Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[Na].[C:32](=O)(O)[O-:33].[Na+]>CO.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]([O:33][CH3:32])=[O:26])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCN(c2ccccc2C=O)C1
Agent: [Mn+4]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccccc1N1CCCC(COCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
2-[3-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methoxymethyl]piperidin-1-yl]benzaldehyde (45.2 mg, 0.102 mmol) was dissolved in methanol (5 mL). To this solution, sodium cyamide (25.8 mg, 0.510 mmol) and manganese dioxide (88.7 mg, 1.02 mmol) were added and the mixture was stirred at room temperature for 3 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (Chromatorex NH-DM2035, Fuji Silysia Chemical Co., Ltd.) (hexane:ethyl acetate=50:1->10:1) gave 27.9 mg (58%) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[C:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)C1(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}butanoyl)cyclopropanecarboxylate (1.16 g) in methanol (25 mL) was added sodium borohydride (180 mg) at 0° C., and the mixture was stirred at 0° C. for 30 min. Aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/1) to give tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-hydroxybutyl)cyclopropanecarboxylate as a colorless oil (yield: 914.8 mg, yield: 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reaction time: 6 h

Procedure:
Compound 73 (1.0 g, 2.296 mmol) was dissolved in methanol 250 mL, Pd/C 400 mg was added, and the reaction was stirred under hydrogen balloon for 6 h. The result was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 74, which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane as half white coloured solid 6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 74. 1HNMR (400 MHz, CDCl3) δ ppm 7.56 (d, 2H), 7.28 (d, 2H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.37 (dd, 1H), 3.15 (m, 4H), 3.06 (m, 1H), 2.96 (m, 1H), 2.66 (in, 2H); MS (ESI) m/z 438.0 (M+H).
Reaction SMILES: [Al].[CH2:2](Br)[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>O1CCCC1.[Hg](Cl)Cl>[OH:15][CH:14]([C:13]1[C:8]([O:7][CH3:6])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:3]=[CH2:2]
Reactant: COc1ncccc1C=O
Reactant: C=CCBr
Agent: Cl[Hg]Cl
Agent: [Al]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCC(O)c1cccnc1OC
Temperature: 40 °C
Yield: 99.3 %

Procedure:
29.9 g (1.1 g-atom) of aluminium flakes and 100 mg of mercury(II) chloride are suspended in 300 ml of anhydrous tetrahydrofuran under argon. The mixture is heated to 40° C. and 1-2 ml of 214.0 g (1.77 mol) of allyl bromide in 250 ml of anhydrous tetrahydrofuran are slowly added dropwise. The temperature during this rises to approximately 50° C. The allyl bromide solution is then added dropwise with stirring at such a rate that the temperature of the solution does not exceed 50° C. The solution is subsequently stirred for 1 hour at 60° C., and cooled to -60° C. and 112.4 g (0.765 mol) of 2-methoxypyridine-3-carbaldehyde in 250 ml of anhydrous tetrahydrofuran are added dropwise at this temperature. The mixture is then stirred for 1 hour at 0° C. and for 2 hours at 20° C. Subsequently, 500 ml of saturated ammonium chloride solution are added dropwise with cooling, the mixture is stirred for 0.5 hours, filtered and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulphate. 136.1 g of a light yellow oil is obtained which is fractionally distilled.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.[Cu]I>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:9]2[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[N:18][CH:19]=1
Reactant: COC(=O)c1c[nH]nc1-c1ccccc1
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(-c2ccc(F)cn2)nc1-c1ccccc1
Temperature: 150 °C
Yield: 74.9 %

Procedure:
To a solution of methyl 3-phenyl-1H-pyrazole-4-carboxylate (0.50 g, 2.47 mmol) in toluene (9.9 mL) were added 2-bromo-5-fluoropyridine (0.52 g, 2.97 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (78 μL, 0.50 mmol), copper(I) iodide (24.0 mg, 0.12 mmol) and potassium carbonate (0.72 g, 5.19 mmol). The mixture was heated in a microwave reactor for 20 min at 150° C. Additional (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (78 μL, 0.50 mmol) and copper(I) iodide (24.0 mg, 0.12 mmol) were added and the mixture was heated in the microwave reactor for another 20 min at 160° C. Saturated aqueous NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (0.55 g). MS 298.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[OH:12]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(C(O)c2ccccn2)c(Cl)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)c2ccccn2)c(Cl)c1Cl

Procedure:
α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol (31.86 g) is dissolved in 600 ml of acetic acid and 100 ml of H2O. Chromic anhydride (11.0 g) is added portionwise over five minutes. After three hours the reaction mixture is poured into H2O and extracted with ether. The combined organic phase is washed well with 10% NaHCO3, then brine and dried. Removal of the solvent under reduced pressure gives a crystalline product of (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp 104°-107° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:12][O:13][C:14](=[O:35])[CH:15]=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2[nH]cnc2c1
Product: COC(=O)C=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 1H-benzoimidazole-5-carboxaldehyde (250 mg in 12 mL dry tetrahydrofuran) at 0° C. was added 1.43 g methyl(triphenylphosphoranylidene)acetate and the mixture allowed to warm to room temperature. After 24 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 93:7) to give the title compound (257 mg).
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([F:17])[CH:5]=[CH:4][C:3]=1[NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20].I[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:1][C:2]1[C:3]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:20])=[O:21])=[CH:4][CH:5]=[C:6]([F:17])[C:7]=1[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2I)n1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1F
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: CCO
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1F
Temperature: 80 °C

Procedure:
A mixture of crude Intermediate N-(2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (854 mg), Intermediate (S)-methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (350 mg, 90% pure), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2 M aqueous sodium carbonate solution (6 ml), toluene (50 ml), and ethanol (6 ml) was heated at 80° C. for 16 h. The cooled mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (70:1 to 40:1 DCM/methanol eluant) to provide the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.I[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.O1CCCC1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][C:30]([O:29][CH2:28][CH2:27][CH2:26][N:15]2[CH2:16][CH2:17][CH:12]([C:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:11])[CH2:13][CH2:14]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCI)cc1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCCCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone.CF3CO2H (7.08 g, 19.7 mmol), 4-(3-iodopropoxy)benzoic acid, methyl ester (6.50 g, 20.3 mmol), sodium hydrogen carbonate (3.41 g, 40.6 mmol), tetrahydrofuran (100 mL) and water (20 mL). Heat at reflux under an argon atmosphere overnight. Cool to room temperature, dilute with ethyl acetate (150 mL), wash with 10% sodium hydrogen carbonate (50 mL), water (2×50 mL) and saturated sodium chloride (50 mL). Dry (MgSO4), evaporate the solvent in vacuo and triturate with hexane. Collect the solid by filtration and recrystallize (methanol) to give the title compound as a pale yellow solid; mp 108°-109.5° C.
Reaction SMILES: [CH:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[CH:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]=2[N+:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(C2CCCC2)[nH]n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1n[nH]c(C2CCCC2)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 43.7 %

Procedure:
5-Cyclopentyl-1H-pyrazol-3-carboxylic acid (13 g, 72.1 mmol) was added portionwise to concentrated sulfuric acid (75 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 12.7 ml, 202 mmol) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-cyclopentyl-4-nitro-1H-pyrazol-3-carboxylic acid (7.1 g) as a yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=14.00-14.41 (1H, brs), 13.28-13.85 (1H, brs), 3.20-3.56 (1H, brs, partially masked by solvent), 1.96-2.10 (2H, m), 1.54-1.80 (6H, 2×m) ppm. LRMS (electrospray): m/z [M−H]+ 224, [2M−H]+ 449. Anal. Found C, 43.83; H, 5.35; N, 16.94. C9H11N3O4. 1.2 mol H2O requires C, 43.80; H, 5.47; N, 17.02%.
Reaction SMILES: [Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:26][C@@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C@H:28]1[OH:36].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:26][C@@H:27]5[C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[CH2:29][C@H:28]5[OH:36])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3c4ccccc4C[C@H]3O)sc2c1
Temperature: 160 °C
Yield: 19.2 %

Procedure:
To a suspension of 6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (279 mg, 0.07 mmol) and (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (30 mg, 0.2 mmol) was added DIEA (60 μL, 0.3 mmol). The mixture was heated in a Biotage microwave synthesizer at 160° C. in a sealed tube for 30 min. The mixture was then subjected to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (7 mg, 20%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=7.9 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.33-7.41 (m, 2H), 7.28 (m, 1H), 7.12-7.24 (m, 4H), 5.49 (s, 2H), 5.17 (t, J=7.1 Hz, 1H), 4.29 (br s, 1H), 3.87 (s, 3H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74 (dd, J=7.3, 15.5 Hz, 1H). LCMS (ESI) m/z 522 and 524 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.N12CCCN=C1CCCCC2>CS(C)=O.O>[N:14]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccc(N2CCCC2)nc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A reaction mixture of ethyl (6-chloropyridin-3-yl)acetate (0.30 g, 1.5 mmol) (Asymchem, Cat. #110112), pyrrolidine (0.14 mL, 1.6 mmol and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL, 1.6 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 150° C. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product (0.10 g, 28.4%). Analytic LCMS (M+H)+: m/z=235.2.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21]([OH:22])=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[C:14]([N:23]4[CH2:28][CH2:27]S[CH2:25][CH2:24]4)[N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.O[O:36][S:37]([O-:39])=O.[K+]>CO>[O:36]=[S:37]1(=[O:39])[CH2:27][CH2:28][N:23]([C:14]2[N:13]=[C:12]([C:9]3[NH:8][C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=4)=[N:11][N:10]=3)[C:21]([OH:22])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH2:24][CH2:25]1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(N2CCSCC2)c2cccnc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S1(=O)CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
A 100 mL flask was charged with 7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-5-thiomorpholin-4-yl-1,6-naphthyridin-8-ol (26 mg, 0.062 mmol). Methanol (15 mL) and chloroform (˜3 mL to dissolve insoluble solids) were added, followed by a freshly prepared 0.16 M solution of Oxone (0.75 mL, 0.12 mmol) in methanol. The solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted twice. The combined organics were concentrated in vacuo and purified by preparative HPLC. Thus, 5-(1,1-dioxidothiomorpholin-4-yl)-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (7.3 mg, 26%) was prepared as a tan solid. 1H NMR (CD3OD/CDCl3): δ 8.99 (dd, J=4.4, 1.6 Hz, 1 H), 8.31 (dd, J=8.4, 1.6 Hz, 1 H), 7.52 (dd, J=8.4, 4.4 Hz, 1 H), 7.24 (m, 2 H), 6.91 (m, 2 H), 4.08 (s, 2 H), 3.85 (m, 4 H), 3.25 (m, 4 H); MS m/z 455 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1

Procedure:
Basic displacement reaction of 4-hydroxy benzaldehyde and 3,5-difluorobenzonitrile using potassium carbonate in anhydrous DMF at reflux temperatures affords the above compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ncccc1CCl

Procedure:
(2-Fluoropyridin-3-yl)methanol (508 mg, 3.998 mmol) was first treated with SOCl2 (1.5 ml) in CH2Cl2 (5 ml) at rt for 3 hrs. The solvent was removed to get a crude 3-(chloromethyl)-2-fluoropyridine. Then following General Procedure A, the title compound (910 mg, 85%) was prepared from 2-amino-4-chlorobenzenethiol (957 mg, 5.995 mmol), K2CO3 (2.7 g, 19.98 mmol) in DMF (20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cc(I)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-iodophenol (509 mg, 2.00 mmol) in dimethylformamide were added potassium carbonate (415 mg, 3.00 mmol) and t-butyl bromoacetate (0.440 ml, 3.00 mmol) and the mixture was stirred for 1 hour at room temperature. Thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order, and dried over magnesium sulfate. The solvent was removed and purified with silica gel chromatography (hexane:ethyl acetate, 20:1) to give t-butyl (2-chloro-5-iodophenoxy)acetate (851 mg, quantitatively) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: Cc1cccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1F

Procedure:
From 2-fluoro-3-methylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=381.1, tR (minutes, Method D)=0.74
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([O:24][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1F)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccccc1F)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 1j, 1.5 g (3.47 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o-fluorophenyl)methyl]hexanoic acid in 15 ml of DMF are silylated with 2.4 g (16 mmol) of tert-butyldimethylchlorosilane and 1.95 g (28.5 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.8 g of potassium carbonate in 50 ml of methanol/THF/water, 4:1:1, yields the title compound after column chromatography (SiO2, hexane/ethyl acetate, 2:1): TLC Rf (D)=0.33; tRet (II)=20.7 min.