Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([O-])([OH:9])=[O:8]>S(=O)(=O)(O)O>[Br:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Brc1c[nH]cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nc[nH]c1Br
Temperature: 25 °C
Yield: 88.1 %

Procedure:
4-Bromo-1H-imidazole (2.0 g, 13.6 mmol) was reacted with concentrated nitric acid (0.947 mL, 14.96 mmol) in concentrated sulfuric acid (20 mL) at 110° C. for 1 hour. The reaction was cooled to 25° C. and poured into 200 mL of ice water. The resulting white precipitate formed was collected by filtration to give the title compound (2.3 g, 87%). MS (ESI−) m/z 191 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.99 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][NH:5][NH:6]C(OCC1C=CC=CC=1)=O.[ClH:19]>CCO.[Pd]>[ClH:19].[ClH:19].[F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][NH:5][NH2:6]
Reactant: O=C(NNCCC(F)(F)F)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NNCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1.7 g, 6.49 mmol, 1 eq.) in a mixture of EtOH (30 mL) were added Pd/C (1.0 g) and HCl (12 N, 2.0 mL). The mixture was charged with H2 (60 psi), stirred at rt for 1 h, filtered, and concentrated to give (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. LRMS (M+H) m/z 129.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:28][C:27]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 77.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.143 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.033 g, 0.143 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH:13]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH3:16])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC(C)C)cc1O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC(C)C)cc1OC
Reaction time: 12 h

Procedure:
A 1.60 g portion of methyl 2-hydroxy-4-isopropoxybenzoate was dissolved in 30 ml of 2-butanone, 1.60 g of potassium carbonate and 1.1 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, insoluble matter was removed by filtration through celite, and the solvent was again evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give 1.70 g of methyl 4-isopropoxy-2-methoxybenzoate.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[NH:7]1)=[O:5])C.[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C)C=O.O.C(O)C>[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19]([N:7]1[C@H:6]([C:4]([OH:3])=[O:5])[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2)=[O:20])=[O:16]
Reactant: CCOC(=O)[C@H]1NC2CCC1C2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(=O)O)C(C)C
Reaction time: 2 h

Procedure:
(3S)-ethyl2-azabicyclo[2.2.1]heptane-3-carboxylate (1.25 g, 7.39 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (1.42 g, 8.13 mmol), diisopropylethylamine (6.45 mL, 36.9 mmol), and HATU (2.95 g, 7.76 mmol) were combined in dimethylformamide (40 mL) at ambient temperature and stirred for 2 hours. The solution was diluted with water and the product filtered and dried. The dried ester (1.0 g, 3.06 mmol) was taken up in water (15 mL) and ethanol (15 mL) and treated with sodium hydroxide (0.5 g, 12.5 mmol) at ambient temperature for 17 hours. The solution was washed with ether then the aqueous was neutralized with concentrated HCl to pH 7 and the product extracted into ethyl acetate, dried over sodium sulfate, and concentrated to give the title compound as a waxy solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[CH:30][C:17]([NH:18][C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)=[CH:16][CH:15]=1.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([NH:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:23])=[CH:30][CH:31]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Yield: 95 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (1.90 g, 11.6 mmol), 2-(4-fluoro-anilino)-4,5-difluorobenzoic acid (Example N, 2.59 g, 9.7 mmol), O-benzylhydroxylamine hydrochloride (1.55 g, 9.7 mmol), and triethylamine (1.63 mL, 11.6 mmol) provided 3.43 g of the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.ClC(OC)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: COc1cccc([Mg]Br)c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 6-methoxyquinoline-N-oxide (175 mg, 1.0 mmol) in THF (3 mL) at room temperature is added methyl chloroformate (77 uL, 1.0 mmol). The mixture is cooled to 0° C. and 3-methoxyphenylmagnesium bromide (2 mL of 1M, 2 mmol) is added dropwise. The mixture is stirred for 16 h while warming to room temperature. The solvent is removed in vacuo and the resulting residue is partitioned between water and CH2Cl2. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated. Flash chromotography (0–20% EtOAc/hexanes) yields 6-methoxy-2-(3-methoxy-phenyl)-quinoline (123 mg, 46% yield).
Reaction SMILES: CI.[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2([CH3:24])[CH3:23])=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:26](=O)([O-])[O-].[K+].[K+]>COCCOC>[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:26])[CH2:19][C:18]2([CH3:24])[CH3:23])=[CH:12][N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Methyl iodide (954 μL, 15.3 mmol, 1.3 equiv) was added dropwise to a suspension of [5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.3) (3.8 g, 11.8 mmol) and potassium carbonate (2.13 g, 15.4 mmol, 1.3 equiv) in DME (25 mL). The reaction mixture was heated to 50° C., stirred for 2 h, allowed to cool, quenched by addition of a H2O and extracted with DCM. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1) to afford 1.94 g of the title compound as an off-white solid. Title compound: ESI-MS: 335.3 [M+H]+; TLC: Rf=0.31 (DCM/MeOH, 9:1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:16][CH:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:22][CH2:23]2)=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2ccc(Cl)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(Cl)cn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.63 ml) was added directly to formic acid (2.48 ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.6 g) in tetrahydrofuran (10 ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2SO4), and evaporated to dryness. The residue was purified by chromatography using a 10 g silica isolute eluting with 10% ethyl acetate/heaxane—80% ethyl acetate/hexane and then evaporated to dryness. The resulting white solid was filtered from diethyl ether to give N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.43 1 g), 211-212° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[K+].C(O)C>O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(C#N)cc1
Yield: 83 %

Procedure:
A 1-liter round bottom flask was charged with 50 g of p-hydroxybenzonitrile, 89.2 g of octyl bromide, 23.5 g of potassium hydroxide and 500 ml of ethanol. A calcium chloride tube was attached to the flask and the content was refluxed for 4 hours. Then, one liter of water was added into the flask, followed by extraction with 1300 ml of dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. After distilling the solvent off, the remaining system was purified by means of silica gel column chromatography to provide 80.6 g of 4-octyloxybenzonitrile (Compound A).
Reaction SMILES: [OH-].[Na+].S(=O)(=O)(O)O.[Cl:8][CH2:9][C:10](=[O:24])[C@@H:11]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:8][CH2:9][C@@H:10]([OH:24])[C@@H:11]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Reaction time: 24 h
Yield: 61 %

Procedure:
A culture was obtained by the same method as in Example 1 using Candida gropengiesseri IFO 0659 as the microorganism and adjusted to pH 6 with an aqueous sodium hydroxide solution and an aqueous sulfuric acid solution. A 75-ml portion of this culture was separated into a supernatant and cells by centrifugation. To the whole amount of the cells was added a portion of the supernatant to make the total volume 25 ml. This cell suspension (25 ml), 1 g of glucose and 250 mg of (3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanone were mixed together in a 500-ml Sakaguchi flask and the mixture was shaken for 1 day to allow the reaction to proceed. A further 250-mg portion of (3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanone was added. The reaction was allowed to proceed by shaking for further 6 days while controlling the glucose concentration within the range of 0 to 4% by adding glucose portionwise. Water, 100 ml, was added to the reaction mixture and the whole mixture was extracted with 100 ml portion of ethyl acetate for 3 times. The organic extract layers were combined, washed with 100 ml of water and further with 100 ml of a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. This solution was concentrated to dryness to give (2S,3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanol as a white solid (401 mg; yield 61%; purity 76.8 wt %; selectivity 2S,3S/2R,3S=98/2; optical purity 98.3% ee).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[CH:10][C:9]([O:22]C)=[C:8]([NH:24]C(=O)C)[CH:7]=2)#[N:2].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:24][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][C:9]=1[OH:22]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cc1NC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2cc(N)c(O)cc2c1Nc1ccc(Cl)cc1Cl
Temperature: 200 °C
Yield: 30.1 %

Procedure:
An amount of 200 mg (0.50 mmol) of N-[3-cyano-4-(2,4-dichloroanilino)-6-methoxy-7-quinolinyl]acetamide, was stirred with pyridine hydrochloride (1.4 g, 12.5 mmol), and heated at 200° C. for 2 hours. The mixture was cooled to room temperature, stilled with ethyl acetate and saturated sodium bicarbonate solution, and filtered. The layers were separated, and the organic layer was subsequently washed with saturated brine solution, dried over sodium sulfate, and evaporated to a yellow oil. Purification was carried out by preparative thin layer chromatography (5% methanol in ethyl acetate), to yield a yellow solid (52 mg, 30% yield), mp 265° C. decomp.; 1H NMR (DMSO-d6) δ 10.26 (bs, 1H), 8.93 (s, 1H), 8.34 (s, 1H), 7.66 (d, J=2 Hz, 1H), 7.35 (dd, J=9Hz, J=2Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=9 Hz, 1H), 6.99 (s, 1H), 5.90 (s, 2H); HRMS (EI) m/z 344.0897 (M+1). Analysis for C16H10Cl2N4O.0.5CH3OH: Found: C, 54.43; H, 3.12; N, 15.34. Calcd: C, 54.74; H, 3.32; N, 15.48.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[C:4]([F:17])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>[NH4+].[Cl-].CCOC(C)=O.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.Cl[Pd]Cl.[Fe+2].COCCOC>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:7]=[CH:6][C:5]=1[C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(-c2cnn(C)c2)cc1F
Temperature: 100 °C
Yield: 71 %

Procedure:
To a two microwave vials with stir bars were added (R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.65 mmol), 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol, 2.0 M aq) and PdCl2(dppf).CH2Cl2 adduct (190 mg, 0.23 mmol) divided between the two vials. The vials were capped and heated by microwave irradiation for 20 min at 100° C. respectively. The reaction mixtures combined, diluted with a saturated solution of NH4Cl and EtOAc. The phases were partitioned and the aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided a orange crystalline of (R)—N—((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.07 g, 3.31 mmol, 71% yield. 1H NMR (400 MHz, CDCL3) δ ppm 1.21 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.36 (d, J=4.25 Hz, 1H) 3.96 (s, 3H) 4.79-4.91 (m, 1H) 7.13 (dd, J=11.69, 1.61 Hz, 1H) 7.23 (dd, J=8.00, 1.64 Hz, 1H) 7.30-7.37 (m, 1H) 7.60 (s, 1H) 7.74 (s, 1H). LCMS m/z 324.0 (M+H)+, Rt 0.74 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18]CC)=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]([OH:18])=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccc(C)c(F)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
45 g (0.14 mol) of ethyl 4-(3-fluoro-4-methylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in 1,4-dioxan (300 ml), and a solution of 39 g (0.28 mol) of potassium carbonate and water (300 ml) was added thereto. The solution was stirred for 1 hour at 60° C. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Water was added to the residue thus obtained and was washed with chloroform. Then, the aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and the aqueous layer was extracted again with chloroform. Anhydrous magnesium sulfate was added to the organic layer to dry the layer, and the solvent was distilled off under reduced pressure to obtain 32 g (yield: 76%) of 4-(3-fluoro-4-methylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:20]([NH:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:21])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: O=C=NC1CCCC1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC2CCCC2)c1O
Yield: 43.3 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (200 mg, 0.90 mmol) and cyclopentyl isocyanate (100 mg, 0.90 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from diethyl ether and hexane, gave the desired product (130 mg, 43%). LC-MS (m/z) 334.2 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[Cl:26][C:18]1[CH:17]=[C:16]([C:12]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:10][C:13]=2[CH3:14])[CH:21]=[CH:20][C:19]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: NC(=S)Nc1cnccn1
Reactant: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Solvent: CCO
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)c(Cl)c1
Temperature: 60 °C

Procedure:
Pyrazin-2-yl-thiourea (Example 1a) (0.047 g, 0.31 mmol) is added to a stirred solution of 4-(1-bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (0.10 g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C. for 3 hours. The mixture is filtered to remove the precipitate which is washed with methanol and dried. (0.055 g).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].C([O-])(=O)C.[Na+].[CH3:20][C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25]>>[CH3:25][C:24]1[N:2]([NH:1][C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:7][CH:8]=2)[C:21]([CH3:20])=[CH:22][CH:23]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NNc1ccc(N2CCCCC2)nn1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1ccc(C)n1Nc1ccc(N2CCCCC2)nn1
Temperature: 65 °C

Procedure:
A mixture of 7.4 g (28 m moles) of 3-hydrazino-6-piperidino-pyridazine, 2.3 g of sodium acetate and 3.7 g 2,5-hexanedione is heated for two hours at 65° C. The solvent is evaporated off under vacuum and the solid residue is dissolved in water and neutralized with sodium hydroxide. The product is purified by chromatography through a silicagel column using as the eluent a mixture methanol-chloroform 2.5:97.5. The solid recovered by evaporation of the eluate is crystallized from ethyl acetate yielding 2 g (27%) of the product of the title which melts at 185°-187° C.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58]>O1CCCC1>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:58][CH2:57][CH2:56][CH:55]([CH3:59])[CH3:54])=[O:10]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCNC(=O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.24 g, 0.73 mmol) in dry tetrahydrofuran (10 ml) are added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.30 g, 0.80 mmol) and triethylamine (0.38 ml, 2.2 mmol) at RT. The reaction mixture is stirred for 5 min at RT followed by the addition of 3-methyl-butyl-amine (0.1 ml, 0.88 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with saturated sodium hydrogen carbonate solution (20 ml) before extraction with EtOAc (3×30 ml). The organic layer is washed with saturated ammonium chloride solution (30 ml), water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-benzamide (example 1) (0.16 g, 0.41 mmol, 56%). [M+H]+ 396.1.