Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([NH:21][C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:24](C3CCCCO3)[N:23]=2)=O)=[N:8]1.CO.Cl>C1COCC1>[C:30]1([CH3:33])[CH:31]=[CH:32][C:27]([C:25]2[NH:24][N:23]=[C:22]([NH:21][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[NH:7][N:8]=3)[CH:26]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(-c4ccc(C)cc4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CNc3cc(-c4ccc(C)cc4)[nH]n3)n[nH]2)cc1
Temperature: 0 °C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (142 mg, 0.27 mmol) was suspended in anhydrous THF (10 mL) and borane dimethylsulfide complex (177 μL, 1.86 mmol) was added dropwise. The reaction mixture was stirred under reflux for 16 hrs. The reaction mixture was then cooled down to 0° C. and MeOH (500 μL) was added. The mixture was then stirred for 10 min. Concentrated hydrochloric acid (12 N) was added, until a pH<2 was obtained, and the resulting mixture was stirred under reflux for 16 hrs. The mixture was cooled to room temperature and the precipitate was filtered and added into an aqueous solution of sodium hydroxide (1M). The aqueous phase was extracted with DCM (3×10 mL) after drying the organic layers with Na2SO4, the solvent was evaporated. The residue was purified by chromatography on silica gel column (eluent: EtOAc); 5-p-tolyl-N-((5-p-tolyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-3-amine was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)(O)[CH3:11])[NH:7][CH:8]=1.C1C=CN=CC=1.[FH:34].C[Si](C(O)C)(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)([F:34])[CH3:11])[NH:7][CH:8]=1
Reactant: F
Reactant: CC(C)(C)Cc1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: CC(O)[Si](C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)Cc1c[nH]c(CC(C)(F)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]propan-2-ol (250 mg, 0.68 mmol) in a minimal volume of methylene chloride was added to HF-pyridine (0.5 mL). After stirring at ambient temperature for 1 h, the reaction was added dropwise to trimethylsilylethanol at 0° C. and concentrated in vacuo azeotroping with toluene. The residue was partitioned between ethyl acetate and 1 M aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. High pressure liquid chromatography (Chiralcel AD column) eluting with 20% isopropanol/heptane afforded the separate enantiomers. 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J=2.7 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.69 (dd, J=4.3, 8.7 Hz, 1 h), 7.48-7.42 (m, 3h), 6.62 (s, 1H), 3.39 (d, J=25.4 Hz, 1H), 2.39 (s, 2H), 1.68 (d, J=22.8, 3H), 0.86 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:17])=[O:4].[H-].[Na+].CI.[C:22](OCC)(=O)C>O1CCCC1.O>[CH3:22][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:17]
Reactant: COC(=O)C1CCc2c(OC)cccc2C1=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC(=O)C1(C)CCc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (3.9 g) in tetrahydrofuran (50 ml) were added NaH (0.73 g, 60% in oil) and then methyl iodide (3 ml) at 0° C. under N2. After being stirred for 1 hour at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-methyl-2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](O)OC.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C@H:15](/[N:17]=[CH:4]\[C:3]([O:2][CH3:1])=[O:8])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)C(O)OC
Solvent: Cc1ccccc1
Product: COC(=O)/C=N\[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-2-methoxyacetic acid methyl ester (151 g) in toluene (300 mL), was added (R)-(+)-1-phenylethylamine (150 g) dropwise. The mixture was then stirred for 1 hr at room temperature. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to obtain the target compound as a yellow oil. The target compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (24.6 mg, 0.090 mmol) in CH2Cl2 (2 mL) was added 4-fluorophenyl isocyanate (0.12 μL, 0.107 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 125 as a colorless solid (27.0 mg, 73%). LCMS m/z (%)=412 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (bs, 1H), 8.58 (bs, 1H), 7.48-7.41 (m, 4H), 7.36 (d, J=2.70 Hz, 1H), 7.14-7.06 (m, 3H), 6.23 (d, J=1.82 Hz, 1H), 3.97 (t, J=6.34 Hz, 2H), 3.65 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH3:5][Si:6]([CH3:37])([CH3:36])[O:7][C@H:8]1[CH2:31][C@@:30]2([CH3:32])[C@@H:19]([CH2:20][CH:21]=[C:22]2[C:23](=[O:29])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:18]2[C@H:9]1[C@:10]1([CH3:35])[C:15]([C@@H:16]([F:33])[CH2:17]2)=[CH:14][C:13](=[O:34])[CH:12]=[CH:11]1.[Cl-].[NH4+]>ClCCl>[CH3:37][Si:6]([CH3:5])([CH3:36])[O:7][C@H:8]1[CH2:31][C@@:30]2([CH3:32])[C@@H:19]([CH2:20][C@@H:21]([CH3:2])[C@@H:22]2[C:23](=[O:29])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:18]2[C@H:9]1[C@:10]1([CH3:35])[C:15]([C@@H:16]([F:33])[CH2:17]2)=[CH:14][C:13](=[O:34])[CH:12]=[CH:11]1
Reactant: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: -10 °C

Procedure:
750 mg cuprous iodide was suspended in 10 ml dichloromethane in an atmosphere of nitrogen and cooled to -10° C. To this suspension under stirring and cooling was added 9 ml of a 2% solution of lithium-methyl by drop wise addition maintaining the temperature below -5°. To the so obtained lithium-dimethyl-copper solution was added 425 mg 11β-trimethylsiloxy-21-acetoxy-6α-fluoropregna-1,4,16-triene-3,20-dione obtained according to Example 8 dissolved in 3 ml dichloromethane. The temperature of the reaction mixture was kept below -1°, and the stirring was maintained for a period of 15 minutes. The reaction mixture was poured into an aqueous ammonium chloride solution, the organic phase separated and the aqueous phase re-extracted with dichloromethane. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Trituration with acetone afforded a crystalline product 11β-trimethylsiloxy-21-acetoxy-6α-fluoro-16α-methyl-pregna-1,4-diene-3,20-dione (compound 14) yield 320 mg TLC: homogeneous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(F)c(C)c1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Cc1cc(-c2cc(-c3cncc(Cl)c3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 4-ethynyl-1-fluoro-2-methylbenzene (Aldrich, 40 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ2.34 (d, J=2.0 Hz, 3H), 7.38 (t, J=9.2 Hz, 1H), 7.72 (s, 1H), 7.74-7.81 (m, 1H), 7.84-7.91 (m, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.07 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 289 (M+H)+, 291 (M+H)+.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)=[O:6].O>CO>[O:6]1[C:5]([C:7]2[CH:27]=[CH:26][C:10]3[N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]5[CH:25]=[CH:24][N:23]=[CH:22][N:21]=5)[CH:15]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Solvent: O
Solvent: CO
Product: c1cc(-c2ccncn2)cc(-n2cnc3cc(-c4ccno4)ccc32)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 5-(3dimethylamino-1-oxo-2-propen-1-yl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (307 mg) and NH2OH,HCl (135 mg, 2.5 equivalents) in methanol (14 ml) was stirred at 80° C. for 2 hours. After cooling the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographied (CH2Cl2 -methanol 40:1 (v/v)) to give 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (226 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)=[CH:5][CH:4]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OC)(OC)OC>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=2)[S:10][CH:11]=1
Reactant: O=C(O)Cc1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: CO
Solvent: O
Product: COC(=O)Cc1csc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 338.5 %

Procedure:
A solution of [2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid (3 g, 10.4 mmol) and p-toluenesulfonic acid mono-hydrate (0.5 g, 2.6 mmol) in methanol (30 ml) and trimethyl orthoformate (2 ml) was heated under reflux for 5 hours. After neutralization with aqueous sodium bicarbonate solution and evaporation of the solvents under reduced pressure, the residue was redissolved in tert-butyl methyl ether and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.65 g (8.8 mmol, 84%) of [2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester as light brown solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:15]=1[C:16]1[C:17]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([C:27]([OH:29])=[O:28])[N:19]=[CH:20][C:21]=1[NH:22]2>O1CCCC1>[N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:15]=1[C:16]1[C:17]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([C:27]([OH:29])=[O:28])[N:19]=[CH:20][C:21]=1[NH:22]2
Reactant: c1c[nH]cn1
Agent: COCCOCc1c(C(=O)O)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: c1c[n-]cn1
Reaction time: 8 h

Procedure:
1.5 g (0.0022 mol) of imidazole in 20 ml of tetrahydrofuran is mixed with 0.4 ml (0.0054 mol) of thionylchloride dissolved in 5 ml of tetrahydrofuran. The precipitate is suctioned off, the filtrate is instilled in a suspension of 0.693 g (0.00163 mol) of 5-(2-chlorobenzyl)-4-methoxyethoxymethyl-β-carboline-3-carboxylic acid in 30 ml of tetrahydrofuran. After it is left standing overnight the solvent is distilled off, the residue is dissolved in ethyl acetate, the solution is washed imidazole free with water. After concentration by evaporation 0.55 g (71% of theory) of 5-(2-chlorobenzyl)-4-methoxyethoxymethyl-β-carboline-3-carboxylic acid imidazolide remains.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:3]=12.[C:14]([Cu])#[N:15]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:11]([N:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:14]#[N:15])[C:3]=2[CH:10]=[CH:9]1)(=[O:13])[CH3:12]
Reactant: CC(=O)n1ccc2c(I)ccnc21
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)n1ccc2c(C#N)ccnc21

Procedure:
A mixture of 1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanone (4.30 g), CuCN (6.841 g), Pd2 dba3 (0.729 g), and dppf (1.636 g) in 85 mL of dioxane was heated to reflux for 2 h. Solid was removed by filtration through a pad of Celite®. The filtrate was concentrated to give a yellow solid as crude compound, which was purified by chromatography through silica gel (250 g, 5-30% EtOAc/hexanes, stepwise gradient) to afford 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile as a white fluffy solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:14][CH:15]=2)=[N:4][CH:3]=1
Reactant: OCCCCCCCCCl
Reactant: O=Cc1ccc(-c2ncc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(-c2ncc(OCCCCCCCCO)cn2)cc1
Yield: 55 %

Procedure:
A solution of 6.1 g of 4-(5-hydroxypyrimidin-2-yl)benzaldehyde and 6.0 g of 8-chloro-1-octanol in 100 ml of ethyl methyl ketone was treated with 16.9 g of finely powdered potassium carbonate and the mixture was heated under slight reflux overnight. The suspension was suction filtered and the filtrate was concentrated in a vacuum. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) gave 5.5 g of 4-(5-[8-hydroxyoctyloxy]-pyrimidin-2-yl)benzaldehyde.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:6]=[CH:7][S:8](Cl)(=[O:10])=[O:9]>CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:6]=[CH:7][S:8]([NH2:1])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)c(Cl)c1
Reactant: N
Solvent: CCOCC
Product: NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 97 %

Procedure:
Ammonia is bubbled through a solution of 3,4-dichlorostyrylsulfonyl chloride (27.2 g., 0.1 mole) in 250 ml. of ether for a period of 30 min. at about 20° C. The solvent is evaporated and the residue stirred with water, collected and dried at 100° C. under vacuum affords 24.6 g. (97% yield) of 3,4-dichlorostyrylsulfonamide, m.p. 127°-130° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25]Cl)=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9].[CH3:29][NH2:30]>CO>[OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][NH:30][CH3:29])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Reactant: CN
Solvent: CO
Product: CNCc1nc2c(c(=O)n(CCCC[C@H](C)O)c(=O)n2C)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (prepared as described for the synthesis of CT 30289) (2.3 g, 5.68 mmol) in methanol (50 ml) was added methylamine (40% in water, 50 ml). After stirring at room temperature for 2 hours, the solvent and excess reagent were evaporated under reduced pressure. A solution of triethylamine and ethanol (1:4) (100 ml) was added and then evaporated under reduced pressure to give (S)-1-(5-hydroxyhexyl)-7-benzyl-8-methylaminomethyl-3-methylxanthine as a white powder.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:12]([S:14]([C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH:22]=1)(=[O:16])=[O:15])[CH3:13]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([O:8][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:22][C:21]=2[C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH2:4][CH2:3]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3cncn23)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC2CCC(F)(F)CC2)c(-c2cn(C)c(=O)c3cncn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]#[N:11].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-:17])=[C:4]([CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)c(C#N)c(C)n1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C#N)c(C)[n+]1[O-]
Reaction time: 8 h

Procedure:
50 g (0.3 mol) of 4-chloro-3-cyano-2,6-dimethylpyridine were dissolved in 1 L of dichloromethane and, at room temperature, 130 g (0.6 mol) of 80% pure m-chloroperoxybenzoic acid were added in portions, and the mixture was stirred overnight and the precipitated m-chlorobenzoic acid was filtered off. Water was added to the filtrate, the pH was adjusted to 12 with solid potassium hydroxide, and the two phases were shaken together to extract. The dichloromethane phase was separated off, dried over sodium sulfate, filtered and evaporated. 4-Chloro-3-cyano-2,6dimethylpyridine 1-oxide was obtained as a solid compound which sintered at 140° C. Yield: 49.3 g (90% of theory).
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10](Cl)[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc(SC)nc(Cl)c1C=O
Reactant: OB(O)c1ccccc1F
Product: CCC(C)Nc1nc(SC)nc(-c2ccccc2F)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-sec-butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.96 (m, 3H), 1.30 (m, 3H), 1.67 (m, 2H), 2.58 (s, 3H), 4.38 (m, 1H), 7.11-7.31 (m, 2H), 7.42-7.58 (m, 2H), 9.07 (br s, 1H), 9.63 (s, 1H). LC MS (m/e)=306 (MH+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH:21]([O:42][CH2:43][N:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46][C:45]1=[O:51])[CH2:22][O:23][C:24](=[O:41])[C@H:25]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C1CC=CCC=1.O>[Pd].C(O)(=O)C>[NH2:11][C@H:12]([C:17]([O:19][CH2:20][CH:21]([O:42][CH2:43][N:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46][C:45]1=[O:51])[CH2:22][O:23][C:24](=[O:41])[C@H:25]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH2:26])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)OCn1ccc(N)nc1=O
Agent: [Pd]
Solvent: O
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)[C@@H](C)CC)OCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cool mixture of 2.54 g of 2-((4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl)methoxy)-1,3-propanediyl bis(N-((benzyloxy)carbonyl)-L-isoleucinate) and 5.16 g of 10% palladium catalyst in acetic acid was slowly added 6.4 mL of 1,4-cyclohexadiene. The mixture was allowed to stir at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite, the filtrate was then concentrated and dried in the lyophiliser for 3 d. The residue was scraped off, affording 2.079 g (82%, as the acetic acid salt) of a beige foam. The elemental analysis (showing 2M of acetic acid and 1M of water), UV, 1H, 13C-NMR spectra were consistent with the title structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:9][CH2:8]1.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[C:19]([C:3]1[C:2]([NH:1][S:21](=[O:24])(=[O:23])[NH2:22])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:8][CH2:9]1)#[N:20]
Reactant: NS(=O)(=O)Cl
Reactant: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Product: CCCNC(=O)C1(COc2cccc(NS(N)(=O)=O)c2C#N)CC1
Yield: 78 %

Procedure:
Prepared as in Example 111a from 1-((3-amino-2-cyanophenoxy)methyl)-N-propylcyclopropanecarboxamide (Example 198b) and sulfamoyl chloride in 78% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.45 (broad s, 1H), 7.51-7.61 (m, 2H), 7.26 (broad s, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=7.6 Hz, 2H), 1.08-1.14 (m, 2H), 0.83-0.88 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).