Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1[O:13][CH2:14][CH2:15][O:16][C:6]=1[C:5]2=[O:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1.[O:31]1CC[CH2:33][CH2:32]1>CN(C)C1C=CN=CC=1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:18](=[O:20])[CH3:19])=[C:7]1[O:13][CH2:14][CH2:15][O:16][C:6]1=[C:5]2[O:17][C:32](=[O:31])[CH3:33]
Reactant: C1CCOC1
Reactant: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c2c(c(OC(C)=O)c3cc(Cl)ccc13)OCCO2
Reaction time: 1 h

Procedure:
A supension of 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone (2 g) in tetrahydrofuran was hydrogenated at 1 atm over 10% palladium-on-carbon (0.5 g). When the solution was colorless, a solution of acetic anhydride (4 g), pyridine (3.16 g) and 4-dimethylaminopyridine (0.2 g) in tetrahydrofuran (25 mL) was added. After 1 hour, the solution was filtered and evaporated, and the resdiue was dissolved in dichloromethane. The organic layer was washed with 1 M hydrcholoric acid and brine and then dried. The dried layer was filtered and evaported. Crystallization from ether gave 1.20 g of 6-chloro-2,3-ethylenedioxy-1,4-diacetyloxynaphthlene, mp 179°-180° C.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[O:4]=[O:5].[C:6]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(=O)CCCCC1.C(OCC)(=O)C.[Co]>[C:6]1(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1.[C:1]([O:4][OH:5])(=[O:3])[CH3:2].[CH:11](=[O:12])[CH3:10].[C:6]([OH:12])(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:2][C:1]([OH:4])=[O:3]
Reactant: O=O
Reactant: O=C1CCCCCO1
Agent: [Co]
Agent: CC=O
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)OO
Product: O=C(O)CCCCC(=O)O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
450 g of cyclohexanone, 1160 g of ethyl acetate used as a solvent and 0.08 g cobalt naphthanate containing 6% of Co as a catalyst were introduced in a batchwise type reactor of 2 liters. 360 g of acetaldehyde were then dropped therein for 5 hours and the reaction temperature was maintained at 40° C. 2.2 liter/hour of oxygen gas was introduced from the beginning of the acetaldehyde dropping until one hour after the end of the dropping. The composition of the solution obtained was ε-caprolactone: 10.4%, unreacted cyclohexanone: 11.7%, unreacted peracetic acid: 13.8%, unreacted acetaldehyde: 8.4%, by-produced adipic acid: 0.3%, caprolactone polymers: 0.50%, acetic acid: 21.16% and ethyl acetate which was the solvent: 55.0%.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[Cl:10][C:11]1[N:16]=[C:15]([CH:17]2[CH2:20][CH2:19]C2)[N:14]=[C:13]([NH:21][CH:22]2[CH2:24][CH2:23]2)[N:12]=1>>[Cl:10][C:11]1[N:16]=[C:15]([CH:17]2[CH2:20][CH2:19]2)[N:14]=[C:13]([NH:21][CH:22]2[CH2:23][CH2:24]2)[N:12]=1
Reactant: Clc1nc(NC2CC2)nc(C2CCC2)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(NC2CC2)nc(C2CC2)n1

Procedure:
This compound is recrystallized from hexane. Yield (calculated on the basis of cyanuric chloride): 71.5%. M.P.: 66°-67° C. 2-Chloro-4-cyclobutyl-6-cyclopropylamino-1,3,5-triazine. Crude yield (calculated on the basis of the cyanuric chloride): 23%. The product is used as such, without other purification, in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:10](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[CH:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(Cc1ccccc1)CCC2
Yield: 95.8 %

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxylic acid ethyl ester (3.4 g) in ethyl acetate (150 ml) is treated with 10 percent palladium on carbon (0.70 g) and reduced at 40 p.s.i. hydrogen pressure for 3 hours. Catalyst is filtered and the filtrate is evaporated to yield 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethyl)-3-quinolinecarboxylic acid ethyl ester (3.28 g) as an oil.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:16]I>O1CCCC1>[CH3:1][C@@H:2]([N:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH3:16])[C:3]([OH:5])=[O:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To 48 ml of a solution of Boc-D -Ala-OH (3.0 g, 15.9 mmol) in tetrahydrofuran (THF) was added 60% sodium hydride (1.9 g, 47.6 mmol) under ice-cooling and the mixture was stirred for 10 minutes. Then, methyl iodide (7.9 ml, 127 mmol) was added and the mixture was further stirred at room temperature for 22 hours. The reaction mixture was then concentrated under reduced pressure, ice-cooled, acidified with 10% citric acid-H2O, and extracted with ethyl acetate. The extract was washed with saturated NaCl-H2O, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane and the crystal crop was washed with hexane to provide the title compound. Yield 3.07 g (94.8%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[F:25]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(O)=O>>[F:25][C:10]1[CH:9]=[C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1[C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23]
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1F
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 2-Fluoro-4-(quinolin-2-ylmethoxyl)-benzoic acid provided the title compound. MS: (M+H m/z=341.2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])=O.B#B>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O=C(CCCCCBr)Nc1ccccc1O
Agent: B#B
Product: Oc1ccccc1NCCCCCCBr
Yield: 81 %

Procedure:
was prepared in 81% yield from 30.6 g (0.11 mol) of 6-bromo-N-(2-hydroxyphenyl)hexanamide according to the procedure of Example 1, part b, except that the amide was added to the diborane (inverse addition). The product was crystallized from acetonitrile by the addition of chloroform and then ether, mp 124°-126° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5]1([CH:10]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.C([BH3-])#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:10][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=CC1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCNCC1CCCC1

Procedure:
To 100 mL of methanol is added 5.7 g (0.1 mol) of 2-propen-1-amine, 9.8 g (0.1 mol) of cyclopentanecarboxaldehyde and 12 g (0.2 mol) of sodium cyanoborohydride. Adjust the pH to 6 with concentrated HCl and monitor the reaction with thin-layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of ether. Add 1N NaOH to the aqueous solution until it is basic and extract twice with 200 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Br)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][SH:25].CCN(C(C)C)C(C)C.Cl>C(O)C.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][S:25][CH2:24][C@@H:23]([C:26]([OH:28])=[O:27])[NH2:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCBr)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N[C@@H](CSCCCC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
The title compound of example 1 (3.0 g, 8.72 mmol) was added to a solution of L-cysteine (1.0 g, 8.26 mmol) and DIEA (4.4 mL, 24.7 mmol) in EtOH-H2O (1:1, 100 mL). The resulting heterogeneous mixture was stirred vigorously at room temperature (20°-22° C.) for 18 h. The mixture was rendered acidic by the addition of 1N HCl (ph=6). The solid in the reaction mixture was collected on a filter and washed with H2O and EtOH. A suspension of the solid in EtOH (70 mL) was heated with stirring then allowed to cool. The solid in the suspension was collected on a filter, washed with EtOH, Et2O and dried to give the title compound (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:24])[C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([N+:14]([O-])=O)[CH:13]=1>[Pd].C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:24])[C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2c(F)cncc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(-c2c(F)cncc2F)c(-c2cccnc2)nc1N
Reaction time: 12 h
Yield: 98.9 %

Procedure:
A suspension of 3″,5″-difluoro-5′-nitro-3,2′:3′,4″-terpyridin-6′-amine (0.2 g, 0.608 mmol) and 10% palladium on carbon (0.04 g) in a mixture of THF/ethanol 40:60 (8 mL) was stirred under hydrogen atmosphere at 2.76 bar. After 12 h, the mixture was filtered through Celite® and the filter cake was washed with ethanol and THF. The combined filtrate and washings were evaporated to give the title compound as a solid (0.180 g, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NCCN(C)C)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(c1nc2ccsc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-7, 0.030 g, 0.081 mmol) was dissolved in DCE (1.0 mL) and treated successively with 4-bromo-benzoylchloride (0.026 g, 0.12 mmol) and TEA (0.03 mL, 0.24 mmol). The reaction was stirred at 25° C. for 1 h. The reaction was diluted with DCM (10 mL), washed with 5% NaHCO3 and dried over MgSO4. The organics were concentrated under reduced pressure and subjected to flash column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) to provide N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-8). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=5.2 Hz, 1H), 7.54 (m, 2H), 7.32 (m, 5H), 7.15 (m, 2H), 6.11 (d, J=16.0 Hz, 1H), 5.96 (t, J=7.0 Hz, 1H), 5.12 (d, J=16.0 Hz, 1H), 3.40 (m, 2H), 2.04 (m, 2H), 1.85 (m, 1H), 1.77 (s, 6H), 1.59 (m, 1H), 0.65 (t, J=6.9 Hz, 3H); MS 553.1 found, 553.5 required.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[C:21](=[N:26]\[O:27][CH3:28])/[C:22]([NH:24][CH3:25])=[O:23])[CH:10]=[CH:9][CH:8]=1.Cl>O>[CH3:1][O:2][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[C:21](=[N:26]\[O:27][CH3:28])/[C:22]([NH:24][CH3:25])=[O:23])[CH:10]=[CH:9][CH:8]=1
Reactant: C[O-]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(OC)n1
Reaction time: 4 h

Procedure:
28% sodium methoxide--methanol solution (1.16 g) was added to (E)-2-[2-(6-chloropyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (400 mg), and the mixture was heated under reflux with stirring for 4 hours. The mixture was neutralized with 1N hydrochloric acid, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (61 mg). mp. 81°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O-])=[O:13].[Na+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH:12]=[O:13]
Reactant: O=C[O-]
Reactant: COc1cc(I)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1Cl
Yield: 44.1 %

Procedure:
A mixture of 22.6 g of 2,4-dichloro-5-iodo-1-methoxybenzene, 7.61 g of sodium formate, 1.05 g of dichlorobis(triphenylphosphine) palladium, and 60 ml of N,N-dimethylformamide was stirred, while bubbling carbon monoxide at 90° to 100° C. over 12 hours. After completion of the reaction, the reaction mixture was returned to room temperature, followed by dilution with diluted hydrochloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 6.75 g (yield, 44%) of 2,4-dichloro-5-methoxybenzaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([F:7])[F:6].C(=O)([O-])[O-].[K+].[K+].[SH:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>ClCCl>[F:6][C:5]([F:7])=[CH:4][CH2:3][CH2:2][S:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Sc1nc2ccccc2s1
Reactant: FC(F)=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: FC(F)=CCCSc1nc2ccccc2s1
Temperature: 55 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
To the solution of 4-bromo-1,1-difluorobut-1-ene prepared in Example 6 was added potassium carbonate (10.76 g) and 2-mercaptobenzthiazole (9.18 g). The mixture was stirred at 55° C. for 6 hours and then at room temperature overnight. Gas-liquid chromatography of a sample of the reaction mixture showed that a small amount of 4-bromo-1,1-difluorobut-1-ene remained. More potassium carbonate (1.0 g) was added and the mixture heated for another two and a half hours at 55° C., when all of the bromo compound had been consumed. The mixture was cooled to room temperature and filtered. The residue was washed with acetone and the filtrate and washings combined and evaporated under reduced pressure to give the crude product (16.18 g). This was dissolved in dichloromethane. The solution was filtered and washed with dilute sodium hydroxide (2×25 ml) and with brine (2×25 ml), dried over magnesium sulphate, filtered, the filtrate evaporated to give 2-(4,4-difluorobut-3-enyl)thiobenzthiazole, having a gas chromatographic retention time identical with that of an authentic sample. The yield was 63% based on the quantity of 1,4-dibromo-1,1,2-trifluorobutane used in step (b) of Example 1. 2-(4,4-Difluorobut-3-enyl)thiobenzoxazole was prepared in the same way, but using 2-mercapto benzoxazole instead of 2-mercapto benzthiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]=[C:25]=[S:26]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:25]([NH:24][CH3:23])=[S:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 108.4 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 124 mg of methyl isothiocyanate was added and the mixture was heated to reflux for 3.5 hours. The reaction solution was filtered with NH silica gel and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (537 mg, 100% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[C:3]1=[O:26].OOS([O-])=O.[K+].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[C:3]1=[O:26]
Reactant: CSc1ncc2cc(-c3cc(-c4nnc[nH]4)ccc3C)c(=O)n(C)c2n1
Reactant: NC1CCOCC1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1ccc(-c2nnc[nH]2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O

Procedure:
8-Methyl-2-methylsulfanyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 8-methyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=418, MP=214.9-216.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 95.7 %

Procedure:
A reactor was charged with acetic acid (8.7 L), followed by N-(4-tert-butylphenyl) acetamide (Preparation 110, 6.0 kg, 31.4 mol), The mixture was stirred for ten minutes, followed by the addition of acetic anhydride (6.47 kg, 63.4 mol) slowly at room temperature. The reaction was stirred for fifteen minutes. A solution of fuming nitric acid (3.56 kg, 56.5 mol) in acetic acid (2.1 L) was added slowly at 20-25° C., and stirred at that temperature for another 2 hours. The reaction mixture was added to ice water (42 L) at 10-15° C. and the mixture stirred for one hour. The resulting solids were collected by filtration, washed with water (17 L) and dried at 65-70° C. to provide 7.1 kg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:14]([OH:15])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A solution of phenol (Kappe, T.; Witoszynskyj, T. Arch. Pharm. (1975), 308 (5), 339-346) (1.14 g, 5.00 mmol) in THF (15 mL) was cooled in a dry ice/acetone bath and treated dropwise with phenyllithium (7.5 mL, 13.5 mmol, 1.8M in cyclohexane/ethyl ether 70/30). The reaction mixture was allowed to warm gradually to ambient temperature. After 18 h, the reaction was quenched with aqueous saturated NH4Cl solution (1 mL) and partitioned between ethyl acetate (50 mL) and 1N HCl (20 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a brown oil (2.3 g). The crude product was purified by flash chromatography using hexanes:ethyl acetate (3:1 to 2:1) to give a pale yellow oil (1.42 g, 93%): 1H NMR (400 MHz, CDCl3) δ2.79 (s, 1H), 4.92 (s, 2H), 5.95, (s, 1H), 6.51 (s, 1H), 6.81 (d, 3H, J=1.5 Hz), 7.28-7.38 (s, 10H); MS (ES) m/e 305 [M−1].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH:22](I)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH:22]([CH3:24])[CH3:23])=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: CC(C)I
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(Cl)cc(F)c(N2C(=O)C3C=CCCC3C2=O)c1N

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), isopropyl iodide (1.2 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 2 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.21 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH2:5])[CH3:2].[C:6]1(C)[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+].C1C[O:27][CH2:26][CH2:25]1>>[CH2:4]([O:3][CH:1]=[CH:2][C:6]1([O:27][CH2:26][CH3:25])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)[CH3:5]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC=CC1(OCC)C=CC=CC1
Reaction time: 12 h

Procedure:
After dissolving 12 g of poly-hydroxystyrene (poly(HST)) in 60 ml of THF, 3.6 g of ethylvinylether was added to the solution. The p-toluene sulfonic acid (p-TSA) was added to the mixture in sufficient quality to act as a catalyst, and reacted for 12 hours at room temperature. After 12 hours, the reaction product was slowly dropped into water in a ratio of 5 parts water to one part reaction product, and neutralized using potassium carbonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC#N)CCC2c2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)N2C(CCCC(N)=O)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile (2.0 g, 5.17 mmol) and conc. sulfuric acid (20 ml) was stirred at RT for 17 h, poured into 150 ml ice/water and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water (100 ml), dried (MgSO4) and evaporated to give the title compound as a white foam, MS: m/e=404 (M+).