Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH:14]1CC1)([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31](C)[CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.Cl[CH2:46][Cl:47]>>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:30]=[CH:31][C:46]([Cl:47])=[C:33]([CH3:32])[CH:34]=2)([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1CC1
Reactant: Cc1cc(/C(C#N)=C/c2cccc(Cl)c2F)ccc1Cl
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C2c2cccc(Cl)c2F)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (0.93 g, 7.3 mmol) and To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (1.6 g, 7.3 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.5 g, 4.9 mmol) prepared in Example 100a in dichloromethane (100 mL) were added triethylamine (1.7 g, 12 mmol) and AgF (0.9 g, 7.3 mmol), in one portion. The mixture was stirred at room temperature for 18 h. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into tert-butanol (30 mL), and DBU (5 mL) was added. The mixture was heated at 100° C. for 18 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10, 1:5) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 80%).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO>[CH3:28][C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1cc(N)c(C)c2[nH]cnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.03 g) in CH2Cl2 (150 mL) is added dropwise over 30 minutes a solution of 5-amino-4,7-dimethylbenzimidazole (0.816 g) in methanol (50 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with a gradient of 50% to 80% ethyl acetate/hexane to afford 4,7-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:3]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][C:29]1[S:33][C:32]([CH:34]=[O:35])=[N:31][CH:30]=1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH2:11][CH2:12][C:34]([C:32]2[S:33][C:29]([CH2:28][O:27][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)=[CH:30][N:31]=2)=[O:35])=[N:3]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1cc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)nn1C
Yield: 61.1 %

Procedure:
A mixture of 4-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.60 g), 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (0.48 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (54 mg), triethylamine (0.11 mL), tetrahydrofuran (6 mL) and ethanol (6 ml) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography to give the title compound (0.65 g, yield 60%) as a yellow oil from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 522 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)[CH2:2][CH2:3][CH3:4].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8](/[CH:9]=[CH:17]/[N+:14]([O-:16])=[O:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCOc1cccc(/C=C/[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A mixture of 3-butoxy-benzaldehyde (4.23 g, 23.7 mmol) described in Manufacturing Example 65-1-1, nitromethane (2.55 mL, 47.7 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (40 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (3.92 g, 75%).
Reaction SMILES: [Si](O[C@H:9]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)C=1)(C(C)(C)C)(C)C.[Si]([O:58][C@H:59]([C@H:94]1[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][N:95]1C(OC(C)(C)C)=O)[C@@H:60](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)[CH2:61][C:62]1[CH:67]=[C:66]([F:68])[CH:65]=[C:64]([F:69])[CH:63]=1)(C(C)(C)C)(C)C>Cl.O>[F:69][C:64]1[CH:63]=[C:62]([CH2:61][C@H:60]([NH:29][C:28](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][CH:10]([C:11]3[CH:12]=[CH:17][C:16]([F:18])=[CH:15][CH:14]=3)[CH3:9])=[O:31])[CH:23]=2)[C@H:59]([OH:58])[C@H:94]2[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][NH:95]2)[CH:67]=[C:66]([F:68])[CH:65]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Agent: Cl
Solvent: O
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)NC(C)c3ccc(F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 16 (B): N1-((1R,2 S)-3-(3,5-Difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propran-2-yl)-N3-(1-(4-fluorophenyl)ethyl)isophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyoxy)-2-(3-(carbonyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 16 (A), 38 mg) in HCl (4.0 M solution in dioxane, 1 mL) was added 2 drops of H2O and the mixture was stirred at rt for 1 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S5 column, 34-90% methanol/H2O/0.1% TFA) to give 30 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.97 (3H, m), 1.58 (3H, d, J=5 Hz), 1.62 (2H, m), 2.17 (1H, m), 2.50 (1H, m), 2.86 (1H, m), 3.34-3.49 (5H, m), 3.81 (1H, m), 4.06 (1H, dd, J=5, 10 Hz), 4.22-4.25 (2H, m), 5.21-5.27 (1H, m), 6.73 (1H, m), 6.89-6.90 (2H, m), 7.07 (2H, m), 7.41-7.44 (2H, m), 7.53 (1H, t, J=10 Hz), 7.79-7.82 (1H, m), 7.96 (1H, m), 8.12-8.14 (1H, m), MS (ESI) (M+H)+ 584.32.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a suspension of 1,5-diaminopentane dihydrochloride (2.9 g, 16.7 mmol) in THF (100 mL) was added 20% aqueous sodium hydroxide (10.0 g, 50 mmol) at 0° C. A solution of benzyl chloroformate (1.7 g, 10 mmol) in THF (10 mL) was added rapidly dropwise and the resulting mixture stirred at RT. After 1 h, the organic layer was separated and concentrated to give a residue which was dissolved in ethyl acetate (200 mL). This solution was extracted with water (3×50 mL.), dried (sodium sulfate) and concentrated. The residue was redissolved in ether (50 mL) and 1.0 ethereal hydrogen chloride (3.0 mL) was added. The resulting precipitate was filtered, suspended in CH2Cl2 (75 mL) and shaken with 5% sodium hydroxide (15 mL). The organic layer was washed with water (75 mL), dried (sodium sulfate) and concentrated to give the title compound 0.25 g, 30%): 1H NMR (400 MHz, CDCl3) δ7.15-7.4 (m, 5H), 5.15-5.4 (m, 1H), 5.05 (s, 2H), 3.05-3.2 (m, 2H), 2.55-2.7 (m, 2H), 1.2-1.5 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[Br:13]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:10])=[C:8]([Br:13])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c(F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid methyl ester (1.0 g) in THF (10 mL) was added N-bromosuccinimide (1.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1, v/v) to give the title compound (1.16 g). (In the above, THF is tetrahydrofuran)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=2[C:12]#N)=[CH:4][CH:3]=1.[OH-:19].[Na+].[OH2:21].Cl>C(O)CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=2[C:12]([OH:21])=[O:19])=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1cc(F)ccc1CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: O=C(O)c1cc(F)ccc1CCc1ccc(F)cc1
Temperature: 190 °C
Yield: 88.4 %

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-fluorobenzonitrile (2.12 g, 8.72 mmol, 1 equiv) and aq. NaOH (10N; 3.9 mL, 39.3 mmol, 4.5 equiv) in ethylene glycol (25 mL) was heated at 190° C. for 24 h. After allowing the mixture to cool, H2O (100 mL) was added followed by 12N HCl (8 mL). The cloudy mixture precipitated the desired product as a cream-colored solid. This material was washed with H2O (3×20 mL) and dried under vacuum (18 h, 25° C., 0.1 mm Hg°) to provide 2.02 g (88.4%) of a cream-colored solid.
Reaction SMILES: OO.[Cl:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[OH2:26].C(O)(=[O:29])C>>[Cl:3][CH2:4][CH2:5][S:6]([CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:26]
Reactant: Cc1c(-c2ccccc2)oc2c(CSCCCl)cccc2c1=O
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: Cc1c(-c2ccccc2)oc2c(CS(=O)(=O)CCCl)cccc2c1=O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
41.6 ml of 30% hydrogen peroxide was added dropwise at 40° C. over a period of 20 minutes to a solution of 26.2 g of Intermediate XII in 300 ml of glacial acetic acid. The mixture was heated at 60° C. with stirring for 4.5 hours, then cooled to ambient temperature and poured into 60 ml of water. Suction filtration gave a solid which was washed with water and dried, to give 29.4 g of the title compound. Melting point 158°-161° C. (ethanol).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>[C:8]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: C=C(OC(C)=O)C(=O)OC
Yield: 34.7 %

Procedure:
102.1 Grams(1 mole) of methyl pyruvate is dissolved in 204.2 g(2 moles) of acetic anhydride and 5.0 g(20 millimoles) of pyridinium p-toluenesulfonate is added thereto, followed by conducting a reaction at 100 to 110° C. for 7 hours with stirring and refluxing with stirring for 11 hours. After cooling, the reaction solution is poured into 5000 ml of water and the precipitated oily substance is extracted with ethyl ether. The extract layer is washed with water, dried over anhydrous magnesium sulfate, concentrated and distilled under reduced pressure to give 50.0 g of methyl 2-acetyloxyacrylate as colorless oil having bp. 65 to 68° C./11 mmHg.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1>O>[CH3:7][C:6]1[N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-iodo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (700.0 mg, 1.789 mmol) in THF (20 mL, 300 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (5.5 mL, 7.2 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 8.9 mmol), and allowed to stir at rt for 2 h. Water was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.30 (s, 12H), 1.48 (s, 9H), 1.84 (d, J=10.4 Hz, 2H), 1.99 (dtd, J=12.6, 12.3, 12.3, 4.5 Hz, 2H), 2.47 (s, 3H), 2.94 (br. s., 2H), 4.21 (d, J=13.6 Hz, 2H), 4.30-4.42 (m, 1H), 7.57 (s, 1H). MS (ES+): m/z=391.26/392.26/393.27 (50/100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]([O-:10])=[O:9].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:22](Cl)Cl>>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH2:4][CH:3]1[C:8]([O:10][CH3:22])=[O:9]
Reactant: ClCCl
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])C1CNCCC1=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 4-oxo-3-piperidinecarboxylate (5 g) in dry DCM (50 ml), under N2 atmosphere, TEA (9 mL) was added at rt and then, at 0° C., benzylchloroformate (4.2 mL) was added slowly and stirring was continued for 30 minutes at 0° C. and 1 h at RT. The mixture was quenched at 0° C. with HCl 2N. The aqueous phase was extracted with DCM (2 times) and the combined organic layers were washed with saturated NaCl aqueous solution, dried and concentrated in vacuo to give the title compound (7.5 g).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][SiH:16]([Cl:18])[Cl:17]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Si:16]([Cl:18])([Cl:17])[Cl:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 75.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.75 mmol) of tetrabutylphosphonium chloride, 1.52 g (7.5 mmol) of 4-phenylbenzyl chloride, 10 ml of dried benzene, and 3.05 g (22.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.70 g of (4-phenylbenzyl)trichlorosilane (yield; 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[S:23]([NH:1][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:25])=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Reactant: N#Cc1ccc(S(N)(=O)=O)c(N)c1
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(C#N)ccc1S(N)(=O)=O
Yield: 36 %

Procedure:
The title compound was synthesized as described for Example 178 in 36% yield, starting from 2-amino-4-cyanobenzenesulfonamide and 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]([O:15][CH2:16][CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COCCOC>[Cu].[Zn].C(OCC)C>[CH2:8]([O:15][CH2:16][CH:17]1[CH2:18][C:3](=[O:4])[C:2]1([Cl:7])[Cl:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: O=C1CC(COCc2ccccc2)C1(Cl)Cl

Procedure:
Trichloroacetyl chloride (108 ml, 0.96 mol) was added slowly to a stirred suspension of freshly activated zinc-copper couple (56 g), allyl benzyl ether (50 ml, 0.32 mol), dry 1,2-dimethoxyethane (95 ml) and dry diethyl ether (550 ml) in a 2 L three-neck flask under argon. The reactants were heated under gentle reflux for 3d. The products were then filtered and the residue was washed with ether. The combined filtrate and washings were concentrated under reduced pressure. Light petroleum ether was added and the mixture was stirred vigorously. The supernatant was decanted and more light petroleum ether was added. After vigorous stirring the supernatant was again decanted and mixed with the original supernatant. The resulting solution was washed with saturated NaHCO3 twice and brine once. The organic phase was dried over MgSO4 and the solvent was evaporated to give a light yellow oil which was used directly in the next step. 1H NMR (CDCl3, 300 MHz): δ 3.10-3.25 (m, 2H), 3.36-3.57 (m, 1H), 3.65-3.75 (m, 1H), 3.83-3.88 (m, 1H), 4.57 (s, 2H), 7.27-7.40 (m, 5H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=O.[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[C:16](C(O)=O)=[N:17][CH:18]=[CH:19][CH:20]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.O>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:16]1[C:15]([F:14])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:5])[CH3:9]
Reactant: CC[K]
Reactant: O=C(O)c1ncccc1F
Reactant: O=C(O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ncccc1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl potassium malonate (2) (452 mg, 2.66 mmol) in tetrahydrofuran (5 mL) was added MgCl2 (202 mg, 2.13 mL). The mixture was stirred at 50° C. for 4 h and then cooled to room temperature. In another flask a solution of 3-fluoro-pyridine-2-carboxylic acid (1) (250 mg, 1.77 mmol) in tetrahydrofuran (5 mL) was taken and CDI (carbonyldiimidazole) (489 mg, 3.01 mmol) was added at 10° C. The mixture was stirred at room temperature for 1 h, this reaction mixture was then added to the above suspension and stirred at room temperature for 18 h. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.CCOCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH3:7][N:5]1[CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:3]=[N:4]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cc(Br)cn1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-methylpyrazole (15 g, 38.5 mmol) in ether (150 mL) n-Butyllithium (2.5M in hexanes, 17 mL, 42.4 mmol) was added at −78° C. After the reaction solution was stirred at −78° C. for 30 minutes, tributyltin chloride (11.5 mL, 42.4 mmol) was added. It was stirred at −60° C. for 1 hour and warmed to room temperature, at which it was stirred for 1 more hour. Then, it was diluted with ethyl acetate (300 mL) and washed with water (200 mL) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel with hexanes/ethyl acetate=10/1 as eluant to get 1-methyl-4-tributylstannylpyrazole as a white wax. 1H NMR (CDCl3, 300 MHz): δ7.42 (s, 1H), 7.23 (s, 1H), 3.93 (s, 3 H). 1.28-1.55 (m, 18 H), 0.91 (t, J=15 Hz, 9 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:27][CH2:28]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:12]([O:24][CH3:25])[CH:11]=3)[CH2:28][CH2:27][N:5]2[CH:6]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCCN1CCCC1
Product: COc1cc(N2CCn3cc(Br)cc3C2=O)ccc1OCCN1CCCC1
Yield: 95 %

Procedure:
The title compound was prepared by alkylating the carboxamide of step B with 1,2-dibromoethane via the procedure described in step D of Example 1 in 95% yield. MS (ESI) 434, 436 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[C:12]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13].[C:35]1(C)C=CC=C[CH:36]=1>>[CH2:35]([O:14][C:12](=[O:13])[CH2:15][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1)[CH3:36]
Reactant: O=C1COc2ccc(Cl)cc21
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1coc2ccc(Cl)cc12

Procedure:
A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(5-chloro-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.8 g (75%); 239 (M+H).