Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].C(O)(=O)C.[CH3:23][O:24][C:25](=O)[O:26]C>>[Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH2:8][C:25]([O:24][CH3:23])=[O:26]
Reactant: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: 95 °C
Yield: 41 %

Procedure:
To a solution of 1-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanone (Preparation 63, 9.53 g) in dimethylcarbonate (200 mL) is added NaH (1.53 g; 60%, dispersion in mineral oil) portionwise at ambient temperature. The reaction mixture is heated to 95° C. for 3 h. The reaction vessel is cooled to ambient temperature and the mixture is poured into ice cold water (500 mL) containing acetic acid (15 mL). The aqueous layer is extracted with Et2O (3×100 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude brown liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 4.77 g (41%) of the title compound as a tan solid. Physical characteristics: m.p. 67-68° C.; 1H NMR (300 MHz, CDCl3) δ7.21, 3.99, 3.78, 3.71, 3.60, 2.50; IR (diffuse reflectance) 2822, 1738, 1663, 1461, 1399, 1350, 1336, 1316, 1286, 1265, 1156, 1113, 1009, 1004, 864 cm−1; MS (ESI+) m/z 318; Anal. Found: C, 48.89; H, 5.13; N. 4.45.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[OH-].[Na+]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cl)cc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (10.0 g, 43.1 mmol) and pyridine (43 mL) under nitrogen. To the resultant solution was added methanesulfonyl chloride (7.06 mL, 90.5 mmol) and the reaction was stirred at room temperature overnight. The following morning, the organics were concentrated in vacuo at 60° C., followed by hydrolysis of the bis-sulfonamide employing THF (65 mL) and sodium hydroxide (65 mL, 4.0 M). The resultant homogeneous solution was stirred at room temperature for 120 min. Upon completion of the hydrolysis, the THF was removed under reduced pressure and the pH of the aqueous layer was adjusted to 5-6 with 6 M HCl. The resultant solution was diluted with EtOAc and the organics were washed with 10% HCl and saturated sodium bicarbonate, dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to generate the desired methanesulfonamide: MS (ES) (M+H)+ expected 311.0, found 311.1.
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:10][C:9]2[C:11]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])=[C:12]([CH3:14])[S:13][C:8]=2[CH:7]=1)=[O:5].[H-].[Na+].[CH3:28]OCCl.O>CN(C)C=O>[C:4]([C:6]1[NH:10][C:9]2[C:11]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])=[C:12]([CH3:14])[S:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:28]
Reactant: CON(C)C(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of N-methoxy-N,2-dimethyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxamide (230 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, oily, 25 mg), and the mixture was stirred at room temperature for 30 min. Chloromethyl methyl ether (51 mg) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), methyl magnesium bromide (ca. 3.0M diethyl ether solution, 0.4 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), 6N hydrochloric acid (5.0°mL) was added thereto, and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-(5-acetyl-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (55.2 mg, yield 26%) as gray crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 220° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=3)[C:9]=2[N:10]=1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 478 mg (2.00 mmol) of 3-(trifluoromethyl)benzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 320 mg (83%) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.31 (t, J=7.3 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.3 Hz, 2H), 5.44 (s, 2H), 6.31 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J=7.8 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=3[C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[N:36][NH:37]2.[Cl:43]N1C(=O)CCC1=O>C(#N)C>[NH:37]1[C:38]2[C:34](=[C:33]([O:32][C:5]3[CH:6]=[C:7]([N:10]4[CH2:15][CH2:14][N:13]([CH2:16][C:17]5[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=5[C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)[CH2:12][CH2:11]4)[C:8]([Cl:43])=[CH:9][C:4]=3[C:3]([O:2][CH3:1])=[O:42])[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2[nH]ncc12
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2[nH]ncc12

Procedure:
A mixture of EXAMPLE 400D (0.5 g) and 1-chloropyrrolidine-2,5-dione (0.126 g) in acetonitrile (10 mL) was stirred at room temperature for 4 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCOCC3)cc21
Yield: 87.6 %

Procedure:
Morpholine (0.06 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 100 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of a solid. The solid was purified by column chromatography (chloroform/methanol 99:1). The appropriate fractions were combined to give 0.17 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17]O)[CH2:13][O:14]2)=[C:9]([F:19])[CH:8]=1.[Br-:30].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][Br:30])[CH2:13][O:14]2)=[C:9]([F:19])[CH:8]=1
Reactant: OCC1=Cc2c(F)cc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc2OC1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1cc(OCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc2c1C=C(CBr)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 mL) was added triphenylphosphine dibromide (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added EtOAc and IPE, the resulting solid was removed by filtration, and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium hydride (24 mg) was added to a DMF solution (5 mL) at 0° C., and subsequently, ethyl 1H-pyrazole-4-carboxylate (76 mg) was added thereto. The mixture was stirred at room temperature for 0.5 hours, and a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (220 mg) in DMF (5 mL) was added thereto at 0° C. The reaction liquid was stirred at room temperature for 13 hours, quenched with a saturated NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:26])[C:21]2[O:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: O=Cc1ccco1
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)c1ccco1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.87 ml (~10 mMol) of furfural for 5 days in the manner described in Example 29 and worked up by aqueous extraction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH2:7]Br)[CH2:5]Br.[C:10]1(N2CCCC2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C.C(O)(=[O:30])C>CC#N.O>[CH3:1][O:2][C:3]([CH:4]1[CH2:7][CH:11]2[C:10](=[O:30])[CH:15]([CH2:14][CH2:13][CH2:12]2)[CH2:5]1)=[O:9]
Reactant: CC(=O)O
Reactant: COC(=O)C(CBr)CBr
Reactant: C1=C(N2CCCC2)CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1CC2CCCC(C1)C2=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
3-Bromo-2-bromomethyl-propionic acid methyl ester (30 g, 115 mmol) was added to a stirred solution of freshly distilled 1-cyclohex-1-enyl-pyrrolidine (20.4 mL, 126 mmol) and triethyl amine (35 mL, 252 mmol) in dry CH3CN (400 mL). After the addition, the mixture was heated (100° C.) and stirred for twelve hours before acetic acid (20 mL) and water (100 mL) were added. Then, heating was continued for another three hours. The solvent was evaporated and the residue was partitioned with diethyl ether and water. The organic phase was washed with a NaHCO3 solution until the washes became basic. It was then dried, filtered, and evaporated. The residue was purified over silica gel using 2-30% diethyl ether in hexanes to give the title compound as a clear oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1N2CCN(CC2)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][O:16][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CO)CC1
Agent: C1CN2CCN1CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol (555 mg, 2.24 mmol) in DCM (20 mL) at 0° C. was added DIPEA (0.59 mL, 3.37 mmol), DMAP (20 mol %, 54 mg), and p-toluene-sulfonyl chloride (570 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 2 h, DABCO (250 mg) was added. The reaction mixture was stirred overnight. The solution was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Solvent was removed in vacuo to give the title intermediate. 1H NMR (300 mHz, CD3OD): 7.75-7.77 (d, 2H), 7.40-7.42 (d, 2H), 3.80-3.81 (d, 1H), 3.45-3.51 (m, 1H), 2.40 (s, 3H) 1.78-1.82 (m, 2H), 1.62-1.71 (m, 2H), 1.48-1.58 (m, 1H), 1.30-1.33 (m, 1H), 1.15-1.21 (m, 2H), 0.85-1.00 (m, 2H), 0.85-0.90 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: O1CCOCC1.Cl.C(OC([NH:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1>O1CCOCC1>[NH2:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 0.5 h

Procedure:
An HCl dioxane solution (4N, anhydrous, 0.27 mL) was added to 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole (54) (50.0 mg, 0.11 mmol), anisole (59 ml, 0.55 mmol), and dioxane (4 mL) in one portion. After 30 min at 23° C., the reaction was concentrated with a stream of nitrogen in a hood. The residue was diluted with saturated bicarbonate (30 mL), extracted with ethyl acetate (3×50 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate: methanol 19:1) to afford 6-(2′-amino-1-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (55): Mass Spectrum (CI) 362 (MH+).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)=[S:3].[Cl:18][CH:19]([C:25](=O)[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[ClH:18].[NH2:10][CH:7]1[CH2:6][CH2:5][N:4]([C:2]2[S:3][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[N:1]=2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)C(Cl)C(=O)COCCOC
Reactant: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Solvent: CCO
Product: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COCCOC
Product: Cl
Temperature: 90 °C

Procedure:
tert-Butyl [1-(aminocarbonothioyl)piperidin-4-yl]carbamate (Intermediate 125, 400 mg) was dissolved in anhydrous EtOH (5 ml). Ethyl 2-chloro-4-(2-methoxyethoxy)-3-oxobutanoate (Intermediate 124, 368 mg) was added and the mixture was heated at 90° C. for 18 h. Partial removal of Boc group was detected. Solvent was removed in vacuo and the dried material was treated with 4 N HCl/dioxane for 2 h. Solvent was removed in vacuo to give a brown/yellow solid which was dried to afford the title compound which was used without further purification (508 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC(C)=O.FC(F)(F)C([O:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:16]1)=O.C(#N)C>O>[OH:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([N:1]=[N+:2]=[N-:3])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH2:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(COC(=O)C(F)(F)F)CN1c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(N2CC(CO)OC2=O)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 10 g sodium azide in 20 ml water was added to 200 ml reagent grade acetone and then cooled to -5° C. A 19 g portion of dl-4-[5-(trifluoroacetoxymethyl)-2-oxooxazolidin-3-yl]benzenesulfonyl chloride (prepared as in Example 1) was added to the solution while maintaining the temperature of the mixture below 0° C. After stirring the mixture for one hour, it was allowed to stand overnight. The acetone was removed under reduced pressure, water was added and the product was filtered and washed with water to yield 12.8 g, m.p. 108°-110° C. This product was stirred with 250 ml acetonitrile at 25° C. and filtered to remove some insoluble material. The acetonitrile was concentrated and the crystallized product filtered to yield 12.3 g. This product was recrystallized from ethyl acetae to yield 6.0 g of the title compound, m.p. 112°-113° C.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH3:10][N:11]([CH3:21])[C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>C(OCC)C>[CH3:21][N:11]([C:12]([O:20][Si:23]([CH3:26])([CH3:25])[CH3:22])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)C(=O)Cc1ccccc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CN(C)C(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -70 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Methyllithium in diethyl ether (140 ml of 1.8 M solution, 0.25 mol) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of dry diethyl ether. The reaction mixture was cooled to -70° C. and a solution of 26.1 g (0.16 mol) of N,N-dimethylbenzeneacetamide in 75 ml of diethyl ether was added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of trimethylchlorosilane were added dropwise. The reaction mixture was stirred at 25° C. overnight, the solid was filtered off, and the filtrate was distilled to give 7.65 g of β-(N,N-dimethylamino)-β-trimethylsiloxystyrene as a light yellow oil: bp 75°-78° C. (0.5 mm); 1H NMR (CDCl3) δ 2.18 ppm (s, 6H), 4.83 ppm (s, 1H), 6.7-7.6 ppm (m, 5H) and 0.04 ppm (s, 9H). Anal. Calcd. for C13H21NOSi: C, 66.33; H, 8.99; N, 5.95; Found: C, 66.47; H, 9.11; N, 5.78.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:25]C(Cl)(Cl)Cl.FOC(F)(F)F>>[F:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: FC(Cl)(Cl)Cl
Reactant: CC1=C(CC(=O)O)c2ccccc2C1=Cc1ccc(S(C)=O)cc1
Agent: FOC(F)(F)F
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Temperature: -15 °C
Reaction time: 1.33 h

Procedure:
2-Methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid (2.25 g.) dissolved in 80 ml. of fluorotrichloromethane was ultraviolet irradiated and stirred at -15° C. for 80 min.; meanwhile 1.2 g. of fluoroxytrifluoromethane was passed in. The residue obtained after evaporation of the solvent was subjected to chromatography on a silica gel column, to give 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid, m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].CCN(CC)CC.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:35]([NH:34][CH2:32][CH3:33])=[O:36]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH2:11][CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([Cl:17])=[CH:16][C:8]=2[N:7]=1)([OH:5])[CH3:4].[F:19][C:20]([F:24])([F:23])[CH2:21][SH:22].C[O-].[Na+]>CO>[Cl:17][C:15]1[C:14]([Cl:18])=[CH:13][C:9]2[N:10]([CH2:11][CH3:12])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[N:7][C:8]=2[CH:16]=1
Reactant: CCn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Reactant: FC(F)(F)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(C(C)(O)CSCC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol (249 mg) in methanol (5 mL) at room temperature was added a solution of 2,2,2-trifluoroethanethiol (109 mg) and sodium methoxide (0.222 mls of 25 wt % in MeOH). The resulting mixture was then stirred at room temperature overnight. The reaction mixture was concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.