Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.C(OCC)(=O)C.[CH:16]([NH2:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:18][CH:16]=[O:17])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=CNc1cccc(F)n1
Temperature: 25 °C

Procedure:
A solution of 0.63 g of 2,6-difluoropyridine in 0.2 mL of formamide was stirred for 3 hours at 150° C. The reaction mixture was cooled to room temperature, to which were added water (100 mL) and ethyl acetate (100 mL×3) for extraction. The extract solution was dried over anhydrous magnesium sulfate, followed by concentration to give powdery precipitate of 2-fluoro-6-(formylamino)pyridine. The powdery product was collected by filtration and dried for 2 hours at 40° C. under reduced pressure (0.4 g).
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[OH:10][C:3]([CH2:7][CH2:8][CH3:9])([CH2:4][CH2:5][CH3:6])[C:1]#[C:2][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(C#N)c1)CCC

Procedure:
Coupling of 4-ethynylheptan-4-ol with 3-bromobenzonitrile following the method described in Example 12 gives 3-(3-hydroxy-3-propylhex-1-ynyl)benzonitrile.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].Cl.[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5]([NH:13][CH2:12][C:11]([F:15])([F:14])[F:10])=[S:6]
Reactant: NCC(F)(F)F
Reactant: FC(F)(F)CN=C=S
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)CNC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2,2-Trifluoroethylisothiocyanate (2.12 g.) was added to a mixture of 2,2,2-trifluoroethylamine hydrochloride (1.36 g.), triethylamine (1.01 g.) and acetonitrile (10 ml.), and the mixture stirred at room temperature for 4 hours and then evaporated to dryness. The residue was partitioned between water and ethyl acetate, and the ethyl acetate phase was dried and evaporated to dryness. The residue was recrystallised from a mixture of acetone and light petroleum ether (b.p. 60°-80°) to give 1,3-di(2,2,2-trifluoroethyl)thiourea, m.p. 152°-153°.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N:19][CH:20]=1)([O-:14])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N+:19]([O-:9])[CH:20]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 88.2 %

Procedure:
mCPBA (198 mg, 0.883 mmol) was added slowly to a solution of tert-butyl [(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (301 mg, 0.83 mmol) in DCM (1.1 mL) at 0° C. The reaction mixture was then stirred at room temperature for 67 h. The mixture was treated with aq. Na2S2O3 and 1 M NaOH, and then stirred for 30 min. at room temperature. The reaction mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (277 mg, 88%) as light orange powder, which was used without further purification. LCMS calc. for C18H22N4O5 (M+H)+: m/z=379.2. Found: 379.2.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:26])[F:25])=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)ccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methyl-4-(trifluoromethyl)phenylboronic acid (0.411 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 3 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)quinoline as a yellow oil. Mass Spectrum (ESI) m/e=372.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)O.[ClH:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Cl
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Product: Fc1ccc(C(Cl)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol and 240 parts of hydrochloric acid solution 12N is stirred for 40 hours at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 13.2 parts of 2,4-dichloro-1-[chloro-(4-fluorophenyl)methyl]benzene; bp. 146° C. at 0.15 mm. pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]([Cl:36])([Cl:35])[S:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=2[Cl:34])=[CH:21][CH:22]=1)[S:15][C:14]([Cl:36])([Cl:35])[Cl:13])=[O:8])=[O:5]
Reactant: FC(F)(F)c1ccc(Oc2ccc(NSC(Cl)(Cl)Cl)cc2)c(Cl)c1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(SC(Cl)(Cl)Cl)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)c1ccccc1Cl
Reaction time: 240 h

Procedure:
A solution of 3.6 g of 2-chlorobenzoyl isocyanate in 15 ml of dry toluene was added over five minutes to a stirred solution of 4.0 g of 1,1,1-trichloro-N-[4-[2-chloro-4-(trifluoromethyl)phenoxy]phenyl]methanesulphenamide in 25 ml of the same solvent at room temperature. After 10 days, the reaction mixture was diluted with 500 ml of light petroleum andd filtered. Evaporation of the filtrate gave a crude residue from which 7 was obtained, as a solid. m.p: 68°-71° C., by rapid chromatography on silica gel using methylene chloride as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-])=O)[CH:27]=2)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][C:28]1[CH:27]=[C:26]([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH:12]=2)([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:21])[F:19])[CH:31]=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1cccc(C(c2cccc(Nc3ccccc3[N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1cccc(C(c2cccc(Nc3ccccc3N)c2)(C(F)(F)F)C(F)(F)F)c1
Yield: 94.9 %

Procedure:
20 g (34.7 mmol) of 2,2-bis[N-(2-nitrophenyl)-(3-aminophenyl)]hexafluoropropane synthesized above were dissolved in 200 ml of ethyl acetate. Thereto was added 1 g of 10% palladium carbon as a catalyst, and replacement with hydrogen was carried out. After that, reaction was conducted at room temperature under a hydrogen pressure of 1.01 MPa (10 atm) for 18 hours with stirring vigorously. The obtained reaction solution was filtered with cerite to remove the catalyst, and ethyl acetate was removed under reduced pressure. The residue was recrystallized by using a chloroform-hexane mixed solution, and ethanol-water mixed solution to obtain 17 g of 2,2-bis[N-(2-aminophenyl)-(3-aminophenyl)]hexafluoropropane (hereinafter mNPN-AF) in white solid(yeild: 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1cccc(O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1cccc(Oc2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenol to give [6-methoxy-1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 363(MH+).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>[OH-].[Na+]>[OH:8][CH2:7][C:1]1([CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: O=CC1(CO)CCCCC1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a cold (0° C. mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of mnethanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]1([C:20]([O-])=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=1)[N+:7]([O-:9])=[O:8].[NH4+].O>S1(CCCC1)(=O)=O>[CH:10]1[C:6]([N+:7]([O-:9])=[O:8])=[C:20]([NH2:5])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 177 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Ammonium acetate (1.16 g, 15.0 mmol) and ammonium picrate (0.18 g, 0.75 mmol) are suspended in sulfolane (3 ml), stirred for 2 hr at 177° C., cooled to ambient temperature and mixed with water (30 ml). The product is collected, washed with water and dried to yield 0.061 g (32%) of picramide (Table 1, entry 7).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:17])=[N:13][O:14][C:15]=1[CH3:16])=[O:10])[NH:2]2.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:25])[N:23]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3c(C)noc3C)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 3,5-dimethyl-isoxazole-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.26 min; [M+H]+=452.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=3)=[C:10]([CH3:24])[CH:9]=2)=[CH:5][CH:4]=1.[Br:27]Br.O>C(O)(=O)C>[Br:27][C:19]1[S:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:16][C:15]=1[C:11]1[C:10]([CH3:24])=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)=[CH:13][C:12]=1[CH3:14]
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(NC(C)=O)n3)c(C)c2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(C)=O)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of N-{4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-2, 465 mg, 1.3 mmol) in acetic acid (10.2 mL) was added bromine (0.060 mL, 1.3 mmol) dropwisely. The reaction was stirred at room temperature for 4.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-3, 547 mg) as white solids, which was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21](=[CH:25][CH:26]=1)[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)[NH:27][C:15]2=[O:16])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOc1ccc(S(=O)(=O)N=C=O)cc1
Product: C=CCOc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 54.3 %

Procedure:
1.50 g (7.03 mmol) of 4-allyloxybenzenesulfonyl isocyanate and 1.2 g (7.03 mmol) of 4-chloroanthranilic acid were treated in the same way as in Example 5 to obtain 1.5 g (yield 53%) of 3-(4-allyloxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. 500 mg (1.27 mmol) thereof was similarly treated to obtain 405 mg of the above-identified compound (yield 90%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.98 (2H, d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1-H, d), 8.00 (2H, d), 11.25 (1H, br).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:15]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[C:13]#[N:14])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCc1ccc(C=O)cc1
Reactant: CCCCOc1ccc(CC#N)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCCCCCCc1ccc(C=C(C#N)c2ccc(OCCCC)cc2)cc1
Temperature: 70 °C

Procedure:
9.4 g of p-butoxyphenylacetonitrile and 10.2 g of p-heptylbenzaldehyde are dissolved in 30 ml of methanol. 5 ml of a 40% solution of benzyltrimethylammoniumhydrate in water are added to the solution. The whole is heated at 70° C for 30 minutes and then cooled. The precipitate is sucked off and recrystallized from successively methanol and petroleum ether (60 : 80). Melting point of the resulting compound is 34.5°-35.5.° C.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:9]([CH3:11])[O:10][C:4]=2[C:3]=1[CH:20]([CH3:22])[CH3:21].[CH3:23]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH3:11][CH:9]1[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]2[S:19][C:2]([CH3:23])=[C:3]([CH:20]([CH3:22])[CH3:21])[C:4]=2[O:10]1
Reactant: CB(O)O
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2sc(Br)c(C(C)C)c2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1sc2c(c1C(C)C)OC(C)CN(C(=O)OC(C)(C)C)C2
Yield: 81.8 %

Procedure:
A solution of tert-butyl 7-bromo-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (390 mg), methylboronic acid (239 mg), potassium phosphate (849 mg), tetrakis(triphenylphosphine)palladium (116 mg) and DME (4 mL) was stirred at 80° C. for 20 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (266 mg, 82%) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16](Cl)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CCO.CCOC(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(Cl)cc2c1=O
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(N3CCCC3)cc2c1=O
Yield: 41.9 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1yl)-6-chloro-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzonitrile (Example 18) (120 mg, 0.3 mmol), pyrrolidine (75 μL, 0.91 mmol) and sodium bicarbonate (76 mg, 0.91 mmol) were stirred in EtOH in a sealed tube at 150° C. for 16 h. After cooling, the reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by preparative HPLC yielded 54 mg (32%) of the title compound as a bright orange solid. 1H NMR (400 MHz, MeOD-d4): δ 8.40 (s, 1H), 7.64 (dd, 1H, J=7.6, 1.2 Hz), 7.48 (dt, 1H, J=7.6, 1.2 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.07 (d, 1H, J=7.6 Hz), 6.67 (s, 1H), 5.43 (s, 2H), 3.20-3.32 (m, 5H), 3.02-3.10 (m, 1H), 2.81-2.90 (m, 1H), 2.69-2.78 (m, 1H), 2.59-2.67 (m, 1H), 1.87-1.99 (m, 5H), 1.51-1.73 (m, 2H), 1.18-1.28 (m, 1H). MS (ES) [m+H] calc'd for C24H27N7O 430; found 430.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][N:39]1[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41](O)=[O:42]>>[CH3:1][N:2]([C:41](=[O:42])[C@@H:40]1[CH2:44][CH2:45][CH2:46][N:39]1[CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CN(C(=O)[C@@H]1CCCN1C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By allowing tert-butyl 4-(methylamino)piperidine-1-carboxylate to react with EDCI hydrochloride, HOBt and 1-methyl-L-proline, tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate was obtained. Then, trifluoroacetic acid was added thereto to obtain N,1-dimethyl-N-piperidin-4-yl-L-prolinamide.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]>FC(F)(F)S(O)(=O)=O>[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([I:1])[C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
N-Iodosuccinimide (3.31 g, 14.7 mmol) was added in portions over a 3-hour period to a stirred solution of 3-fluoro-4-methylbenzoic acid (2.27 g, 14.7 mmol) in trifluoromethanesulphonic acid (15 mL) at 0° C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgSO4) and dried to give the title compound (3.45 g, 59%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:4]=1[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=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]1>CO.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[C:4]([CH:27]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=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]1
Reactant: COc1ccc([N+](=O)[O-])cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-((2-methoxy-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (110 mg, 0.24 mmol) in methanol (3 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 11.0 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to afford 96.0 mg (94%). 1H-NMR (CDCl3, 500 MHz) δ 7.33-7.38 (m, 4H), 7.22-7.25 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 6.51 (dd, J=5.8, 2.7 Hz, 1H), 6.29 (d, J=2.8 Hz, 1H), 4.37 (s, 2H), 3.70-3.74 (m, 2H), 3.43 (s, 3H), 3.42 (s, 2H), 3.03-3.07 (m, 2H), 2.15-2.18 (m, 2H), 1.88-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 427.25 (MH)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8](#[N:12])[CH2:9][C:10]#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH:9]([C:8]#[N:12])[C:10]#[N:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CCC#N
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(C#N)C#N

Procedure:
Pivaloyl chloride (60 g) and malononitrile (33 g) were dissolved in methylene chloride (500 ml) and were placed in a flask equipped with a stirrer and a dropping funnel. Triethylamine (100 g) was added slowly with cooling over a period of 45 minutes. The triethylamine hydrochloride was removed and the filtrate was concentrated to about half volume. The solution was poured onto ice, acidified strongly with concentrated hydrochloric acid and the resulting product was filtered off and air dried.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH2:18][OH:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl]methanol (1.00 g) in acetonitrile were added tetra-n-propylammonium perruthenate (115 mg), N-methylmorpholine N-oxide (0.60 g) and molecular sieves 4A powder (1.15 g) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr, and the reaction mixture was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as crystals (yield 0.53 g, 53%).