Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]([CH3:36])([CH3:35])[CH2:16][N:17]1[C:29]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][CH2:33][CH3:34])[N:17]([CH2:16][C:15]([NH:14][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])([CH3:35])[CH3:36])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Triethylamine (556 μL, 4.00 mmol) and isobutyryl chloride (230 μL, 2.20 mmol) were added sequentially to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted with dichloromethane (50 mL). The organic layer was separated, washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to an amber foam. This material was dissolved in hot propyl acetate (10 mL) and then allowed to cool overnight. Hexanes were added and the now cloudy solution was heated until clear and then allowed stand until crystals formed. The solvent was removed by pipette. The crystals were rinsed with cold propyl acetate/hexanes and then dried under high vacuum at 70° C. to provide 464 mg of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-2-methylpropionamide as an off white crystalline solid, mp 154.5-155.5° C. Anal. calcd for C20H28N6O2: % C, 62.48; % H, 7.34; % N, 21.86. Found: % C, 62.14; % H, 7.62; % N, 21.71.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:26]2[CH2:27][CH2:28][O:23][CH2:24][CH:25]=2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 462 mg, 1.11 mmol), 2-(3,6-dihydro-2h-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (262 mg, 1.22 mmol), Pd(Ph3P)4 (64.1 mg, 0.056 mmol), Na2CO3 (3 mL of 2 M, 5.99 mmol), EtOH (1 mL) and toluene (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 18 h. The RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, n-heptane/EtOAc, from 10% B to 100% EtOAc) to afford the title compound. HPLC (Condition 3) tR=6.04 min, UPLC-MS (Condition 2) m/z=443.1 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH2:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:23])[C:14]2=[CH:24][S:25][CH:26]=[C:13]12)[CH3:11]>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([CH2:10][CH3:11])[C:13]2=[CH:26][S:25][CH:24]=[C:14]2[C:15]1=[O:23]
Reactant: CCN1c2ccccc2NC(=O)c2cscc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2cscc2C(=O)N(CCN(C)C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.50 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.43 g. of 4,9-dihydro-4-ethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is purified by preparative thin layer chromatography on silica gel with 10:1 benzene:methanol as eluent. The oily solid thus obtained is recrystallized from hexane to give white crystals, m.p. 75°-77° C.
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>O1CCCC1.CN(C)C=O>[C:1]([NH:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To a solution of propiolic acid (27 mg, 0.387 mmol) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL) was added N,N′-dicyclohexylcarbodiimide (100 mg, 0.484 mmol) under ice-cooling, and the mixture was stirred for 30 min. To the reaction mixture was added N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), and the mixture was stirred under ice-cooling for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (24 mg, 21%) as a pale-orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH2:38][CH2:39][F:40])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: FCCCBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OCCCF)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH2:38])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:43]([O:45][CH3:46])=[O:44].C(N(CC)C(C)C)(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COC(=O)Cl
Reactant: Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1

Procedure:
A room temperature solution of Example 43B (30 mg, 0.051 mmol), methyl chloroformate (0.05 mL, 0.65 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and DMAP (3 mg, 0.02 mmol) in dichloromethane (1 mL) was stirred for 16 hours, treated with 4M HCl (0.3 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 635 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.92 (, 3H), 7.43 (d, 2H), 7.35 (m, 3H), 7.12 (dt, 1H), 3.50 (s, 3H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(O)Cc1c(F)cccc1F
Product: COc1ccc(N2CCN(C(=O)Cc3c(F)cccc3F)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 33 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(2,6-difluorophenyl)acetic acid and (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine as starting materials. Product was obtained as an off-white solid (33%). LC/MS (Method B) 4.6 min, [M+1]+ 521.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>CCCCCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Solvent: CCCCCC
Product: Ic1ccc(OC2CCCCO2)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
In 1 l of four-necked flask, 178 g (0.81 mol) of p-iodophenol, 81.68 g of dihydropyran and hexane were introduced and stirred for one hour. Then, 15 g of a cation exchange resin Amberlyst 15 (Rohm & Haas Co. "Amberlyst"®) was added thereto and stirred at room temperature overnight. Amberlyst 15 was removed by filtration and the filtrate was washed with an alkali and then with water. The oil layer was dried over sodium hydroxide and the solvent was distilled off to obtain 189.7 g (yield: 77%) of 4-[(tetrahydropyran-2-yl)oxy]iodobenzene.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A mixture of ethyl 2-methyl-1H-indole-3-carboxylate (400 mg, 1.97 mmol) and sodium hydride (47 mg, 2.0 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 0.5 hours, and then (1-bromoethyl)benzene (361 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate=5:1) to give ethyl 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (340 mg, 56%). LRMS (M+H+) m/z: calcd 307.16. found 307.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3cc(Br)ccc23)CC1

Procedure:
(23.2 mg, 68%); from 6-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4f, 25.0 mg, 0.086 mmol) and benzoyl chloride (20 uL, 0.17 mmol); HRMS-FAB+ for C21H19N2OBr: calculated MH+ : 395.07590; found: 395.07848.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:20]
Reactant: CCCCCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 83.3% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>Cl>[CH:9]([O:22][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(C(OCCc2ccncc2)c2ccccc2)cc1
Temperature: 135 °C
Yield: 31.6 %

Procedure:
With reference to FIG. 7, to a stirred solution of 4-vinylpyridine 1 (10 g, 95.1 mmol) and benzhydrol 2 (35.04 g, 190 mmol), was added sodium methoxide (1.541 g, 28.5 mmol). The reaction mixture was heated at 130-140° C. for 20 hrs, cooled to RT and acidified with 1 N HCl (150 ml). The solution was extracted with ethyl acetate (3×30 ml) to remove unreacted benzhydrol and side product dibenzhydryl ether. The aqueous solution was further basified with 10% NaOH solution (pH 10) and extracted with dichloromethane (3×30 ml). The combined organic layers were washed with water (2×20 ml), dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The oily residue was subjected to vacuum distillation to remove unreacted 4-vinylpyridine (3.9 g). The product was dried under vacuum to remove trace amounts of 4-vinylpyridine to yield 8.7 g (52%) of the title compound 3. 1H-NMR (CDCl3; 400 MHz): 2.90-2.93 (t, 2H, J=6.4 Hz, OCH2CH2), 3.66-3.67 (t, 2H, J=6.8 Hz, OCH2CH2), 5.32 (s, 1H, PhCH(O)Ph), 7.13-7.14 (d, 2H, J=5.6 Hz, 3,5-Pyr-H), 7.17-7.33 (m, 10H, ArH), 8.47-8.48 (d, 2H, J=6.0 Hz, 2,6-Pyr-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:29]#[N:30]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21]([C:29]#[N:30])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccc(Br)cc2)(C2CC2)N1CC(F)(F)F
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(C3CC3)c3cc(Cl)ccc3NC(=O)N2CC(F)(F)F)cc1
Temperature: 190 °C

Procedure:
To a solution of 0.39 g (0.85 mmol) 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 2.5 mL DMF was added 0.13 g (1.4 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 125 mL ether, washed 2×100 mL water and 1×100 mL brine, dried over dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (40 g silica gel cartridge, linear gradient 5-75% EtOAc/hexanes) followed by preperative chiral chromatography (5×50 mm Chiralcel OD, 100% MeOH) provided the first peak (−) 6-chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Optical rotation −83° (c=0.00175 g/mL in CH2Cl2, Na lamp,) 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, NH); 7.64 (br d, 2H, J=7.88 Hz); 7.39 (br d, 2H, J=6.22 Hz); 7.26 (obscured, 1H); 6.85 (br m, 1H); 6.74 (d, 1H, J=8.24 Hz); 4.34 (m, 1H); 4.23 (br m, 1H); 1.62 (m, 1H); 0.82 (m, 2H); 0.20 (m, 1H); 0.097 (m, 1H); MS (Electrospray): exact mass calculated for C20H15ClF3N3O+H 406.0925 found 406.0935 Collect 0.1 g second peak Optical rotation +100° (c=0.002 g/mL in CH2Cl2, Na lamp,).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]N1C(=O)CCC1=O>C(#N)C.CO>[Cl:8][C:6]1[C:5]([I:10])=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CO
Solvent: CC#N
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a solution of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 10 g, 70 mmol) in acetonitrile (100 mL) and MeOH (140 mL) was added N-iodosuccinimide (Aldrich, 24 g, 105 mmol) at room temperature. The reaction mixture was heated to 60° C. for 5 h under a nitrogen atmosphere. After the reaction was complete, by monitoring LC/MS, it was allowed to cool to room temperature. The reaction mixture was put on a rotary evaporator and the solvent was evaporated to the half of its original volume. A precipitate was formed by addition of diethyl ether (200 mL). The precipitate was collected by vacuum filtration to afford (15.7 g, 83% yield) of the 4-chloro-5-iodo-6-methylpyrimidin-2-amine; MS (EI) for C5H5ClIN3 (272.65, M+2): analytical HPLC purity >97%.
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])C.CN(C)C(Cl)=O>>[CH3:1][N:3]([CH3:17])[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CCN(CC)C(=O)NC1CCCc2ccccc21
Agent: CN(C)C(=O)Cl
Product: CN(C)C(=O)NC1CCCc2ccccc21

Procedure:
1,1-Diethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 86° to 87° C., is prepared by the above procedure, by substituting diethylcarbamyl chloride for dimethylcarbamyl chloride.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:17][NH2:18].O>CCO>[NH2:6][C:5]1[NH:18][N:17]=[C:3]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:4]=1[C:7]#[N:8]
Reactant: CSC(Nc1cccnc1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2cccnc2)n[nH]c1N
Temperature: 70 °C
Reaction time: 18 h

Procedure:
2-((methylthio)(pyridin-3-ylamino)methylene)malononitrile (0.4 g) was dissolved in EtOH (15 mL) and hydrazine hydrate (1.5 eq., 0.086 mL) was added. Reaction was stirred at 70° C. until complete by HPLC (absence of starting material, 18 hrs) and was brought to room temperature. 20 mL of H2O was then added and precipitate formed which was filtered to obtain 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]#[CH:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(N(CC)CC)C.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.[Cu](I)I>[NH2:1][C:2]1[C:17]([C:18]#[C:19][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Brc1nccs1
Reactant: C#Cc1cccc(C(=O)OCc2ccccc2)c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(C#Cc2nccs2)cccc1C(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A solution of benzyl 2-amino-3-ethynylbenzoate (3.06 g), 2-bromothiazole (1.65 mL), bis(triphenylphosphine)palladium(II) dichloride (0.704 g) and copper iodide (0.232 g) in triethylamine (60 mL) was stirred under a nitrogen atmosphere at 60° C. for 1.5 hr with heating. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (3.32 g, yield 82%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]12[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2.[O:14]1[CH2:33][CH:15]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH:15]([OH:14])[CH2:33][N:10]3[C:9](=[O:13])[CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]4[C:11]3=[O:12])[CH2:23][CH2:22]2)=[O:32])=[CH:30][CH:29]=1
Reactant: O=C1NC(=O)C2CCCCC12
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCC2CO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCC(O)CN2C(=O)C3CCCCC3C2=O)CC1
Yield: 10.2 %

Procedure:
To a mixture of 60% sodium hydride (0.26 g) and dimethylformamide (20 ml), cyclohexane-1,2-dicarboximide (1.13 g) was gradually added. A mixture of 1-(3,4-epoxybutyl)-4-(4-fluorobenzoyl)piperidine (1.7 g) and dimethylformamide (50 ml) was dropwise added thereto at room temperature, and the resultant mixture was kept at an inner temperature of 90° to 100° C. for 3 hours. Insoluble materials were removed by filtration, and the filtrate was distilled to eliminate dimethylformamide. The residue was dissolved in chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the objective compound (0.27 g). Yield, 10.2%. M.P., 129°-130° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[N:6]([CH2:12][CH:13]=[CH2:14])[C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH2:16]([OH:18])[CH3:17]>>[CH2:12]([N:6]1[C:7]([CH3:11])=[CH:8][C:9]([OH:10])=[C:4]([C:1](=[O:3])[CH:2]=[CH:8][C:9]2[CH:4]=[CH:1][CH:2]=[C:16]([O:18][CH2:11][C:7]#[N:6])[CH:17]=2)[C:5]1=[O:15])[CH:13]=[CH2:14]
Reactant: C=CCn1c(C)cc(O)c(C(C)=O)c1=O
Reactant: CCO
Product: C=CCn1c(C)cc(O)c(C(=O)C=Cc2cccc(OCC#N)c2)c1=O

Procedure:
According to the same manner as that of Example a-5 except that 0.20 g of 3-acetyl-1-allyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 6 ml of ethanol was used in place of pyridine, 0.23 g of 1-allyl-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-4-hydroxy-6-methyl-2(1H)-pyridinone [Compound No. (1c)] was obtained as a yellow crystal.