Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[C:15]([C:23]3[N:24]=[C:25]4[C:31]([C:32](O)=[O:33])=[CH:30][N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:26]4=[N:27][CH:28]=3)=[N:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O>[C:44]([NH:47][C:32]([C:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([C:15]3[C:16]4[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:13]([CH2:12][CH:10]4[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]4)[N:14]=3)[N:24]=2)[N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[CH:30]=1)=[O:33])([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Yield: 91.7 %

Procedure:
2-(1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 251 μmol), 2-methylpropan-2-amine (18.4 mg, 251 μmol), HATU (105 mg, 277 μmol) and diisopropylamine (97.5 mg, 754 μmol) in dimethylformamide (12 mL) were stirred at room temperature for 15 h. The mixture was partitioned between ethyl acetate and water then the organic phase was washed with water then dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (150 mg, 91.5%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][CH2:9][CH:10]([CH2:12]O)[CH3:11].CC1C=CC=CC=1.O>CCCCCCC>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([O:6][CH2:11][CH:10]([CH3:12])[CH2:9][CH3:8])=[O:5]
Reactant: CCC(C)CO
Reactant: CC(C)=CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCC(C)COC(=O)C=C(C)C
Yield: 90.5 %

Procedure:
At room temperature under nitrogen in a 500 ml flask, a mixture of 87.3 g of 3,3-dimethylacrylic acid (0.85 mol) and 134.7 g of DL-2-methyl-1-butanol (1.50 mol, 1.75 eq.) and 4.25 g of para-toluene suflonic acid monohydrate (0.024 mol, 0.026 eq.) was treated with 100 ml heptane and then heated at reflux at 90° C. for 14 hours while 15.4 ml (0.85 mol) of H2O was collected in a Dean-Stark trap. The result was an orange solution. The solution was extracted with MTBE/brine (2×350 ml/200 ml brine). The organic layers were washed with NaHCO3 (200 ml saturated solution), brine (200 ml), dried over MgSO4 and concentrated. 205 g of a orange liquid was recovered, which was purified by distillation over a 30 cm plate-column. 131.1 g of a colorless liquid was recovered (bp 58° C./3.5 torr (4.7 bar) 90.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:22]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]([OH:13])[CH3:22])=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline-2-carbaldehyde (0.1650 g, 0.514 mmol) in THF (5.00 mL, 0.514 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.257 mL, 0.771 mmol) dropwise at 0° C., and the mixture was then allowed to warm to room temperature and stirred at room temperature. After 5.5 h, the reaction was quenched with NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (1 H, dd, J=8.4, 1.4 Hz), 8.09 (1 H, dd, J=7.8, 1.2 Hz), 7.88-7.96 (1 H, m), 7.72 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, br. s.), 7.44-7.53 (1 H, m), 5.36 (1 H, d, J=6.3 Hz), 4.83 (1 H, br. s.), 1.49 (3 H, br. s.); LC-MS (ESI) m/z 337.0 [M+]+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl>O>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:15]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:16][C:6]=1[O:5][CH2:4][C:1]([NH2:2])=[O:3])(=[O:11])[NH2:12]
Reactant: O=S(=O)(O)Cl
Reactant: NC(=O)COc1ccccc1OCC(N)=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Temperature: 0 °C
Yield: 77.5 %

Procedure:
2-Carbamoylmethoxyphenoxyacetamide (Intermediate A84, 112 g, 0.50 mol) was added portion-wise over 15 min to rapidly stirred chlorosulfonic acid (582.5 g, 5.0 mol) cooled to 0° C. Dichloromethane (120 mL) was then added, and the mixture was heated in a 60°-70° C. bath for 3 hr. The mixture was slowly poured into 1.5 Kg of crushed ice, and then water (500 mL) was added. The resulting solid was collected, washed with water (3×500 mL) and acetone (3×500 mL), resuspended in acetone (1 L), again collected, washed with acetone (500 mL), and air dried to yield 125 g (77%) of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].C(N(CC)CC)C.O>C(Cl)Cl>[C:8]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:1](=[O:3])[CH3:2])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(C)=O
Temperature: 25 °C

Procedure:
A solution consisting of 20 mL of acetic anhydride in 100 mL of methylene chloride was stirred at room temperature and 20 mL of methyl anthranilate (0.113 mole) was added dropwise over 10 min. Triethylamine (20 mL, 0.14 mole) was added and the solution was stirred at room temperature for 18 hr. An additional 100 mL of methylene chloride was added followed by 20 mL of water while cooling in an ice bath. The phases were mixed and the organic layer was separated. The aqueous layer was extracted with 20 mL of methylene chloride and the combined organic layers were dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 20.05 g of product as a white solid (m.p. 96°-97° C.). 1H NMR (CDCl3) δ8.66 (d, 8.0 Hz, 1H), 8.02 (dd, 8.0 Hz, 2.0 Hz, 1H), 7.53 (dt, 8.0 Hz, 2.0 Hz, 1H), 7.03 (t, 8.0 Hz, 1H), 3.98 (s, 3H, OCH3), 2.27 (s, 3H, COCH3).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc2c3c(n(CCc4ccc(C(F)(F)F)nc4)c12)CCN(C)C3
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to the above solution and stirred for 16 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethyl acetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 40 mg (8.2%) of 5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:40]([Cl:42])=[O:41])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:12]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole (19.7 g, 42.144 mmol) and triethylamine (17.6 mL, 126.432 mmol) in methylene chloride (200 mL) cooled to 0° C. was added phosgene (44.6 mL, 84.288 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The orange residue was taken in methylene chloride (100 mL), and the solution was filtered through a plug of silica gel (50 g). It was washed with methylene chloride (˜600 mL). The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, eluting with 10% ethyl acetate in hexane) to give racemic-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride as white solids (12.650 g). The enantiomers of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Waters Delta Prep 4000 and Modcol spring column (50 mm×70 cm) packed with R,R-Whelk-O1 spherical Kromasil silica gel (purchased from Regis Technologies). Eluent: 30% methylene chloride in hexane. Flowrate: 85 mL/min. Loading scale: 2.4-3.0 g. The first peak coming off the column is the desired (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[Cl:13]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1Cl

Procedure:
A solution of 4-nitro-2-chlorobenzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was treated with 10% Pd/C (50 mg) and hydrogenated at 1 atmosphere for 3 hrs. The mixture was filtered and concentrated to give a light yellow solid which was directly used for the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][CH2:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[CH:12]([Br:15])(Br)[Br:13].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Br:13][C:12]1([Br:15])[C:2]([CH3:1])([CH3:11])[CH:3]1[CH2:4][CH2:5][C:6]([CH3:7])([OH:10])[C:8]#[CH:9]
Reactant: C#CC(C)(O)CCC=C(C)C
Reactant: BrC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C#CC(C)(O)CCC1C(C)(C)C1(Br)Br
Yield: 84.5 %

Procedure:
Dehydrolinalool (60.8 g, 0.4 mol), bromoform (151.6 g, 0.6 mol) and 0.8 g of triethylbenzylammonium chloride are placed in a reaction flask and 64 g of a 50% sodium hydroxide solution are added during 30 minutes. The reaction is exothermic and the mixture is therefore cooled with ice. After stirring the mixture at room temperature for 21.5 hours the same amounts of bromoform and triethylbenzylammonium chloride are again added. The reaction becomes exothermic and is cooled with ice. The mixture is left to react at 0° for a further 4 hours, poured onto ice and extracted with methylene chloride. The organic phases are washed neutral, dried and evaporated. In this manner there are obtained 109.5 g (84%) of 5-(2'2'-dibromo-3'3'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5].C([O-])(O)=O.[Na+].O.[C:51](Cl)(=[O:54])[CH:52]=[CH2:53]>C1COCC1>[ClH:38].[C:51]([NH:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5])(=[O:54])[CH:52]=[CH2:53]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)N)C(C)(C)C
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3F)ncnc2cc1OC)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
The compound (30 mg, 0.046 mmol) obtained in Example 12 and NaHCO3 (11.6 mg, 0.14 mmol) were dissolved in THF (0.8 mL): H2O (0.2 mL), and acryloyl chloride (0.004 mL, 0.046 mmol) was added thereto at 0° C. The mixture was stirred at 0° C. for 30 min, and an aqueous solution of NaHCO3 was added thereto, followed by washing several times with chloroform. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound (15 mg, 8%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]([C:25](OCC)=[O:26])[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:7]([N:14]1[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:17]([CH2:25][OH:26])[CH:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Lithium aluminium hydride (2.50 g) was added to a solution of ethyl 1-benzyl-5-phenyl-1H-pyrazole-4-carboxylate (20.2 g) in tetrahydrofuran (300 ml) at 0° C., and the mixture was stirred at room temperature for one hour. Sodium sulfate decahydrate (21.23 g) and hexane (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for one hour. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-5-phenyl-1H-pyrazol-4-yl)methanol (17.4 g, yield: 100%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR(CDCl3) δ: 4.46(2H, s), 5.25(2H, s), 6.99–7.04(2H, m), 7.23–7.32(5H, m), 7.41–7.45(3H, m), 7.69(1H, s).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].CS(C)=O.[OH-].[K+].[CH2:37](Br)[CH:38]=[CH2:39]>O>[C:6]([S:3]([N:2]([CH2:39][CH:38]=[CH2:37])[CH3:1])(=[O:5])=[O:4])([C:7]([C:8]([C:9]([C:10]([C:11]([C:12]([C:13]([F:16])([F:15])[F:14])([F:18])[F:17])([F:19])[F:20])([F:21])[F:22])([F:23])[F:24])([F:25])[F:26])([F:27])[F:28])([F:30])[F:29]
Reactant: C=CCBr
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 85.3 %

Procedure:
A one-liter three-neck flask equipped with magnetic stirring and an addition funnel was charged with 150 g of N-methylperfluorooctanesulfonamide and 570 g of dimethyl sulfoxide, and the mixture was stirred for a few minutes until the solid dissolved. To this stirred solution was added a solution of 25 g of potassium hydroxide in 25 g of water. This mixture was allowed to stir for 30 min, then 46 g of allyl bromide was added dropwise via the addition funnel. An exotherm was noted after a few minutes. The reaction mixture was allowed to stir for 5.5 hr, during which time a white solid precipitated from solution. This solid was isolated by filtration, washed with 350 mL dimethyl sulfoxide, and dissolved in 450 g of 1,1,2-trichlorotrifluoroethane. This solution was transferred to a separatory funnel, washed with four 200 mL portions of water, and dried over anhydrous sodium sulfate. After removal of solvent by distillation at atmospheric pressure, the product was vacuum distilled to yield 138 g of C8F17SO2N(CH3)CH2CH═CH2, b.p. 98° C. at 0.4 torr (50 Pa) to 105° C. at 0.7 torr (90 Pa). The product was a clear, almost colorless liquid which solidified to a white, waxy solid upon standing at room temperature.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[CH2:8]([CH:15]([CH2:18][CH2:19][OH:20])[CH2:16][OH:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[CH2:8]([C@@H:15]1[CH2:18][CH2:19][O:20][C:16]1=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCC(CO)Cc1ccccc1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: O=C1OCC[C@H]1Cc1ccccc1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-Benzyl-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (R)-2-benzylbutyrolactone as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (8.90 g) synthesized in Example 265-1 and heptyl iodide (5.92 g) were dissolved in N,N-dimethylformamide (100 mL), potassium tert-butoxide (2.94 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. 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 sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (6.20 g) as a colorless oil.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.Cl[C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([C:10]([F:13])([F:12])[F:11])[CH3:9].[OH-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:8]([C:10]([F:11])([F:13])[F:12])([CH3:9])[C:5]#[N:6])=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(C)(C#N)C(F)(F)F)cc1
Yield: 93 %

Procedure:
Trimethylsilyl cyanide (65.1 ml; 423 mmol) was added at room temperature to 1-chloro-1-(4-methoxyphenyl)-1-trifluoromethylethane (77.6 g; 335.5 mmol) in methylene chloride (975 ml) followed by titanium tetrachloride (32.5 ml; 3.25 mmol). After stirring for 20 hours at room temparature, 2N sodium hydroxide was added carefully, dropwise, until the mixture was neutral and the precipitate separated over celite. The aqueous phase was extracted with ethyl acetate and the extract dried over sodium suphate. After concentrating, there was obtained 2-(4-methoxyphenyl)-2-trifluoromethylpropionitrile (71.49 g=90% of theory).