Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].[C:3]([CH:7]=[C:8]([F:10])[F:9])([F:6])([F:5])[F:4]>C(OOC(C)(C)C)(C)(C)C>[C:3]([CH2:7][C:8]([CH2:1][OH:2])([F:10])[F:9])([F:6])([F:5])[F:4]
Reactant: FC(F)=CC(F)(F)F
Reactant: CO
Agent: CC(C)(C)OOC(C)(C)C
Product: OCC(F)(F)CC(F)(F)F
Yield: 76.5 %

Procedure:
Under nitrogen, into a quartz reactor equipped with a dry-ice condenser was added anhydrous methanol (100 g, 3.10 mol) and di-tertiarybutylperoxide (3.95 g, 0.015 mol). The quartz reactor tube was placed in a Rayonet UV photochemical reactor and HFC 1225, CF3CH═CF2 (57.9 g, 0.438 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜5 hours while being irradiated at 254 nm. After complete addition, the reaction mixture was irradiated for additional hour. Then the reaction mixture was concentrated under reduced pressure, the residue (˜65 g) was mixed well with 120 mL aq. Na2SO3 (20%), separated the lower layer, and washed with brine (40 mL). The crude product was then distilled under reduced pressure (24-28 mm Hg) to afford 55 g CF3CH2CF2CH2OH (yield 77% based on HFC 1225).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])(C)(C)C>C1(C)C=CC=CC=1.C1COCC1>[C:9]([C:8]([CH3:12])([CH3:11])[C:4]1[CH:3]=[C:2]([B:13]([OH:18])[OH:14])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C#N)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile [0.5 g, 2.2 mmol, Intermediate (65)] in toluene (8 mL) and THF (2 mL) is added triisopropyl borate (0.61 mL, 2.68 mmol) at −78° C. tert-Butyl lithium (1.7 M in pentane, 1.55 mL, 2.68 mmol) is added dropwise during 15 min. Reaction mixture is stirred at −78° C. for additional 1 hour, warmed up to −20° C. and quenched with 2 N hydrochloric acid (10 mL). The reaction mixture is extracted with ether, combined ether layers are washed with brine, dried and concentrated to obtain 3-(cyano-dimethyl-methyl)-phenyl boronic acid (0.5 g) [Intermediate (66)] as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN([C:38]([O:42]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.N1CCC(N2CCC[C@H]2CO)CC1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][CH2:21][C@H:22]4[CH2:38][OH:42])[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: OC[C@@H]1CCCN1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 9) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 505.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7,4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][Mg]Br.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(CCC(C)(C)O)cn1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (100 mg, 1.18 mmol) in dry THF (3 ml) was added to 3.0 M methylmagnesium bromide solution in ether (0.39 ml) at 30-40° C. Thereafter the reaction mixture was stirred at 45° C. for 3 h. The cooled reaction mixture was poured into saturated NH4Cl solution. Solvents were evaporated and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using EtOAc-MeOH (9:1) as an eluent. The final purification was made by preparative HPLC to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30 (6H, s), 1.97 (2H, m), 4.14 (2H, m), 4.28 (1H, distorted dd), 4.41 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (2H, m), 7.56 (1H, d), 7.61 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 4.05 g of 2-benzyloxyphenol and 9.5 ml of N,N-dimethylformamide was added dropwise to a mixture of 0.80 g of sodium hydride and 20 ml of N,N-dimethylformamide under ice cooling, and the mixture was stirred for 30 minutes. A mixture of 7.1 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene and 17 ml of N,N-dimethylformamide was added dropwise at the same temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:30]([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[O:31])[CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: c1ccc(CN2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCOCC1)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, 1.35 mmol) in 4 mL of CH2Cl2 was added tetrahydro-pyran-4-carbonyl chloride (0.210 mL, 1.637 mmol) and Et3N (0.380 mL, 2.73 mmol). The reaction mixture was stirred at room temperature for 30 min then was quenched with H2O, extracted with CH2Cl2, filtered and evaporated under vacuum. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5) gave [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (420 mg, 73% yield) as a yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.37-1.64 (m, 4H) 1.95-2.29 (m, 2H) 2.56-2.83 (m, 4H) 3.28-3.91 (m, 13H) 5.54-5.68 (m, 1H) 7.24-7.36 (m, 5H) 8.54-8.59 (m, 1H). LCMS: [M+H]+=423.6, Rt(7)=0.68.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[OH-]>O1CCCC1.O>[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([NH2:3])=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to a solution of 4.6 g of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol obtained in Reference Example (2a) (19.4 mmol) in a mixed solvent of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), and the mixture was stirred at room temperature for 16 hours. 11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for three days. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 3.16 g of crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid. 3.0 g of 1,1′-carbonylbis-1H-imidazole (18.5 mmol) was added to a solution of 3.1 g of the crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid obtained above (12.3 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for one hour. 20 ml of a 28% ammonia aqueous solution (914 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1 M hydrochloric acid aqueous solution and brine and dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate/n-hexane=2/1-3/1) to obtain 2.54 g of the title compound (yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1Cl)c1cccc(F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g, 177.5 mmol) was added to this suspension, and the mixture stirred at rt for overnight. The reaction mixture was filtered through a thin pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aqueous solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf=0.4, 30% EtOAc/Hex.(3:7)]. 1H-NMR (DMSO-d6) δ 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[CH2:16]([C@@H:23]([CH2:34][OH:35])[C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1F)[OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH2:16]([C@@H:23]1[C@@H:24]([OH:25])[C:26]2[C:31](=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[O:35][CH2:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to a solution of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. The mixture was slowly heated to 60° C. under aspirator vacuum to displace the tetrahydrofuran from the reaction mixture, and then heated at 60 to 65° C for 5 hours under aspirator vacuum at which point the reaction was judged to be complete according to thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambient temperature and quenched by adding water (10 L) followed by 1N aqueous hydrochloric acid (10 L). The resulting tan suspension was filtered, washed with water (2 L), and dissolved in ethyl acetate (12 L). This solution was washed with water (two times 12 L), concentrated to a low volume, dissolved in isopropyl ether (4 L), and concentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids began to precipitate. The resulting suspension was cooled to ambient temperature, stirred for 12 hours, concentrated to one-half its volume, cooled to 0 to 5° C., and filtered giving 916 g (49%) of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L) at reflux, cooled to ambient temperature, stirred, and filtered yielding an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich fractions were concentrated and recrystallized from isopropyl ether yielding an additional 82 g of solid. The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs,1H), 4.21 (dd, J =2.6, 11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd, J=6.5, 13.8 Hz, 1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3 Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1673, 1493, 1480, 1410. 1219, 1070, 1052, 1023, 859, 700 cm-1 ; mp 143.5-144.0° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)=[O:5])#[N:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:1]([C:3](=[CH:20][N:21]([CH3:23])[CH3:22])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1ccccc1-n1cccc1
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1-n1cccc1

Procedure:
As for Example 1, 2-cyano-2'-(1-pyrrolyl)acetanilide, colorless needles, m.p. 143°-144° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2-cyano-3-dimethylamino-2'-(1-pyrrolyl)acrylanilide as yellow crystals, m.p. 169°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].S(=O)(=O)(O)O.[CH3:18]O>>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 70 °C
Yield: 84 %

Procedure:
To the solution 2-(3-cyanophenyl)acetic acid (700 mg, 43.4 mmol) in methanol was slowly added sulfuric acid (0.42 mL, 4.34 mmol) at room temperature. The reaction mixture was refluxed for 3 h at 70° C. under nitrogen atmosphere. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. Solvent was removed in vacuo and extracted with ethyl acetate. The organic part was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography to afford methyl 2-(3-cyanophenyl)acetate (660 mg, 84%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[S:14][C:15]([Cl:20])=[CH:16][C:17]=1[O:18][CH3:19].[CH:21]1([C:24]2[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1>[Cl:20][C:15]1[S:14][C:13]([C:28]([C:27]2[CH:34]=[CH:35][C:24]([CH:21]3[CH2:22][CH2:23]3)=[CH:25][CH:26]=2)=[O:29])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CON(C)C(=O)c1ccc(C2CC2)cc1
Reactant: COc1cc(Cl)sc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)sc1C(=O)c1ccc(C2CC2)cc1
Temperature: -78 °C
Yield: 62.9 %

Procedure:
In a nitrogen stream, an n-butyllithium n-hexane solution (1.6 M, 2.43 mL, 3.88 mmol) was added dropwise to a solution of 2-bromo-5-chloro-3-methoxythiophene (882 mg, 3.88 mmol) as synthesized by the method described in a document [L. Org. Chem., 58, 4629-4633 (1993)] in anhydrous THF (15 mL) at −78° C. This mixture was stirred at −78° C. for ten minutes, and a solution of 4-cyclopropyl-N-methoxy-N-methylbenzamide (875 mg, 4.26 mmol) in THF (3 mL) was added dropwise thereto. The reaction mixture was stirred at −78° C. for 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:ethyl acetate (4:1)] to obtain the title compound (714 mg, 63%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[Hg]Cl)(=[O:3])[CH3:2].[Cl:13][C:14](=[CH2:17])[C:15]#[N:16].[BH4-].[Na+]>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:17][CH:14]([Cl:13])[C:15]#[N:16])(=[O:3])[CH3:2]
Reactant: C=C(Cl)C#N
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1[Hg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@@H]1CCCC[C@H]1CC(Cl)C#N
Temperature: 25 °C

Procedure:
31 g of trans-1-acetamido-2-chloromercuriocyclohexane are suspended in 250 ml of 95% strength ethanol: 187 ml (4 equivalents) of 2-chloroacrylonitrile are added. While cooling in ice, a solution of 3 g of sodium borohydride in 50 ml of ethanol is added as rapidly as possible. After warming up to room temperature, the precipitated elemental mercury is filtered off with suction over kieselguhr, thoroughly washed with ethanol and the filtrate is evaporated. The residue is taken up in methylene chloride, washed three times with 1N sodium hydroxide solution to destroy the boric esters, dried over sodium sulfate and evaporated. 13 g of the title compound are obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:25]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:25])[CH:9]2[CH2:10][CH2:11][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CCCCCC
Reactant: CCOC(=O)C1(C)CCC(Nc2ncc(Br)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(N(C)c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To an ice-cold solution of ethyl 4-(5-bromopyrimidin-2-ylamino)-1-methylcyclohexanecarboxylate (0.30 g, 0.88 mmol) in THF (10 mL) was added NaH (0.053 g, 1.32 mmol, 60% dispersion in mineral oil) portion wise and the mixture stirred at 0° C. for 10 min followed by drop wise addition of MeI (0.066 ml, 1.06 mmol). The mixture was heated up to 65° C. for 6-8 h. After completion (by TLC), the reaction was cooled up to 0° C. and quenched with ice-cold water (20 mL), extracted with EtOAc (2×50 mL) and the combined organics washed with water, brine and dried over Na2SO4. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the desired product as a yellow liquid (0.074 g, 24% yield). 1H NMR (DMSO-d6): δ 8.42 (s, 2H), 4.51 (m, 1H), 4.15 (q, J=6.80 Hz, 2H), 2.85 (s, 3H), 2.15 (m, 2H), 1.52 (m, 4H), 1.36 (m, 2H), 1.29 (t, J=6.80 Hz, 3H) and 1.21 (s, 3H).