Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: COc1ncc(F)cc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 5-fluoro-2-methoxypyridine-3-boronic acid (CAS RN 957120-32-0) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=474.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]1([CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[C@H:27](C)[O:26]1.[C:35](OCC)(=O)C>CN(C)C=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:26])([C@:29]([N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)([S:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[CH3:35])[CH3:27]
Reactant: CCOC(C)=O
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(S[C@@](C)(n2cncn2)[C@](C)(O)c2ccc(F)cc2F)CC1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
In 6 ml of dimethylformamide was dissolved 1-(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2 mmol) as described in Reference example 12, and 86 mg (1.97 mmol) of 55% sodium hydride were added to the solution at 0° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 20 minutes. Then, 503 mg (2.00 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane were added to the reaction mixture and the mixture was stirred at 60° C. for 3 hours. After cooling, ethyl acetate was added to the reaction mixture to dilute it and washed successively with water and a saturated aqueous NaCl solution. An oil obtained by evaporation of the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield: 53%) of the desired compound as an oil.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc2c(ccn2C(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc2c(ccn2C(=O)c2ccccc2)c1
Yield: 67 %

Procedure:
The benzyl 1-benzoyl-1H-indole-5-carboxylate (100 mg) obtained above was dissolved in ethanol, and 5% palladium on carbon (20 mg) was added thereto and stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (50 mg, Y.:66%) as white crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17](OCC(Cl)(Cl)Cl)=O)[N:14]([CH:25]([N+:36]#[C-])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C.[Zn]>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:13](=[O:38])[N:14]2[CH:15]1[S:16][CH:17]=[N:36][CH:25]2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#[N+]C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To a solution of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-isocyanoacetate (2.20 g.) in N,N-dimethylformamide (15 ml.) was added zinc powder (3.30 mg.) at 0° C., and the mixture was stirred at the same temperature for 10 minutes. Thereto was added dropwise acetic acid (2.0 ml.) over a period of 3 minutes and the mixture was stirred at 0° C. for 25 minutes. The reaction mixture was diluted with ethyl acetate (50 ml.) and filtered through a pad of Celite. To the filtrate was added ethyl acetate (50 ml.) and washed with a mixture of 5 to 6% aqueous solution of sodium bicarbonate (60 ml.) and a saturated aqueous solution of sodium chloride (30 ml.), a dilute aqueous solution of sodium chloride (30 ml.×2), a saturated aqueous solution of sodium chloride (30 ml.), water (50 ml.) and a saturated aqueous solution of sodium chloride successively. Drying and removal of the solvent left an amorphous solid (1.51 g.). Chromatography on silica gel (15 g.) with a mixed solvent of methylene chloride and ethyl acetate (5:1 by volume) as an eluent and crystallization from diethyl ether gave benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (750 mg.), mp 141.5°-143.0° C.
Reaction SMILES: C1(C([O-])=O)([C:4]([O:6][CH2:7][CH3:8])=[O:5])CC1.[OH-].[K+].[K].[C:15]1(C([O-])=O)([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]1.BrC[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[CH:38][O:39][CH3:40])[C:34]([O:36][CH3:37])=[O:35]>>[CH2:7]([O:6][C:4]([CH:21]([O:20][C:18]([CH:15]1[CH2:16][CH2:17]1)=[O:19])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:27][C:28]=1[C:33](=[CH:38][O:39][CH3:40])[C:34]([O:36][CH3:37])=[O:35])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)[O-])CC1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: COC(=O)C1(C(=O)[O-])CC1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: CCOC(=O)C(OC(=O)C1CC1)c1ccccc1C(=COC)C(=O)OC
Yield: 66 %

Procedure:
A method similar to Example 1 was used and 7.9 g (50 mmol) of monoethyl cyclopropane-1,1-dicarboxylate (prepared according to Example 5a) were converted with 2.8 g (50 mmol) of potassium hydroxide into the potassium salt of monomethyl cyclopropane-1,1-dicarboxylate, and said salt was then reacted with 10 g (35 mmol) of methyl alpha-[2-(bromomethyl)-phenyl]-beta-methoxyacrylate. The product was purified by distillation. Yield: 66%; bp.: 220° C. at 0.3 mbar; colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>CN(C)C=O>[C:13]([O:16][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=c1cc(CCl)nc2scnn12
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(=O)n2ncsc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (10 g), prepared according to Example 1, was dissolved in dimethylformamide (40 ml) and reacted with anhydrous potassium acetate (10 g) under stirring at room temperature for 20 hours. After dilution with ice water the precipitate was filtered and washed with water to give 7-acetoxymethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (9.7 g) which was hydrolyzed by treatment with 37% HCl (50 ml) in dioxane (100 ml) under stirring at room temperature for 2 hours. The reaction mixture was diluted with acetone and the precipitate was filtered and then treated with aqueous Na2HPO4 : filtration and washings with water until neutral gave 7-hydroxymethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (6.2 g) which was reacted with dicyclohexylcarbodiimide (14.4 g) in benzene (90 ml) and dimethylsulphoxide (25 ml) in the presence of trifluoroacetic acid (1 ml) and pyridine (1.71 ml) under stirring at room temperature for 20 hours. After treatment with oxalic acid bihydrate (3.1 g) at room temperature, the precipitate of dicyclohexylurea was filtered of and the organic solution was evaporated in vacuo to dryness: the residue was purified over a SiO2 column using chloroform: ethyl acetate=95:5 as eluent. The 7-formyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one so obtained (2.5 g) was reacted with the ylide obtained by treatment of triphenylphosphonium-benzyl chloride (2.94 g) with 50% NaH (0.43 g), in dimethylsulphoxide (40 ml) at room temperature for 22 hours. After dilution with ice water the precipitate was filtered and washed with water: crystallization from CH2Cl2 -ethanol gave 2.1 g of 7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 216°-218° C.
Reaction SMILES: CC(=C(C)C)C.B.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([C@H:27]([CH3:30])[CH:28]=[CH2:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C[O:34]CC1>>[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([C@H:27]([CH3:30])[CH2:28][CH2:29][OH:34])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=C[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: B
Agent: CC(C)=C(C)C
Product: C[C@H](CCO)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a 0° C. solution of 2,3-dimethyl-2-butene in THF (43.2 mmol, 1.0 M) is added a solution of borane in THF (43.2 mmol, 1.0 M) dropwise over 20 min. After stirring an additional 60 min at 0° C., tert-butyl (2S,3R)-2-benzyloxycarbonylamino-3-methyl-4-pentenoate (13.15 g, 41.2 mmol) in 20 mL THF is added dropwise, and the resulting solution is allowed to come to 25° C. over 60 min. The solution is cooled again to 0° C. and quenched with 6 ml of 1:1 THF-ethanol, added cautiously, then 40 mL of pH 7.0 phosphate buffer. 40 mL 30% hydrogen peroxide is added and the reaction mixture is stirred at 25° C. for 14 h. The mixture is partially concentrated, added to saturated aqueous sodium chloride, and extracted with ether. The combined organic layers are washed twice with ice-cold saturated aqueous sodium sulfite, water, and saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo and purification by silica gel chromatography (elution with hexanes-EtOAc, 3:2) provides tert-butyl (2S,3R)-2-benzyloxycarbonylamino-3-methyl-5-hydroxypentanoate as an oil (12.3 g, 89%).
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using 2-benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzo[b]thiophene (5.50 g, 15.3 mmol) and 1M boron tribromide/CH2Cl2 (49.1 mL) in CH2Cl2. Purification on silica gel eluting with a 5 & 10% EtOAc/pet. ether step gradient gave the title compound as an oil. 1H NMR; consistent. mass spectrum (EI) m/z 344 (M+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:20]=[C:19]([CH2:21][OH:22])[C:18]=2[CH:23]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:20]=[C:19]([CH2:21][O:22][S:8]([CH3:7])(=[O:10])=[O:9])[C:18]=2[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)C(CO)=C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.1 ml (76 mmol) of pyridine and 3.6 ml (46 mmol) of methanesulphonic acid chloride are added at 0° C., while stirring, with the exclusion of moisture, to 5.0 g (30.5 mmol) of (5-methoxybenzocyclobuten-1-yl)methanol in 50 ml of dichloromethane. The mixture is then stirred at room temperature for a further 18 hours to complete the reaction. 50 ml of ice-water are then added and the whole is stirred for 30 minutes. The organic phase is separated off, washed once in each case with 2N sodium hydroxide solution, 2N hydrochloric acid and water, dried over sodium sulphate and concentrated under reduced pressure. Methanesulphonic acid (5-methoxybenzocyclobuten-1-ylmethyl) ester is obtained in the form of a viscous oil, Rf=0.4, toluene/ethyl acetate (9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[CH:8]=2)=[O:4].Cl.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])(C)C.C([O-])(O)=O.[Na+].[CH3:32][CH2:33]OC(C)=O>>[CH2:18]([O:22][C:23]([CH2:24][NH:25][C:14]([C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[NH:6]2)=[CH:11][CH:10]=1)=[O:16])=[O:26])[CH2:21][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)OC)[nH]c2c1
Yield: 86 %

Procedure:
2-(Methoxycarbonyl)indole-6-carboxylic acid was coupled with glycine t-butyl ester hydrochloride in the presence of NaHCO3 (1 equivalent) by the method described above to give N-[(butoxycarbonyl)methyl]-2-(methoxycarbonyl)indole-6-carboxamide as a white solid (86%), mp 181-183.5° C. (EtOAc). 1H NMR (CDCl3) δ9.58 (s, 1H, indole NH), 8.06 (s, 1H, H-3 or H-7), 7.68 (d, J=8.4 Hz, 1H, H-4), 7.52 (dd, J=8.4, 1.5 Hz, 1H, H-5), 7.20 (dd, J=2.0, 0.8 Hz, 1H, H-3 or H-7), 6.82 (t, J=4.7 Hz, 1H, amide NH), 4.20 (d, J=5.0 Hz, 2H, CH2), 3.96 (s, 3H, CO2Me), 1.51 (s, 9H, t-Bu); 13C NMR δ169.5, 167.7, 162.1 (3×CO), 136.4, 130.6, 129.7, 129.5 (C-2,6,8,9), 122.5, 118.8, 112.3, 108.4 (C-3,4,5,7), 82.6 (OCMe3), 52.2 (OCH3), 42.7 (CONHCH2), 28.1 (t-Bu). Anal. (C17H20N2O5) C,H,N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(c1ccccc1)C1CCCCC1
Reactant: Fc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CSc1ccc(F)cc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-fluorothiophenol (0.13 mL, 1.2 mmol) in tetrahydrofuran (4 ml) was added aqueous 15% sodium hydroxide. 2-Chloro-N-cyclohexyl-N-phenylacetamide (320 mg, 1.3 mmol) was added, and the solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on a preparatory plate using 20% ethyl acetate/hexanes to furnish 2-(4-fluorophenylthio)-N-cyclohexyl-N-phenylacetamide as a white solid. (M+1)=343.9.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:15].[C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][NH:19]2)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C(=O)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccccc1)c1cc(OC[C@@H]2CCN2)cnc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
5-benzoyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 107a is dissolved in methylene chloride (10 mL). The mixture is cooled to 0° C., TFA (10 mL) is added and the reaction is stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture is basified with 15% NaOH and extracted with CH2Cl2 (200 mL), which is dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et2O, cooled to 0° C., and treated with HCl in ethanol to afford the hydrochloride salt.
Reaction SMILES: O1C2C=CC(C3(C(O)=O)CCC3)=CC=2OC1.Cl[C:18]([Cl:20])=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[Cl:20][CH2:18][C:33]([C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:32][CH2:31][CH2:30]1)=[O:34]
Reactant: COc1ccccc1C1(C(=O)O)CCC1
Reactant: O=C(Cl)Cl
Agent: O=C(O)C1(c2ccc3c(c2)OCO3)CCC1
Product: COc1ccccc1C1(C(=O)CCl)CCC1

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclobutanecarboxylic acid was converted to the corresponding chloroketone following the same procedure used for the conversion of 1-(2-Methoxy-phenyl)-cyclobutanecarboxylic acid to give 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone. 300 mg of 1-benzo[1,3]dioxol-5-yl-cyclobutanecarboxylic acid thus provided 285 mg (83%) of 1-(1-Benzo[1,3]dioxol-5-yl-cyclobutyl)-2-chloro-ethanone. Data for this chloride: 1H NMR (300 MHz, CDCl3): δ 6.7-6.85 (m, 3H), 5.98 (s, 2H), 4.03 (s, 2H), 2.75-2.85 (m, 2H), 2.35-2.45 (m, 2H), 1.85-2.0 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 201.9, 148.6, 147.1, 135.8, 119.8, 108.9, 107.0, 101.6, 57.7, 45.4, 31.2, 16.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:37]([F:38])=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][C:26]=3[F:39])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:40][CH3:41].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:39])=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][C:37]=3[F:38])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:40][CH3:41]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100550.6 %

Procedure:
To a solution of tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, 0.16 mmol) in CH2Cl2 (500 mL) at 0° C. was added TFA (500 mL) and then was stirred at room temperature. After 3 h, the reaction mixture was evaporated and the residue was diluted with CH2Cl2(1.5 L), washed with water (600 mL×2). To the organic layers more water (600 mL) was added, it was neutralized with slow addition of aq. NaHCO3 solution and organic layer was separated. Water (600 mL) was added to the organic layer and adjusted aqueous layer to pH 3-4 with 1N HCl. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Toluene (600 mL) was added to the residue and the solution was evaporated and same process was repeated one more time to give the title compound as a white solid (88 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.46-7.49 (d, 2H), 7.16-7.19 (m, 1H), 6.92-6.97 (t, 2H), 6.69-6.71 (t, 2H), 6.62 (s, 1H), 6.49-6.51 (d, 1H), 3.84 (s, 3H), 3.53 (s, 2H), 1.58 (s, 6H); MS (EI) m/z 547 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1.CCN(CC)CC.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)#[N:13]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
6-Amino-4-(3,4-dibromophenylamino)quinoline-3-carbonitrile (0.750 g. 1.79 mmol) in 10 mL of THF was treated with 0.217 g (2.15 mmol) of Et3N and 0.195 g (2.15 mmol) of acryloyl chloride at 0° C. under N2. After stirring overnight at 25° C., the solvent was evaporated and the residue was slurried with water and collected. The residue was boiled twice with EtOAc and then dried in vacuo (50° C.) to give 0.609 g of N-[3-cyano-4-(3,4-dibromophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): 470.9, 472.9.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30]>>[CH2:29]([N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30]
Reactant: CCNc1ccccc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CCN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and N-ethylaniline, the title compound was isolated as a yellow solid in 70% yield (96% purity by HPLC).