14])=[CH:8][CH:9]=1)(=[O:25])=[O:24]
Reactant: COC(=O)Nc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Yield: 89.4 %

Procedure:
6.0 g (30.7 mmole) methyl N-[4-(2-hydroxyethyl)phenyl]carbamate was dissolved in acetonitrile. 6.17 g (61 mmole) triethylamine and 7.0 g (61 mmole) methanesulfonyl chloride were added. The mixture was stirred until completion, then the solvent was evaporated in vacuo, water was added to the residue and the product was extracted with dichloromethane to give 7.5 g (yield 89.4%) of 4-[(methoxycarbonyl)amino]phenethyl methanesulfonate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH:15]([O:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([CH3:17])[CH3:16]
Reactant: COc1cc(CCN)ccc1O
Reactant: CC(C)Oc1cccc(-c2ccnc(Cl)n2)c1
Product: COc1cc(CCNc2nccc(-c3cccc(OC(C)C)c3)n2)ccc1O

Procedure:
Intermediate 45 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.36 (m, 1H) 6.9 (m, 2H) 6.83 (m, 1H) 6.72 (m, 2H) 5.5 (m, 1H) 4.62 (m, 1H) 3.75 (s, 3H) 3.7 (m, 2H) 2.88 (m, 2H) 1.32 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20]N1C(=O)CCC1=O.O>C1COCC1>[Cl:20][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Cl)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.00 g, 7.84 mmol) in THF (30 mL) at −78° C. was slowly added n-butyllithium (4.0 mL, 2.5 M in hexane). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-chlorosuccinimide (1.26 g, 9.40 mmol) in THF (30 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (2% ethyl acetate/heptane) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C@:15]([C:28]#[N:29])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni].O>[C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C@:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH2:28][N:29]=2)=[CH:9][C:8]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Alternatively, the title compound can be obtained by carrying out the following experiment: To a vigorously stirred solution of 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (150 mg) in ethanol (9 mL) was added Raney Nickel (1.44 g, 50% suspension in water, previously washed with dry ethanol) and the reaction was stirred at room temperature under hydrogen (1 atm) for 2 hours then under arong overnight. Then the solution was filtered over celite, and the resulting filtrate was concentrated in vacuo to give the title compound (138 mg) as a pale yellow oil. The crude product was purified by flash chromatography (15% dichloromethane in ethyl acetate) to afford 4-[(R)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid tert-butyl ester as a pale yellow oil (0.070 g). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 5.93 minutes (major enantiomer), 8.57 minutes (minor enantiomer).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: C1CCNCC1
Product: O=C(c1cc2ccccc2[nH]1)N1CCCCC1
Yield: 100 %

Procedure:
Treat 5-fluoro-1H-indole-2-carboxylic acid 3 (X═F, 1.7 g, 9.5 mmol) with piperidine as described in General Synthetic Procedure VIa to afford 5-fluoro-1H-indol-2yl-piperidin-1-yl-methanone 8 (X═F, R4=piperidin-1-yl; 2.3 g, 100%) as a white solid. 1H NMR (DMSO-d6) δ 11.7 (brs, 1H), 7.5-7.3 (m, 2H), 7.1-7.0 (m, 1H), 6.7 (s, 1H), 3.7 (m, 4H), 1.7-1.5 (m, 6H). Treat 5-fluoro-1H-indol-2yl-piperidin-1-yl-methanone (125 mg, 0.51 mmol) with 2-aminophenyldisulfide (347 mg, 1.4 equiv.) as described in General Synthetic Procedure VIIa to afford the title compound Iac (92 mg, 25%) as an ivory-colored solid, m/z=369 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: Fc1ccccc1-c1cccnc1
Reactant: COB(OC)OC
Product: OB(O)c1cccc(-c2cccnc2)c1F

Procedure:
3-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 31 to give 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).