Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:55])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:55])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([O:47][Si:48]([C:51]([CH3:53])([CH3:52])[CH3:54])([CH3:50])[CH3:49])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogen carbonate (2.81 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.82 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.77 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.70 g, 78%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([O:22][C:23]([O:26][CH3:27])([CH3:25])[CH3:24])C)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1)(=[O:49])=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:27][O:26][C:23]([CH3:25])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28]([C:53]2[CH:54]=[CH:55][C:50]([S:47]([CH3:46])(=[O:49])=[O:48])=[CH:51][CH:52]=2)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(C)(C)OC(C)Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(Cc2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Yield: 43.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-{1-benzenesulfonyl-5-[2-(1-methyloxy-1-methyl-ethoxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-2-cyclopentyl-vinyl ester (1.12 g, 1.76 mmol), 4-(methanesulfonyl)phenylboronic acid (704 mg, 3.52 mmol), dichlorobis(triphenylphosphine)palladium (II) (124 mg, 0.17 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.2 mL). The resulting mixture was subjected to microwave irradiation for 1 h at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 44%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O6S2 [M+H]+ 621.79, observed 621.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[N:31](COCC[Si](C)(C)C)[C:30]3=[O:46])[CH2:25][CH2:24]2)=[O:22])[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:47]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH2:47][C@@H:10]1[C:11]2=[N:16][CH:15]=[CH:14][N:13]=[C:12]2[C@H:17]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:46])[CH2:27][CH2:28]2)=[O:22])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](NC(=O)N2CCC(n3c(=O)n(COCC[Si](C)(C)C)c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@@H]1c2nccnc2[C@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
In a 50 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(4-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamido)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (31 mg, 0.041 mmol) in methylene chloride (1 mL) to give a colorless solution. trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h: LCMS showed complete conversion. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (12 mg, 55%) as a white solid: MS (ESI) [M+H]+=535.3; 1H NMR (400 MHz, CDCl3) δ 10.98-9.87 (m, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.07 (dd, J=5.3, 1.2 Hz, 1H), 7.35 (dd, J=7.9, 1.2 Hz, 1H), 7.21-7.05 (m, 4H), 6.98 (dd, J=7.9, 5.3 Hz, 1H), 5.29 (dd, J=10.4, 5.1 Hz, 1H), 4.71-4.55 (m, 2H), 4.35 (d, J=13.6 Hz, 2H), 3.05 (1, J=13.0 Hz, 2H), 2.94 (t, J=9.3 Hz, 1H), 2.53 (t, J=11.7 Hz, 2H), 2.41-2.23 (m, 2H), 2.16-1.69 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −137.32 (ddd, J=21.4, 9.6, 4.5 Hz), −142.66 (d, J=19.5 Hz).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH3:17])=O.CNC(C1CC2C(C=1C)=CC=CC=2)=O>>[CH3:17][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:5][NH:4][CH3:3]
Reactant: CNC(=O)c1ccc2ccccc2c1C
Agent: CNC(=O)C1=C(C)c2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Product: CNCc1ccc2ccccc2c1C
Yield: 36 %

Procedure:
According to the procedure of Preparation 20 (b), except substituting N,1-dimethylnaphthalene-2-carboxamide (0.3 g, 1.5 mmole) for the N,3-dimethylindene-2-carboxamide, the title compound (0.1 g, 36%) was prepared as a colorless oil: MS (ES) m/e 186 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])C>CO>[NH2:16][C:15]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: NNC1CCCC1
Reactant: CCOC=C(C#N)C#N
Solvent: CO
Product: N#Cc1cnn(C2CCCC2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentylhydrazine (6.5 g, 64.9 mmol) is slowly added to a solution of ethoxymethylenemalononitrile (7.93 g, 64.9 mmol) in 100 ml of methanol at room temperature under argon, subsequently heated under reflux for 3 h and then stirred at room temperature overnight. The solvent is stripped off in a rotary evaporator and the residue is stirred with diethyl ether. The solid is filtered off with suction, washed with diethyl ether and dried under high vacuum.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[CH2:4]1.[BrH:9].[CH2:10](O)[CH3:11]>>[CH2:10]([O:6][C:5](=[O:8])[CH2:4][C@H:3]([CH2:2][F:1])[CH2:7][Br:9])[CH3:11]
Reactant: O=C1C[C@H](CF)CO1
Reactant: CCO
Reactant: Br
Product: CCOC(=O)C[C@H](CF)CBr
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A 250 mL round bottom flask equipped with a condenser was charged with 3.22 g (27.3 mmol) (S)-4-fluoromethyl-dihydro-furan-2-one. 16 mL (91 mmol) hydrobromic acid (33% in acetic acid) was added in one portion and the mixture was stirred at 60° C. for 45 minutes. A second portion of 16 mL (91 mmol) hydrobromic acid (33% in acetic acid) was added and stirring was continued at the same temperature for an additional 45 minutes, whereupon 96 mL ethanol were added. The resulting mixture was stirred at 60° C. for 65 minutes. The solvent was evaporated under reduced pressure (90 mbar) and the residue was dissolved in 300 mL toluene. The organic solution was washed with 300 mL saturated aqueous NaHCO3 and 300 mL water. Following drying over Na2SO4, filtration and evaporation of the solvent, the crude mixture was distilled under reduced pressure (82° C./1 mbar) to give 3.96 g product (64%; assay 98.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 3-methylbutylamine (43 mg, 0.49 mmol). The title compound was obtained as a solid (40 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.76 (1H, m), 8.42 (1H, s), 3.21 (2H, t), 1.58 (1H, m), 1.37 (2H, m), 0.93 (6H, m). MS m/z: 418.06, 420.08 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=[CH:31]1>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:34]5[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Yield: 20 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.70 g, 1.81 mmol), 1-methyl-5-[tri(n-butyl)stannyl]imidazole (prepared according to the published method: K. Gaare et. al., Acta Chem. Scand., (1993), 47(1), p57-62) (2.2 g, 6 mmol), 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.41 g, 0.7 mmol) and silver oxide (0.224 g, 1.8 mmol) were reacted in dry dioxane according to Procedure B. Purification by silica gel chromatography, eluting with 10%MeOH/EtOAc, gave the product as a pale brown solid (0.16 g, 0.37 mmol, 20%); δH CDCl3 10.62 (1H,s), 9.25 (1H,s), 8.75 (1H,s), 8.60 (1H,s), 8.13 (1H,s), 8.03 (1H,s), 7.20-7.78 (9H,m), 5.61 (2H,s), 3.96 (3H,s); m/z (M+1+) 433.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:13]=[C:12]([C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=3)[S:1][C:2]=2[CH:10]=1
Reactant: Cc1ccc(C(=O)O)c(S)c1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: Cc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Yield: 53.5 %

Procedure:
2-Mercapto-4-methylbenzoic acid (1.56 g, 9.3 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.46 g, 6.3 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 6 hrs. The reaction mixture was concentrated under reduced pressure, subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3:2, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (1.29 g, 53%).
Reaction SMILES: [CH2:1]([O:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:11])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[S:25](Cl)([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[S:25]([O:27][CH2:28][CH3:29])([O:10][CH2:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])=[O:26]
Reactant: CCOS(=O)Cl
Reactant: CCCCCCOC(C)(CO)OCCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
To a solution of alcohol 4 (20.6 g, 79.1 mmol) in CH2Cl2 (200 mL) is added pyridine (8.12 g, 102.8 mmol) and ethyl chlorosulfite (12.2 g, 94.9 mmol). The reaction mixture is stirred at 23° C. for 10 hours. The reaction is quenched with water (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers are washed with HCl (1N, 100 mL), saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfite 6 (24.5 g, 88%) as a colorless oil: Rf(15% EtOAc/hexane)=0.44; IR (thin film, cm−1) 2932, 2872, 1467, 1379, 1213, 1194, 1176, 1001, 888; 1H NMR (600 MHz, CDCl3) δ 4.11-4.00 (m, 2H), 3.93 (d, J=10.8 Hz, 1H), 3.77 (d, J=10.8 Hz, 1H), 3.42-3.37 (m, 4H), 1.51-1.48 (m, 4H), 1.33 (s, 3H), 1.31-1.24 (m, 15H), 0.85 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 99.0, 62.9, 60.8, 58.5, 58.3, 31.6, 29.8, 25.9, 22.6, 20.9, 15.3, 14.0.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=[N:16][OH:17]
Reactant: O=Cc1c(C(F)(F)F)ccc(F)c1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(C(F)(F)F)ccc(F)c1F
Yield: 44.8 %

Procedure:
To a solution of 0.5 g of 2,3-difluoro-6-trifluoromethylbenzaldehyde in 8 ml of ethanol was added 0.4 g of hydroxylamine hydrochloride and a solution prepared by dissolving 0.23 g of sodium hydroxide into 2 ml of water and the mixture was heated at reflux for 40 minutes. The reaction mixture was allowed to room temperature, then concentrated under reduced pressure and extracted with ethyl acetate. The extract obtained was washed with water and with saturated saline solution and dried over anhydrous magnesium sulfate. After concentrating the extract solution, the crude product obtained was washed with n-hexane to obtain 0.24 g of the title compound (mp. 111-112° C.).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].[C:25]1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(=O)(OCC)OCC=C>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:30]([O:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[N:11]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH:25]=[CH2:26]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: [Pd]
Agent: C=CCOC(=O)OCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 65 °C
Reaction time: 4 h
Yield: 715.2 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (510 mg) in tetrahydrofuran (5.0 mL), were added 1,4-bis(diphenylphosphino)butane (64.8 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (39.3 mg) and allyl ethyl carbonate (0.4 mL). The mixture was stirred at 65° C. for 4 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (408 mg).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1.O.C(=O)(O)[O-]>CCOC(C)=O>[Br:8][C:9]1[CH:10]=[C:11](/[C:16](=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cc(Br)cnc1F
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Titan (IV)-ethoxide tech. (0.298 mL, 1.441 mmol) was added to a solution of (R)-2-methyl-2-propanesulfinamide (1.44 mmol) and 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.720 mmol) in methylene chlorice (15 mL). The reaction mixture was stirred at room temperature (light-yellow solution) for 4 h (or until complete conversion by LCMS). The reaction mixture was poured into water and saturated aqueous bicarbonate solution and EtOAc were added. The suspension was stirred vigorously for 20 min. The organic phase was separated. The aqueous phase was extracted twice with EtOAc. The organic phases were combined and filtered through a pad of celite. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue (239 mg of a yellow oil) was purified by column chromatography (silica gel, 10-70% hexanes/EtOAc) to yield (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide as a yellow oil (106 mg; 43%). MS m/z=338.9 [M+H]+. Calculated for C11H13BrFN2OS: 339.2.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20]O)=[C:18]([F:26])[C:17]=1[F:27].[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([OH:36])=[O:35])[C:32]1([CH3:38])[CH3:37]>C1(C)C=CC=CC=1>[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([O:36][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:15][O:14][CH3:13])=[C:23]([F:24])[C:22]=2[F:25])=[O:35])[C:32]1([CH3:38])[CH3:37]
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added to a mixture of 4-methoxymethyl-2,3,5, 6-tetrafluorobenzyl alcohol, 3- (2-methyl-1-propenyl) -2, 2-dimethylcyclopropanecarboxylic acid {containing the stereoisomers in a ratio of (1R)-trans form: (1R)-cis form: (1S)-trans form: (1S)-cis form=49:49:1:1} and toluene under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water to be separated. The organic layer thus separated is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (hereinafter referred to as the present compound 6).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH2:14][C:15](OCC)=[O:16])=O)=[CH:10][CH:9]=1.P(Cl)(Cl)[Cl:23].[ClH:26]>>[Cl:26][C:12]([C:11]1[CH:20]=[CH:21][C:8]([CH3:7])=[CH:9][CH:10]=1)=[CH:14][C:15]([Cl:23])=[O:16]
Reactant: Cl
Reactant: ClP(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccc(C(Cl)=CC(=O)Cl)cc1

Procedure:
A one liter flask was fitted with a mechanical stirrer, CaCl2 drying tube, condenser and a sidearm addition funnel. 100 gms of PCl5 was placed in the flask. 39 gms of ethyl 4-methylbenzoylacetate and 100 gms of PCl3 were mixed and slowly added to the PCl5 at room temperature. The reaction mixture evolved HCl. After 30 minutes the mixture was cautiously refluxed for 2 hours. At this time PCl3 and POCl3 were distilled from the reaction mixture at reduced pressure. The residue was then distilled at 0.5 mm (bp=116°-121°) to provide 32 gms of β-chloro-4-methylcinnamoyl chloride as a clear oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CCOC(=O)[C@H](N)CC(C)CC
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A suspension of (R)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.57 g, 7.50 mmol) in acetonitrile (9 mL) was treated with N,N-diisopropylethylamine (1.62 mL) and stirred at 60° C. for 15 min. At this time the solution was treated with N,N-diisopropylethylamine (1.62 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 2.39 g, 7.49 mmol) in acetonitrile (4 mL) via a dropping funnel and refluxed for 20 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (1.26 g, 46%).
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=CC=C[C:5]=2N=N1.C(N([CH2:16][CH3:17])CC)C.CN(C)C=O.O1C[CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:25]([N:2]([CH:6]([CH3:5])[CH3:7])[CH2:16][CH3:17])([CH3:26])[CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C

Procedure:
The amine 8 may be coupled to a carboxylic acid using 1-ethyl-3-(3-dimethylainopropyl)carbodiimide (EDC), 1-hydroxybenztriazole (HOBT), and a base, generally triethylamine or diisopropylethylamine (DIPEA), in a solvent such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF), or methylene chloride for 3 to 48 hours at ambient temperature to provide intermediate 10.