Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:24]([C:23]1[CH:26]=[C:27]([CH3:28])[C:20]([O:19][CH2:18][CH2:17][O:16][CH3:15])=[C:21]([CH3:29])[CH:22]=1)=[N:1]2
Reactant: COCCOc1c(C)cc(C=O)cc1C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 150 °C
Yield: 43.4 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxybenzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O.C([BH3-])#N.[Na+].CO>CO.C(O)(=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:26])[F:27])[CH:16]=3)[CH:31]([CH3:33])[CH3:30])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(F)(F)COc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(CCc1c[nH]c2cc(Cl)ccc12)Cc1cccc(OCC(F)(F)C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Combine N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzylamine (254 mg, 0.59 mmol) in 20 mL of 95:5 methanol-acetic acid, treat with acetone (441 μL, 5.9 mmol) followed by sodium cyanoborohydride in portions (148 mg, 2.3 mmol). Stir the reaction mixture at 50° C. overnight; then at room temperature for an additional 2 days. Remove the solvent in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 4% methanol in dichloromethane to give the title compound as a colorless oil. Dissolve the oil (237 mg, 0.49 mmol) in methanol (15 mL) and treat with a solution of ammonium chloride (27 mg, 0.49 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before concentrating it to a tacky white solid. Dissolve the tacky solid in 10 mL of 1:1 acetonitrile-water and lyophilize to give 241 mg (96%) of the title compound as the hydrochloride: mp: 77.0–80.2° C.; 1H NMR (400 MHz, methanol-d4): 7.31 (br t, 1H, J=7.8 Hz), 7.26–7.21 (m, 1H), 7.16 (br d, 1H, J=8.4 Hz), 7.15–7.07 (m, 2H), 7.05–6.95 (m, 2H), 6.83 (dd, 1H, J=8.0, 2.0 Hz), 4.52 (t, 2H, J=12.8 Hz), 4.12 (br s, 2H), 3.53 (br s, 1H), 3.11 (br s, 2H), 2.89 (br s, 2H), 1.27 (br s, 6H); MS (APCI): m/e 475.1 (M+1).
Reaction SMILES: [P:1]([O-:16])([O:9][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][CH2:12]1)[O:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][CH2:5]1.[O:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH3:19].[Na].[C:25]([OH:28])(=O)[CH3:26]>C1C=CC=CC=1>[O:9]=[P:1]1([O:2][CH2:3][CH:4]2[O:28][CH2:25][CH2:26][CH2:5]2)[C:21]([CH3:23])([CH3:22])[CH2:20][C:18]([CH3:19])([P:1]([O:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][CH2:5]2)([O:9][CH2:10][CH:11]2[O:15][CH2:14][CH2:13][CH2:12]2)=[O:16])[O:17]1
Reactant: [O-]P(OCC1CCCO1)OCC1CCCO1
Reactant: CC(=O)O
Reactant: CC(=O)C=C(C)C
Agent: [Na]
Solvent: c1ccccc1
Product: CC1(C)CC(C)(P(=O)(OCC2CCCO2)OCC2CCCO2)OP1(=O)OCC1CCCO1

Procedure:
As described in Example 1, a mixture of 37.6 g of bis-(tetrahydrofurfuryl) phosphite and 4.9 g of mesityl oxide in 80 ml of benzene was reacted by heating in the presence of 1.3 g of sodium over the course of 1 hour. The reaction was vigorously exothermic. The sodium was neutralized by addition of 3.4 g of glacial acetic acid. The inorganic salt was extracted from the mixture with 2 portions of 20 ml of water. The benzene solvent was removed in a rotary evaporator, leaving as residue 32.6 g of crude product which still contained di-tetrahydrofurfuryl phosphite. Distillation of 4.3 g of the crude product in a bulb tube oven in high vacuum yielded the desired product at an oven temperature between 185° C. and 230° C. and a pressure of 0.01 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[C:6]2[OH:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2nccc(O)c2n1
Product: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Temperature: 67 °C
Yield: 70 %

Procedure:
Fuming HNO3 (500 mL) was cooled to 10-15° C. and the compound of Example 1 (80 g, 1 eq.) was added in portions over a period of 20 min. The reaction mixture was heated to 67° C. for 4 h. The mixture was cooled to 20° C. and added to ice (2 kg) with stirring. The yellow suspension was filtered and the product was washed with water (1500 mL). After drying, a yellow solid (70 g; 70% yield) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([CH2:25][N:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[CH:30]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(CN2CCOCC2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CN2CCOCC2)n[nH]1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.147 g, 0.56 mmol), 3-(morpholinomethyl)-1H-pyrazole-5-carboxylic acid (0.119 g, 0.56 mmol), HOBt (0.114, 0.84 mmol), DIPEA (0.29 mL, 1.69 mmol) and EDCI (0.162 g, 0.84 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 0.256 g. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 2.44 (m, 4H), 3.59 (s, 2H), 3.67 (m, 4H), 4.35 (m, 2H), 4.55 (m, 1H), 6.62 (bs, 1H), 6.74 (d, 1H), 7.69 (d, 1H), 7.76 (d, 1H), 7.88 (m, 1H), 8.00 (m, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][C:12](=[N:17][NH:18][C:19](N)=O)[C:13]([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>O.C(OCC)C>[C:13]([C:12]1[C:11]([CH:9]=[O:10])=[CH:19][NH:18][N:17]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=NNC(N)=O)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1n[nH]cc1C=O
Temperature: 60 °C
Yield: 6.3 %

Procedure:
Phosphorus oxychloride (18.2 mL, 195 mmol) was added portionwise to DMF (30 mL, 387 mmol) at <5° C. Pinacolone semicarbazone (15.4 g, 97.6 mmol) was added over 1 h maintaining the temperature at <5° C. The reaction mixture became very thick so an additional quantity of DMF (10 mL) was added. The mixture was heated to 60° C. for 3.5 h then allowed to cool and poured into ice. The reaction was neutralised using sodium hydroxide (40 g, 1 mol) in water (130 mL) then heated at 60° C. for 5 min. The mixture was cooled in an ice bath and acidified to pH 6 and the product extracted into EtOAc. The EtOAc was dried over MgSO4 and concentrated onto silica. The crude product was purified by flash chromatography using eluants EtOAc/heptane. Trituration in diethyl ether gave a white solid (1.02 g, 6.1 mmol, 6%).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[OH:13])[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2].[CH2:26]1COCC1.CI.[H-].[Na+]>CCOC(C)=O>[CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@@H:12]([O:13][CH3:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](OC)c1ccc(C(F)(F)F)cc1
Temperature: 10 °C
Yield: 88 %

Procedure:
To a mixture of (S)-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (4.09 g, 11.4 mmol) (prepared as shown in Scheme 27) and THF (60 mL) at 0° C., was added methyl iodide (4.28 mL, 68.5 mmol) and sodium hydride (60% dispersion in mineral oil, 0.55 g, 13.7 mmol). The mixture was stirred and gradually warmed to 10° C., then diluted with EtOAc and washed with saturated NH4Cl. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by chromatography on silica gel (0-10% EtOAc-hexane) to provide the title product as a white solid (3.7 g, 88%). LCMS (API-ES) m/z: 373 (M+H+).
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([NH:13][C:14]1([CH3:22])[C:18]2([CH2:20][CH2:19]2)[C:17](=[O:21])[NH:16][CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([N:16]1[CH2:15][C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])([CH3:22])[C:18]2([CH2:19][CH2:20]2)[C:17]1=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.67 h
Yield: 98 %

Procedure:
A dimethylformamide solution (65 mL) of 7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-4-one (3.12 g, 12.97 mmol) was added sodium hydride (55%, mineral oil dispersion, 538 mg, 12.33 mmol) over 5 minutes under cooling with ice. This solution was stirred at the same temperature for 40 minutes. After that, to the solution was added benzyl bromide (1.851 mL, 15.56 mmol), and the mixture was stirred at room temperature for 1.5 hours. To this reaction mixture was added ethyl acetate (300 mL) to dilute the mixture, and the mixture was washed with water (100 mL, ×2) and saturated brine (100 mL). To the solution was added anhydrous sodium sulfate to dry the solution. The drying agent was removed by filtration, and then the solvent was removed under reduced pressure. Thus-obtained residue was purified with silica gel column chromatography (hexane/ethyl acetate in the ratio of and in the order of 9:1, 4:1, and 2:1) to obtain 4.20 g (12.71 mmol, 98%) of the target compound as a transparent and colorless gum-like solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.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>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([C:37]4[N:33]([CH:28]5[CH2:29][CH2:30][CH2:31][CH2:32][O:27]5)[N:34]=[CH:35][CH:36]=4)[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
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: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccnn2C2CCCCO2)n1
Temperature: 120 °C
Yield: 3.7 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (300 mg, 0.666 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (222 mg, 0.799 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.020 mmol), THF and 2M Na2CO3 solution were added in a microwave flask and heated in microwave at 120° C. for 2 h. 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (37 mg) and tetrakis(triphenylphosphine)palladium (8 mg) were added and the reaction mixture was heated in 120° C. for 1 h. The reaction mixture was diluted with DCM and washed twice with Na2CO3 solution. Organic phase was dried and evaporated to dryness. The product was purified by Flash-chromatography. Yield 3.7%. m/z [522.0+1].
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([CH2:22][CH:23]=O)=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:15][C:16]1[C:21]([CH2:22][CH2:23][NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1
Reactant: O=CCc1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Sodium triacetoxy borohydride (9.47 g) was added to a THF (60 mL) solution of (2,6-dichloropyridin-3-yl)acetaldehyde (5.66 g) and tert-butyl 4-aminopiperidine-1-carboxylate (7.16 g), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (10.5 g).
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([S:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14].[OH-].[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:12])=[O:1])[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14]
Reactant: OO
Reactant: COc1cc(SC)c(C)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)c(C)cc1O

Procedure:
10% v/v Aqueous hydrogen peroxide (27 ml) was added to 2-methoxy-5-methyl-4-(methylthio)phenol (1.72 g) in glacial acetic acid (15 ml). After 24 hours the acetic acid was neutralised with 2 N aqueous sodium hydroxide and the product was extracted into methylene chloride (100 ml). The organic extract was washed with 10% w/v aqueous sodium sulphite solution and water, dried (Na2SO4) and the solvent was removed in vacuo. Recrystallisation from ethanol/diethyl ether gave 2-methoxy-5-methyl-4-methylsulphinylphenol (0.16 g) as colourless crystals m.p. 166°-168° (identical to that prepared in (i) above).
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@@H:9]([OH:37])[CH2:10][C@@H:11]([NH:26]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:37])[C@@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(C[C@H](N)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing the product from Example 92G (0.198 g, 0.325 mmol) in a mixture of methanol (1.6 mL) and ethyl acetate (1.6 mL) was treated with Pd(OH)2 on carbon (0.060 g, 20% Pd by wt.) and HCl solution (0.080 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 18 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.CCCCCC>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:16][CH2:15][S:14](=[O:33])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCSCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
In dichloromethane (30 ml) was dissolved 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran (200 mg, 0.508 mmol). Under ice cooling, 3-chloroperbenzoic acid (106 mg, 0.614 mmol) was added. After stirring at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (163 mg, 0.403 mmol, 79%) was obtained as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.ON1C(=O)CCC1=O.FC(F)(F)C(O)=O.[NH2:28][CH2:29][C:30]1[C:31]([F:49])=[C:32]([F:48])[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[F:47])=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]>C(Cl)Cl>[C:1]([NH:28][CH2:29][C:30]1[C:31]([F:49])=[C:32]([F:48])[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[F:47])=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acryloyl chloride (100 μL, 0.986 mmol) and triethylamine (689 μL, 4.93 mmol) were added to a solution of hydroxy-pyrrolidine-2,5-dione (commercially available, 227 mg, 1.973 mmol) in methylene chloride (anhydrous, 2 mL), and the mixture was stirred at room temperature for 30 minutes. 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (150 mg, 0.355 mmol) obtained in Step A was added to this solution, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-(acryloylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid as a white solid. This product was confirmed for the structure by LC/MS. LC/MS (positive mode) m/z 477 (M+1). This compound was dissolved in methylene chloride (anhydrous, 10 mL) under argon flow. N,N-diisopropylethylamine (250 μL, 1.42 mmol), O-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-hydroxylamine (135 mg, 0.71 mmol), 1-hydroxy-1H-benzotriazole (71 mg, 0.533 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.533 mmol) were added sequentially to the solution. The mixture was stirred at room temperature for 20 hours.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH-:11].[Na+]>>[OH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: [OH-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)nc1
Temperature: 102 °C
Yield: 60 %

Procedure:
A mixture containing 500 g (3.6 mol) of 2-amino-5-nitropyridine in 2000 ml of 10% sodium hydroxide was refluxed at about 102° C. for 10 hours, cooled and filtered. The filter cake was dissolved in water and neutralized with hydrochloric acid. The product was filtered and dried to give 301.7 g (60%) of product as a white powdery solid, m.p. 188°-190° C.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2.O>C1(C)C=CC=CC=1.[Ti]>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal, 67 mg of 5-amino-2-methylquinoline and 163 μl of titanium tetraethylate are stirred in 8 ml of toluene for 2 hours at 100° C. After cooling, the batch is mixed with 2 ml of water, stirred for 15 minutes at room temperature, and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 111 mg of product.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.C[O-].[Na+].Cl.[CH:23]([NH2:25])=[NH:24]>CO>[OH:14][C:13]1[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)=[C:8]([OH:9])[N:25]=[CH:23][N:24]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(O)ncnc2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
At 0° C. a solution of diethyl 2-(p-tolyl)-malonate (14.2 g) in methanol (50 ml) was slowly added to a solution of sodium methylate (9.4 g) in methanol (300 ml). Upon completion of the addition the reaction mixture was allowed to warm up and formamidine hydrochloride (5.4 g) was added. The mixture was stirred at r.t. for 16 h. The solvent was removed under reduced pressure and the remaining residue was treated with 2 N hydrochloric acid (150 ml). The suspension was stirred for 0.5 h. At 0–5° C., the pH was carefully adjusted to 4 using 10 N sodium hydroxide solution. The precipitate was collected, washed with cold water, isopropanol, and diethyl ether and dried under high vacuum at 65° C. to give 4,6-dihydroxy-5-(p-tolyl)-pyrimidine (11.2 g) (or a tautomer) as a white powder.