Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenyl-phosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)([F:4])[F:3].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:4])([F:3])[O:5][C:6]1[CH:7]=[C:8]([C:28]#[C:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[NH2:20])[CH:9]=[CH:10][CH:11]=1
Reactant: C#Cc1cccc(N)c1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 65 °C
Yield: 85.7 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.0 g (0.021 mol) of m-bromophenyl trifluoromethyl ether, 50 ml of dried, degassed triethylamine, 2.43 g (0.212 mol) of 3-aminophenylacetylene, 0.048 g (0.68 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromotography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product as a viscous orange-colored liquid. Short path distillation of the crude product under reduced pressure gave 5.1 g (0.018 mol, 86% yield) of the purified product as a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCCC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of piperidine (2.98 g) and methyl 6-chloronicotinate (5.00 g) in N,N-dimethylformamide (75 ml) was added potassium carbonate (12.08 g). The mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, to the reaction mixture was added water (100 ml) and then the mixture was stirred for 15 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give methyl 6-(1-piperidyl)nicotinate (5.55 g), as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(cc1CCO)COC2=O
Solvent: ClCCl
Product: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-1(3H)-one (1.20 g, 6.25 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL) was added MsCl (1.40 g, 12.5 mmol) at 0° C. The mixture was stirred at ambient temperature overnight, then was washed with water and brine. The organic layer was dried and concentrated to dryness. The collected title compound was used for the next step without any purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nn2)CC1
Yield: 45.9 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and (R)-4-methyloxazolidin-2-one (51 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (97 mg) was obtained.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:15]/[N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of piperonal (75 g, 500 mmol) in methanol (120 mL) at 10° C. was added nitromethane (27.1 mL, 500 mmol, 1 eq)followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1 eq) in sufficient water to achieve a total volume of 50 mL while maintaining the temperature between 10-15° C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon complention of the addition, and the mixture was then diluted with ice-water (˜350 mL) maintaining the temperature below 5° C. until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops (into a rapidly stirred solution of 36% hydrochoric acid )100 mL) in water (150 mL). A yellow solid preciptated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.94 (1H, d, J=13.5 Hz), 7.47 (1H, d, J=13.5 Hz), 7.09 (1H, dd, J=7.5 & 2 Hz), 7.01 (1H, d, J=2 Hz), 6.87 (1H, d, J=7.5 Hz), 6.06 (2H, s). MS (DCl/NH3) m/e 194 (M+H)+, 211 (M+H+NH3)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31].[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:44])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: Nc1nccs1
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
A solution of triphenylphosphine (99 mg, 0.37 mmol) and N-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26 mL) cooled to 0° C. was treated with 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (85 mg, 0.25 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03 mL, 0.37 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. At this time, the reaction was diluted with water (50 mL) and extracted with chloroform (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (69.3 mg, 65.6%) as an off-white solid: mp 163-165° C.; EI-HRMS m/e calcd for C21H28N2O3S2 (M+) 420.1541 found 420.1535.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[C@@H:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:11]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C@@H:10]([O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[CH:27]([CH3:29])[CH3:28])[C:9](=[O:30])[S:38][C:35]1[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)[Si](O[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@H]1c1ncccc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)[Si](O[C@@H](C(=O)Sc1ccc(Br)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ncccc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A concentrated residue of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone (92.7 mmol) was dissolved in diisopropyl ether (410 mL), and 4-bromothiophenol (18.4 g, 97.3 mmol) and potassium carbonate (14.7 g) were added thereto and stirred at room temperature for about 30 minutes. The disappearance of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone was confirmed, and water (290 mL) was added to it for liquid-liquid separation. The organic layer was separated, washed with saturated saline water (290 mL), and dried over magnesium sulfate. The insoluble matter was removed through filtration, and the filtrate was concentrated under reduced pressure to obtain a residue of S-(4-bromophenyl) (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanethioate.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.C1COCC1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C[C@H](CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Alternatively, (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide (1.0 g, 1.83 mmol) was taken up in a solution of 20% THF in ethanol (500 mL) and then Pd on activated charcoal (200 mg) was added portionwise. The resulting slurry was stirred as H2 gas was gently bubbled through the solution. After 4 hours, the reaction mixture was suction filtered through a bed of celite (1.5 cm), and the filtrate was concentrated and then taken up in methanol (30 mL) and filtered through a plug of cotton. Recrystallization from methanol/ethyl acetate/ether/petroleum ether gave (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanamide (768 mg, 92%), MS: 455 (M-H)-.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[S:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[S:4][N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1
Reactant: COc1ccccc1-c1nc(Cl)ns1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1nc(N2CCNCC2)ns1
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole (0.21 g, 0.93 mmol), piperazine (400 mg, 4.65 mmol), and DMF (3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 5 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine. LC/MS: m/z 277.1 (M+H)+ at 2.19 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])=[CH:12][C:7]=2[S:6][CH2:5][CH2:4]1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1OCCC1>[CH3:34][C:3]1([CH3:2])[C:8]2[CH:9]=[CH:10][C:11]([C:13]([CH3:14])=[CH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:12][C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: O=Cc1ccccc1
Reactant: CC(c1ccc2c(c1)SCCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=Cc1ccccc1)c1ccc2c(c1)SCCC2(C)C
Yield: 44.5 %

Procedure:
33 g of [1-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)ethyl]triphenylphosphonium bromide and 6.5 g of benzaldehyde were heated under reflux in 300 ml of butylene oxide for 16 hours. After working-up in analogy to Example 49 and recrystallization from hexane, there were obtained 7.9 g of 3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzothiopyran, melting point 67°-69° C.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N[CH:14]1[CH:21]2[CH2:22][CH:17]3C[CH:19]([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2.C(O)CCC>O>[CH:19]12[CH2:23][CH:15]3[CH2:14][CH:21]([CH2:22][CH:17]([CH2:16]3)[CH:12]1[N:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]1)[CH2:20]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)c1cn(C2C3CC4CC(C3)CC2C4)cn1
Temperature: 150 °C
Reaction time: 13 h
Yield: 29.4 %

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.50 g), 2-aminoadamantane (0.54 g), and n-butanol (2.5 mL) were added and stirred at 150° C. for 13 hours. To the reaction solution, water was added, and organic matter was extracted with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=95/5 and ethyl acetate) to obtain the title compound (0.24 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 67.8 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (4.90 g, 14.0 mmol) and thiourea (1.07 g, 14.1 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 100 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (3.10 g) as yellow solids in 68% yield: 1H NMR (500 MHz, CDCl3) δ 6.98 (m, 2 H), 6.88 (m, 2 H), 6.64 (s, 2 H), 6.27 (s, 1 H), 5.40 (bs, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.CCCCCCC.[C:20](OCC)(=[O:22])[CH3:21]>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:21][CH2:20][OH:22])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(F)c(C=O)c1O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranilidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.78 g) as a solid.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2=[O:27]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2([OH:27])[C:8]1[C:7]([OH:10])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1Nc2c(Br)cccc2C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2c(Br)cccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of sesamol (7.32 g, 53.1 mmol) in anhydrous tetrahydrofuran (150 mL) were added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 30.1 mL, 60.2 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min, followed by the addition of 7-bromo isatin (8.0 g, 35.4 mmol). The suspended mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (300 mL) and ethyl acetate (250 mL), and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL), and the combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was triturated with diethyl ether, filtered and dried under the reduced pressure to afford 7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (9.8 g, 77%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ10.64 (s, 1H), 9.18 (s, 1H), 7.33 (dd, J=7.8, 1.4 Hz, 1H), 7.21 (s, 1H), 6.84-6.75 (m, 2H), 6.54 (s, 1H), 6.21 (s, 1H), 5.92 (dd, J=6.1, 0.8 Hz, 2H); MS (ES+) m/z 363.8 (M+1), 365.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543. 2.8 g, 14.53 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.5 g, 14.53 mmol) in dichloromethane (200 mL) was added HOBT (2.22 g, 14.53 mmol) and N-methyl morpholine (4.82 mL, 43.60 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.12 g, 26.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in pet ether) afforded methyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.4 g (67%) as brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])([F:45])[F:44])=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:41]([C:43]([F:46])([F:45])[F:44])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M57) (318 mg, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (216 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[N:15]2)(=O)=O)=CC=1.[CH3:20][NH:21][CH3:22].C1COCC1>>[I:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][N:21]([CH3:22])[CH3:20])[CH:18]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cn2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
2-(4-Iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (Preparation 58) (1.03 g, 2.63 mmol) was treated with dimethylamine in THF (2M, 10 mL, 20.00 mmol) and stirred at room temperature for 3 days. Solvents were removed under reduced pressure and the residue partitioned between DCM and saturated aqueous NaHCO3. The aqueous were extracted with DCM and the combined organic layers dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give the title compound (616 mg, 89%).