Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2S[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:28]([O-:32])([O-])(=[O:30])=S.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:28](=[O:32])(=[O:30])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.8 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.45 g), and the mixture was stirred at 0° C. for 30 minutes and further at room temperature for 1 hour. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (827 mg). 1H-NMR (200 MHz, CDCl3) δ 3.11 (2H, t, J=6.5 Hz), 3.62 (2H, t, J=6.5 Hz), 3.87 (3H, s), 7.64-7.76 (3H, m), 8.03 (1H, d, J=8.4 Hz). IR (KBr) 1718, 1288, 1263, 1165, 1128, 1090, 797, 748 cm−1; Anal. for C12H11O4SBr; Calcd. C, 43.52; H, 3.35; Found. C, 43.39; H, 3.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:12]#[CH:11])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cc(Br)cc(F)c1F

Procedure:
50.0 g (0.24 mol) of 5-bromo-2,3-difluorophenol are refluxed for 3 h together with 32.0 ml (0.29 mol) of propargyl bromide (80% soln. in toluene) and 39.7 g (0.29 mol) of potassium carbonate in 860 ml of ethyl methyl ketone. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:21][CH2:20]1)=[O:32]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccc(Cl)cc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (74.8 mg, 0.149 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (71.4 mg, 1.7 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated. Water (˜20 mL) was added and the mixture was neutralized with 1.0 N HCl (30 mL). The resulting white precipitate was collected by filtration and dried under high vacuum overnight to provide {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (57.8 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.5 (br. s, 1H), 8.46 (br. s, 1H), 7.90 (dd, J=8.80, 6.50 Hz, 1H), 7.76-7.86 (m, 1H), 7.68 (m, 2H), 7.50 (d, J=8.78 Hz, 1H), 7.40 (dd, J=8.70, 2.30 Hz, 1H), 7.30-7.37 (m, 1H), 4.20-4.32 (m, 2H), 3.68-3.97 (m, 4H), 3.02-3.24 (m, 2H), 2.43 (s, 3H), 2.16-2.40 (m, 2H), 1.61-1.70 (m, 2H). MS cald. for C25H24Cl2FN2O3 [(M+H)+]: 489, obsd. 489.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][O:12][NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]=[O:22])[N:17]=[C:16]([Cl:23])[C:15]=1[NH:24][CH:25]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(OCC)OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH:10]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][O:12][N:13]1[CH:25]=[N:24][C:15]2[C:14]1=[N:19][C:18]([NH:20][CH:21]=[O:22])=[N:17][C:16]=2[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(NOCC(COCc2ccccc2)COCc2ccccc2)n1
Agent: CCOC(OCC)OC(C)=O
Product: O=CNc1nc(Cl)c2ncn(OCC(COCc3ccccc3)COCc3ccccc3)c2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
6-(3-Benzyloxy-2-benzyloxymethylprop-1-oxyamino)-4-chloro-2,5-diformamidopyrimidine (4.8 g, 9.6 mmol) and diethoxymethyl acetate (50 ml) was stirred at 120° C. for 1.5 hours, cooled and evaporated under reduced pressure. The residue in methanol (80 ml) and concentrated ammonia solution (2 ml) was stirred at 20° C. for 30 minutes, the solvent removed under reduced pressure and the residue co-evaporated with methanol. Column chromatography on silica gel (eluted with chloroform and then chloroform-ethanol, 50:1) afforded the title compound (4.11 g, 89%). IR: υmax (KBr) 3110, 2900, 2860, 1700, 1610, 1575, 1500, 1440 cm-1. 1H NMR: δH [(CD3)2SO] 2.40 (1H, quintet, J=6.1, 6.7 Hz, CH), 3.64 (4H, J=6.7 Hz, 2×CH2OCH2Ph), 4.50 (6H, m, CH2ON, 2×CH2Ph), 7.30 ( 10H, m, 2×CH2Ph), 9.36 (1H, s, OCHNH), 11.31 (1H, s, NHCHO). Found: C, 59.44; H, 5.09; N, 13.62%. C24H24N5O4Cl.0.5EtOH requires: C, 59.45; H, 5.40; N, 13.87%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(N)c(C(N)=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a solution of 2-amino-5-methylbenzamide (5.80 g, 38.6 mmol) and triethylamine (4.69 g, 46.3 mmol) in THF (200 mL) was added dropwise ethyl chloroglyoxylate (5.80 g, 42.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-methylphenyl)amino)(oxo)acetate as a white powder (9.83 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 3-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 425 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.50 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72-8.64 (2H, m), 8.22-8.03 (1H, m), 7.97-7.90 (1H, m), 7.75-7.65 (2H, m), 7.57-7.53 (1H, m), 7.30 (2H, s), 7.21-7.17 (1H, m), 5.63 (1H, m), 3.19-3.17 (3H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:3][C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1](=[O:9])[O:8]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C[C@@H](O)C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)[C@@H](CC(=O)O)O1

Procedure:
A solution of 25.05 g D-malic acid and 68.1 g 2,2-dimethoxypropane in 200 mL toluene was refluxed for 2 hours under nitrogen. The solvent was removed under reduced pressure to give the title compound as a white solid. 1H NMR (CDCl3, 500 MHz) δ 4.76 (dd, J=3.9 & 6.6 Hz, 1H), 3.02 (dd, J=3.9 & 17.2 Hz, 1H), 2.88 (dd, J=6.6 & 17.2 Hz, 1H), 1.64 (s, 3H), 1.59 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1.Br[CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOCC>CN(C)C=O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]#[C:13][CH2:12][CH:6]1[C:7](=[O:9])[CH2:8][CH2:3][CH2:4][C:5]1=[O:10]
Reactant: COC(=O)CCCC#CCBr
Reactant: O=C1CCCC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCC#CCC1C(=O)CCCC1=O
Temperature: 25 °C

Procedure:
Sodium hydride (4.2 g) is suspended in dimethylformamide (50 ml) and while stirring the mixture at room temperature, a solution of 3,5-cyclohexanedione (11.2 g) in dimethylformamide (50 ml) is added over a period of 10 minutes. Several minutes later the mixture is cooled to -10° C., and a solution of methyl 7-bromo-5-heptynoate, described in Example 12, in dimethylformamide (50 ml) is added. The reaction mixture is stirred overnight at -10° to -5° C., then ether is added. The mixture is extracted with sodium carbonate. The aqueous extract after acidification with 10% HCl is extracted with ethyl acetate to yield a crude product, which on crystallization from ether affords 7-(2,6-dioxocyclohexyl)5-heptynoic acid methyl ester, m.p. 108° - 110° C, εmaxEtOH 256nm (ε = 14,200).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:32]2[CH2:33][CH2:34][C@H:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-2,4,5-trifluorobenzoic acid ethyl ester (Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is added triethylamine (6.43 mL, 46.1 mmol) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.72 g, 25.4 mmol). After 48 hours, the mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound (9.34 g). MS CI: m/z 405 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of N-(5-amino-pyridin-2-yl)-acetamide (2.05 g, 13.55 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 13.55 mmol, 1.0 equiv; commercially available) in conc. acetic acid (0.78 mL, 0.81 g, 13.55 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (3.45 g, 16.26 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (50:1→12:1). Recrystallization from diethylether provided 0.91 g (20%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.12-1.28 (m, 2H), 1.40 (s, 9H), 1.86 (d, J=12.3 Hz, 2H), 2.00 (s, 3H), 2.90 (br s, 2H), 3.39 (d, J=9.1 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 5.48 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 10.01 (s, 1H). MS (ESI): 335.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[C:7]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[CH2:19]([N:16]([CH2:17][CH3:18])[C:7]1[C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[CH:11][CH:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]=1)[CH3:20]
Reactant: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a suspension of 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (40 mg, 0.132 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (0.3 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (33 mg, 87%).
Reaction SMILES: [F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: Cc1cc2nc(C(=O)CC(=O)C(F)(F)F)sc2cc1F
Agent: Cl
Product: Cc1cc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2cc1F
Yield: 41 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluoro-5-methylbenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-5-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-benzothiazole (yield, 41%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34].CO>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[CH:14]=[CH:13][NH:12][N:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][CH2:33][OH:34])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reactant: NCCO
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reaction time: 0.5 h

Procedure:
58 mg (0.124 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 1 ml of tetrahydrofuran, and 15 mg (0.247 mmol) of 2-aminoethanol were added. After 30 minutes of stirring, methanol was added, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave 63 mg (100% of theory) of the target compound.
Reaction SMILES: C1COCC1.[C:6]([NH:9][NH:10][C:11]([C:13]1[CH:40]=[CH:39][C:16]2[N:17]([C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[CH3:31])[CH:21]=3)[CH:18]=[N:19][C:15]=2[CH:14]=1)=O)(=[O:8])[CH3:7]>[OH-].C([NH+](CC)CC)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C@H:30]([O:29][C:22]1[CH:21]=[C:20]([N:17]2[C:16]3[CH:39]=[CH:40][C:13]([C:11]4[O:8][C:6]([CH3:7])=[N:9][N:10]=4)=[CH:14][C:15]=3[N:19]=[CH:18]2)[S:24][C:23]=1[C:25]([O:27][CH3:28])=[O:26])[CH3:31]
Reactant: COC(=O)c1sc(-n2cnc3cc(C(=O)NNC(C)=O)ccc32)cc1O[C@H](C)c1ccccc1Cl
Agent: CC[NH+](CC)CC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2cnc3cc(-c4nnc(C)o4)ccc32)cc1O[C@H](C)c1ccccc1Cl
Temperature: 150 °C
Yield: 93.3 %

Procedure:
A 5.0 ml microwave vial was charged with 1.00 ml of THF, 286 mg (1.20 mmol) of methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt, and 154 mg (0.301 mmol) of methyl 5-{5-[(2-acetylhydrazino)carbonyl]-1H-benzimidazol-1-yl}-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophene carboxylate. The reaction was heated in the microwave at 150° C. for 10 min. The crude was adsorbed onto silica gel and chromatographed to give 139 mg of a tan solid as the title compound, MS (APCI): 495 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH2:23][CH3:24])[C:3]=1[OH:25].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:25][C:3]1[C:4]([CH2:23][CH3:24])=[CH:5][C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:7][C:2]=1[Br:1]
Reactant: COC(=O)CCCBr
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1OCCCC(=O)OC
Yield: 82.3 %

Procedure:
A solution of 2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.30 g, 0.76 mmol), 60% sodium hydride (33 mg, 0.83 mmol), 4-bromobutyric acid, methyl ester (0.44 mL, 3.82 mmol), and anhydrous benzene (1.0 mL) was heated at 100° for 6 h. A second portion of 4-bromobutyric acid methyl ester (0.45 mL, 3.91 mmol) and potassium carbonate (0.5 g, 3.62 mmol) was added and the reaction mixture was heated at 100° for 6 h. The crude reaction mixture was chromatographed with hexane/ethyl acetate to give the title compound as a solid (0.31 g, 82%): NMR (DMSO-d6): δ8.00 (d, J=8 Hz, 1H), 7.98 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 7.43 (ddd, J=1, 7, 8 Hz, 1H), 7.35 (ddd, J=1, 7, 8 Hz, 1H), 7.26 (d, J=2 Hz, 1H), 4.03 (dd, J=6, 9 Hz, 1H), 3.98 (dd, J=6, 9 Hz, 1H), 3.63 (s, 3H), 2.74 (d of quartets, J=7, 15 Hz, 1H), 2.69 (d of quartets, J=7, 15 Hz, 1H), 2.62 (t, J=7 Hz, 2H), 2.38 (s, 3H), 2.09 (quintet, J=7 Hz, 2H), 1.56 (s, 3H), 1.18 (t, J=7 Hz 3H); MS(EI): [M+], 1 bromine isotope pattern, 494/496.
Reaction SMILES: O1C2=CC=CC2=CC=C1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:22]([O:25][CH2:26][CH3:27])(=O)[CH3:23]>[Pd].CO>[O:25]1[C:26]2[CH:27]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:23][CH:22]1[CH:14]1[CH2:15][CH2:10][N:11]([C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])[CH2:12][CH2:13]1
Reactant: O=C(N1CCCCC1c1ccc2cccc-2o1)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzofuran-2-yl-piperidin-1-yl)-2,2,2-trifluoro-ethanone (11.50 g), 10% palladium on carbon (1.15 g), ethyl acetate (135 mL) and methanol (15 mL) is shaken under hydrogen atmosphere (3.5 bar) at room temperature for 24 h. The catalyst is then separated by filtration and the filtrate is concentrated to give an oil that is submitted to the next reaction without further purification. LC (method 2): tR=1.34 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-2,6-dimethoxy-pyrimidine (1.92 g, 11.0 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 13.20 mmol, 1.2 equiv) and N-ethyl diisopropylamine (2.24 mL, 1.71 g, 13.20 mmol, 1.2 equiv) in acetonitrile (8 mL) and DMAc (2 mL) was heated by microwave irradiation to 160° C. for 1 h and then to 180° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.22 g (33%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.39-1.48 (m, 2H), 1.46 (s, 9H), 1.97-2.00 (m, 2H), 2.85-2.96 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 3.96-4.02 (m, 3H), 5.52 (d, J=7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 28.16, 31.48, 42.39, 47.95, 53.12, 53.76, 79.24, 100.51, 154.40, 164.60, 164.99, 171.52. MS (ISP): 339.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Product: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Yield: 19 %

Procedure:
2,6-Dichloroquinoline (15.2 mmoles, 3.0 g), 4-aminothiophenol (15.2 mmoles, 1.9 g), and DMAP 15.2 mmoles, 1.85 g) were stirred at room temperature for 3 days. The solvent was removed, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-6-chloroquinoline 830 mg, 19%. Mass spec (FD) 286. Calculated. for C15H11ClN2S: C, 62.82H, 3.87; N, 9.77. Found: C, 63.09; H, 3.94; N, 9.61.