Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C(O)(=O)CS.[N+](C1C=CC=CC=1S([N:20]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:41]=[CH:40][C:28]2[N:29]([CH3:39])[C:30](=[O:38])[C:31]([CH3:37])([CH3:36])[C:32](=[O:35])[N:33]([CH3:34])[C:27]=2[CH:26]=1)(=O)=O)([O-])=O>CN(C=O)C>[CH3:39][N:29]1[C:30](=[O:38])[C:31]([CH3:37])([CH3:36])[C:32](=[O:35])[N:33]([CH3:34])[C:27]2[CH:26]=[C:25]([O:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:42][CH2:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[CH:41]=[CH:40][C:28]1=2
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
Lithium hydroxide (0.36 g, 15 mmol) and thioglycolic acid (0.48 ml, 6.9 mmol) were added to a DMF solution (20 ml) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide (2.05 g, 3.4 mmol), and stirred at room temperature for 3 days. The reaction mixture was added to ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→dichloromethane:methanol=10:1→4:1). The purified product was concentrated under reduced pressure to thereby obtain 1.13 g (yield: 81%) of 1,3,3,5-tetramethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34](O)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:70][CH:71]1[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]1>CN(C=O)C.C(OCC)(=O)C>[C:80]([O:79][C:77]([N:74]1[CH2:73][CH2:72][CH:71]([NH:70][C:34]([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:32][CH3:33])[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:35])[CH2:76][CH2:75]1)=[O:78])([CH3:83])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid (4.4 g, 9.2 mmol), diisopropylethylamine (3.2 ml, 18.3 mmol) and HBTU (5.2 g, 13.7 mmol) in anhydrous DMF (44 ml) was charged 4-amino-1-N-Boc-piperidine (2.3 g, 11.4 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were then dried (Na2SO4), filtered and evaporated to yield 4-[(4,6-bis-benzyloxy-5′isopropyl-2′methoxy-biphenyl-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a brown solid (6.1 g, quant.), carried forward without further purification. M.p.: 168-170° C.; 400 MHz 1H NMR (CDCl3) δ: 8.16 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.42 (s, 4H), 7.34-7.26 (m, 6H), 7.18 (dd, J=8.4, 2.0 Hz, 1H), 7.14 (s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 5.12 (s, 2H), 5.05 (s, 2H), 4.07 (m, 1H), 3.73 (s, 3H), 3.56 (br s, 2H), 2.90 (m, 2H), 1.78 (d, J=7.2 Hz, 2H), 1.57 (s, 1H), 1.47 (s, 9H), 1.24 (d, J=7.2 Hz, 6H), 1.08 (m, 2H); LCMS: 576 [M+H].
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:19])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C>[O:17]=[C:16]1[CH:15]=[CH:14][C:13](=[O:18])[N:12]1[CH2:11][CH2:10][C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:19]
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: NCCCCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCCCNC(=O)CCN1C(=O)C=CC1=O
Temperature: 25 °C

Procedure:
3-(2,5-Dioxo-2,5-dihydropyrrol-1-yl)propionic acid 2,5-dioxopyrrolidin-1-yl ester (787 mg, crude) was dissolved in DMF (15 ml). 8-Aminooctanoic acid (350 mg) and DIPEA (0.45 ml) was added. The mixture was stirred under nitrogen at room temperature over night. The mixture was concentrated. The residue was dissolved in EtOAc and extracted with 0.1 N HCl (2×). The phase separation was not easy. The organic layer was washed with brine (2×), dried (Na2SO4) and concentrated to give a white solid. LC-MS, M/z: 311.34 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:12]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH2:43][O:44][CH3:45])[CH:39]=[CH:38][C:37]=1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:12]1[C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:34][O:33][CH3:32])=[CH:41][C:40]=1[O:42][CH2:43][O:44][CH3:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(B(O)O)c(OCOC)c1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOCc3ccccc3)c2n1
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCOCc3ccccc3)c2n1
Temperature: 110 °C
Yield: 98.9 %

Procedure:
To a suspension of ethyl 1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (592 mg, 1.22 mmol) and 2,4-bismethoxymethoxyphenylboronic acid (384 mg, 1.59 mmol) obtained in the same manner as in Example 2-1, Step 2 in 1,2-dimethoxyethane (12 ml) and water (6 ml) were added lithium chloride (155 mg, 3.66 mmol), sodium carbonate (388 mg, 3.66 mmol) and tetrakis(triphenylphosphine)palladium (141 mg, 0.12 mmol), and the mixture was stirred with heating at 110° C. for 2.5 hr. The reaction mixture was allowed to cool to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give ethyl 1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (727 mg, yield 99%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([OH:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH2:16](N(CC)CC)C.IC>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)O
Reactant: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.4 g (0.076 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfinic acid are suspended in 120 ml of acetone, and 13.3 ml (0.095 mol) of triethylamine and 8.5 ml (0.12 mol) of iodomethane are added. The mixture is stirred at room temperature for 2 hours and then poured onto ice-water. The precipitate which separates out is filtered off with suction and recrystallized from N-butanol.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1)(C)C.[SiH](CC)(CC)[CH2:21][CH3:22].C(=O)C.C([O-])(O)=O.[Na+]>CC#N>[CH2:21]([O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)[CH3:22]
Reactant: CC[SiH](CC)CC
Reactant: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CC[C@H](OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis/trans Ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 35 g, 122 mmol) was dissolved in CH3CN (250 mL) and Et3SiH (1.2 eq., 146 mmol, 23 mL), BiBr3 (4% mol, 4.9 mmol, 2.2 g) were added portionwise at room temperature followed by acetaldehyde (1.2 eq., 8.2 mL) that was slowly added at 25° C. The mixture was stirred at room temperature for 1 hour. The mixture was subsequently poured onto an aqueous saturated solution of NaHCO3 and the mixture obtained was then extracted with EtOAc (3×). Organics were combined, washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude mixture that was purified by silica chromatography (Biotage 65i column, EtOAc-nhex) to afford the title compound, 21 g, 87%.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:21]Br>ClCCl.II>[Br:21][CH:17]1[CH2:16][CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:19][C:18]1=[O:20]
Reactant: BrBr
Reactant: O=C1CCCCC(c2ccccc2)N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)CCCC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Phosphorus pentachloride (4.95 g, 23.8 mmol) was added to a solution of 7-phenylazepan-2-one (4.50 g, 23.8 mmol) in dichloromethane (75 mL) at 0° C. After 1 h, iodine (0.060 g, 0.24 mmol) and a solution of bromine (1.22 mL, 23.8 mmol) in dichloromethane (10 mL) were added sequentially and the mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction was quenched with aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (4.91 g). MS 268 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH:24]=[CH:25][C:26]([N+:38]([O-:40])=[O:39])=[C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:23]3[CH:24]=[CH:25][C:26]([N+:38]([O-:40])=[O:39])=[C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH:28]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)ccc1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4′-benzyloxybiphenyl-4-ol (11.07 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (11.5 g), sodium hydride (55 wt. %, 2.2 g) and anhydrous N,N-dimethylformamide/anhydrous tetrahydrofuran/anhydrous toluene=1/1/1 (360 ml) and the reaction mixture was purified to give the title compound (14.75 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16](=[O:18])[CH3:17].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][CH2:17][C:16]([C:3]1[C:4]([CH3:15])=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[CH3:1])=[O:18]
Reactant: CC(=O)c1c(C)cc(Oc2ccccc2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccccc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 1-(2,6-dimethyl-4-phenoxyphenyl)ethanone (3.60 g, 15.0 mmol) in acetonitrile (30 mL) was added tetrabutylammoniumtribromide (TBABr3, 7.95 g, 15.0 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,6-dimethyl-4-phenoxyphenyl)ethanone (4.8 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].C1(C(C2C=CC=CC=2)N2CCNCC2)C=CC=CC=1.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Al+3].S1C=CC=C1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:15]1([CH2:14][CH:8]2[CH2:9][C:10](=[O:13])[CH2:11][CH2:12][NH:7]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[O-]
Agent: Cc1cc(C)cc(C(=O)N2CCC(=O)CC2Cc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: c1ccsc1
Product: O=C1CCNC(Cc2ccccc2)C1

Procedure:
A mixture of intermediate 2 (3.2 g), 1-(diphenylmethyl) piperazine (2.5 g) and aluminum tributoxide (2 g) in toluene (250 ml) was hydrogenated for 48 hours at 50° C., with palladium on activated carbon (10%; 2 g) as a catalyst in the presence of thiophene (4% solution; 1 ml). After uptake of hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, upgrading to 90/10). Two pure fractions were collected and their solvent was evaporated, resulting in residue 1 and residue 2. Residue 1 was suspended in DIPE. The precipitate was filtered off and dried, yielding 0.94 g (17%) of (±)-cis-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl) piperidine (compound 12; mp. 100.8° C.). Residue 2 was dried, yielding 0.2 g (3.6%) of (±)-trans-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 13).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C(O)C1CC1
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in ca. 750 ml. of 2:1 ether-hexane during 1 hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice-4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, b.p. 102°-104° C. (80 mm), pmr spectrum (CDCl3): δ2.55 (triplet, --CH2CO--).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1ccc(F)cc1
Yield: 68.5 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 105-107° C., was obtained in 68.5% yield.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([CH2:21]Cl)=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]([SH:27])([CH3:26])[CH3:25]>>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([CH2:21][S:27][C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S
Reactant: CC(C)(C)c1nc2cc(CCl)ccc2n1CC1CCOCC1
Product: CC(C)(C)SCc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in step F of Example 15 from 2-tert-butyl-5-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole (step F of Example 25) and 2-methyl-2-propanethiol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([NH:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:9].[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.CCN(CC)CC>C(Cl)Cl>[N:24]1([CH2:23][C:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[CH:11]([NH:10][C:8](=[O:9])[CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=2)(=[O:40])=[O:39])[CH2:12][CH2:13][CH2:14]3)=[CH2:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-piperidin-2-yl-N-[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide (155.8 mg, 0.39 mmol) in CH2Cl2(2 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (Fluka, 0.1 mL, 0.59 mmol) and Et3N (Aldrich, 0.1 mL, 0.79 mmol). The mixture was stirred at rt overnight, diluted with CH2Cl2 (30 mL), washed with 10% Na2CO3 (twice) and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (3%–10% MeOH—CH2Cl2) to provide the title compound. MS (ESI): 604 (M+H)+. Calc'd for C32H40F3N3O3S—603.27.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>ClCCl>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:5][C:4]=1[C:1](=[O:3])[NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Yield: 95.3 %

Procedure:
Using methyl 3-(3-carboxy-4-methoxyphenyl)-2,2-dimethylpropanoate (204 mg, 0.766 mmol), triethylamine (135 ml, 0.969 mmol), ethyl chlorocarbonate (82.0 ml, 0.843 mmol), 4-(trifluoromethyl)benzylamine (120 ml, 0.842 mmol) and 8 ml of dehydrated dichloromethane and conducting the procedure similar to Example 7, 309 mg (95%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1([F:34])[CH2:21][CH2:20][C:19]([CH2:32][NH2:33])([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH2:32][C:19]1([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][CH2:21][C:16]([F:15])([F:34])[CH2:17][CH2:18]1)=[O:6]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(C(F)(F)F)c1Cl

Procedure:
From 2-chloro-3-trifluoromethylbenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=502.1, tR (minutes, Method F)=3.25
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[S:27][C:26]([C:24]2[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:25]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.3 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as an off-white solid (0.08 g, 16%). MS (ISP) 485.9 [(M+H)+]; mp 189° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C[C:9]=3[O:21][C:4]=2[CH:3]=1.Cl.IC1C=CC2C(CCN)=COC=2C=1>>[C:17]([O:16][C:14](=[O:15])[NH:11][CH2:12][CH2:13][C:8]1[C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[O:21][CH:9]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(I)ccc23)C1
Agent: Cl
Agent: NCCc1coc2cc(I)ccc12
Product: CC(C)(C)OC(=O)NCCc1coc2cc(I)ccc12

Procedure:
Synthesized as described for tert-butyl 7-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 2-(6-iodo-1-benzofuran-3-yl)ethanamine hydrochloride. MS m/z 332 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 2.85 (t, 2H), 3.43 (q, 2H), 4.62 (bs, 1H), 7.31 (d, 1H), 7.39 (s, 1H), 7.54 (dd, 1H), 7.84 (d, 1H).
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH2:7][C:8]#[N:9]>N1C=CC=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:7][C:8]#[N:9]
Reactant: COc1ccccc1C(O)(CC#N)c1ccccc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=CC#N)c1ccccc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Thionyl chloride (4.5 mL) was added to a stirred suspension of beta-hydroxy-beta-(2-methoxyphenyl)-2-methoxybenzenepropanenitrile 13.45 g) in dry pyridine (70 mL) maintained at 10° C. during the addition. The reaction was stirred at room temperature for 2 hours, then was diluted with ice-water and extracted with dichloromethane. The organic extract was washed with 3N HCl (1×150 mL; 1×20 mL) and brine and then was dried (MgSO4) and evaporated. The residue was crystallized from isopropanol-hexane to provide 9.0 g of 3,3-bis(2-methoxyphenyl)-2-propenenitrile, mp 99°-100° C. a portion from the same solvents afforded the analytical sample, mp 100.5°-101.5° C.