Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[NH:29][N:28]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 9 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 11.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a white solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=450.2 [M+H]+, m/z=448.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.78-1.88 (m, 1H) 2.94 (d, J=11.92 Hz, 1H) 3.19-3.34 (m, 2H) 3.38-3.50 (m, 1H) 4.20 (br. s, 1H) 4.81-4.93 (m, 1H) 6.33-6.45 (m, 1H) 7.83 (m, J=113.40, 8.20 Hz, 3H) 7.93 (d, J=8.66 Hz, 2H) 7.99-8.08 (m, 1H) 8.70-8.81 (m, 1H) 10.30 (s, 1H) 12.90-13.16 (m, 1H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=2)[CH:8]=1.O>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:36])([F:35])[F:37])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([NH2:1])=[O:16])=[N:11][N:10]=2)[CH:8]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(-c2cc(Cl)ccc2O[C@@H](C)c2nnc(-c3ccccc3C(F)(F)F)n2C)o1
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1ccc(Cl)cc1-c1nnc(C(N)=O)o1)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 29% aqueous ammonia solution (0.3 ml) was added to a solution of ethyl 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxylate (120 mg) in ethanol (1 ml), followed by stirring at room temperature for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was powdered with diisopropylether to obtain, as a light yellow solid, 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxamide (86 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:31])[C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Fe]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[C:7]3[CH:32]=[CH:33][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12][CH2:13]2)=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCN(C(=O)c3ccc(N)cc3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of 1,5-bis(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (737 mg) and iron powder (738 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was refluxed for 2 hours and the solution was cooled to ambient temperature. The mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform and the solution was basified with saturated aqueous sodium bicarbonate solution. The solution was filtered through a bed of celite, and then the filtrate was washed with brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent: 2% methanol in chloroform) to give 1,5-bis(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine as a slightly yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CC)Nc1nc(Cl)ccc1N
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a room-temperature solution containing 6-chloro-3-nitro-N-(pentan-3-yl)pyridin-2-amine (1.8 g, 7.4 mmol) in MeOH (10 mL) and EtOAc (10 mL) was added SnCl2 dihydrate (10.0 g, 44.3 mmol). After 3 h, the reaction mixture was concentrated in vacuo and then re-dissolved in EtOAc and water. After stirring overnight, the layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (25%-50% EtOAc/Hexanes) provided the title compound as a white solid (940 mg, 57%). m/z=223.2 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1>CN(C=O)C>[CH2:7]([O:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
DMF (12 mL), K2CO3(1.19 g, 8.55 mmol) and benzyl bromide (0.75 mL, 6.27 mmol) was added to 4-bromo-2-fluorophenol (1.1 g, 5.7 mmol), and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated and the residue was diluted with 20 mL water. The mixture was extracted with EtOAc. The organic layer was separated and dried with MgSO4 to obtain the title compound (1.62 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[O:15][C:16]([C:19](OC)=[O:20])=[CH:17][CH:18]=3)[N:13]=2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][CH3:26].O1CCOCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH:18]=[CH:17][C:16](=[C:19]=[O:20])[O:15]3)[N:13]=2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCOc1cc(-c2nc(-c3ccc(C(=O)OC)o3)cs2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCOc1cc(-c2nc(C3C=CC(=C=O)O3)cs2)ccc1OC
Yield: 47.1 %

Procedure:
To a suspension of 970 mg of 2-(4-methoxy-3-propoxyphenyl)-4-(5-methoxycarbonyl-2-furyl)thiazole in 30 ml of methanol was added 20 ml of 1,4-dioxane and 5 ml of a 5 N aqueous sodium hydroxide solution. The reaction mixture was refluxed for 3 hours, then concentrated approximately {fraction (1/10)}. Water was added to the residue, and washed with ethyl acetate. To the aqueous layer was acidified with 5 N hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried with magnesium sulfate. Evaporation the solution, the residue was recrystallized from ethyl acetate to obtain 420 mg of 2-(4-methoxy-3-propoxyphenyl)-4-(5-carbonyl-2-furyl)thiazole as a white powder. mp. 191.0-192.0° C.
Reaction SMILES: CS(O[CH:6]([CH3:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH:6]([CH3:16])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 85 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN3 (7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. 1HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH2), 2.9 (m, 1H, CH2), 1.49 (s, 9H, CH3), 1.2 (d, 3H, CH3).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C:9]3[CH:14]=[C:13]([CH3:15])[S:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Ni]>[N:1]1([C:6]2[N:7]=[C:8]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C:9]3[CH:14]=[C:13]([CH3:15])[S:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1
Agent: [Ni]
Solvent: CO
Product: Cc1cc2c(NCc3cccc(N)c3)nc(-n3ccnc3)nc2s1

Procedure:
A solution of 2-(imidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)thieno[2,3-d]pyrimidine in methanol is hydrogenated in the presence of Raney nickel. The catalyst is filtered off and the solution is concentrated. After recrystallization, 2-(imidazol-1-yl)-6-methyl-4-(3-aminobenzylamino)thieno[2,3-d]pyrimidine is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:29]=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:29]=[O:30])(=[O:33])[CH3:32]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (40 mg, 0.10 mmol) in pyridine (8 mL) was added acetic anhydride (0.4 mL). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (60 mg, 99% yield). The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:31](Cl)(=[O:36])[CH2:32][CH:33]([CH3:35])[CH3:34]>C1COCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:4]=[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:2]([C:31](=[O:36])[CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:7][N:6]=1
Reactant: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Reactant: CC(C)CC(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Temperature: 0 °C
Yield: 85 %

Procedure:
5-Bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine (0.5 g, 1.2 mmol) was dissolved in 25 mL THF and cooled to 0° C. Isopropyl magnesium chloride (0.8 mL, 1.44 mmol) was added, and the reaction mixture was stirred for an hour at 0° C. Isovaleryl chloride (1.47 mL, 12.0 mmol) was then added, and the reaction mixture was stirred for another hour at 0° C. The reaction was quenched with 35 mL of saturated aqueous sodium bicarbonate and 25 mL water. The aqueous mixture was extracted three times with 25 mL EtOAc, and the combined organic layers were washed with saturated aqueous brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was eluted through silica gel using 20% EtOAc in hexanes to yield 0.429 g (85%) of 1-[2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-3-methyl-butan-1-one. Mass Spec. M+H=421.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)OC(C)(C)C)c2ccccc21
Yield: 91.7 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of conc. H2SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62 (d, J=8.1, 1 H), 7.16 (d, J=7.8, 1 H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1 H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1 H), 3.71 (m, 2 H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1 H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1 H), 1.61 (m, 1 H), 1.51 (s, 9 H), 1.3 (d, J=6.8, 3 H).
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][N:22]=1.C[O-].[Na+]>C(#N)C.CO>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[N:7]([CH2:20][C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][N:22]=2)[CH:6]=[N:5][CH:9]=1
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reactant: BrCc1noc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: OCCCc1cncn1Cc1noc2ccccc12
Reaction time: 3 h

Procedure:
A solution containing 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl)-imidazole (6.7 g, 0.025 mole), and 3-bromomethyl-1,2-benzisoxazole (5.3 g, 0.025 mole) in anhydrous acetonitrile (30 mL) is stirred at reflux for 72 hours. The reaction mixture is cooled and mixed with a solution of sodium methoxide (3 g, 0.055 mole) in methanol (30 mL). The resulting solution is stirred at reflux for 26 hours. The solvents are evaporated and the residue is taken up in 1N hydrochloric acid (30 mL). This solution is allowed to stand at ambient temperature for 3 hours and is then made basic (pH 9) by addition of 50% aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride (2×25 mL) and the combined extracts are washed with water (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give crude 3-[(5-(3-hydroxypropyl)-1H-imidazol-1-yl)methyl]-1,2-benzisoxazole which is purified by trituration with acetone (15 mL), m.p. 129°-131° C. The compound forms a hydrochloride hemihydrate, m.p. 155°-157° C. when its solution in isopropanol is treated with ethereal hydrogen chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 4'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and the mixture was then stirred. The resulting precipitate was collected by filtration, to give 360 mg of the title compound, melting at 118-119° C.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1>>[CH3:41][N:42]1[CH:46]=[C:45]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH:44]=[N:43]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. MS (ESI): mass calcd. for C35H33N5O3, 571.26; m/z found, 572.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.4, 1H), 8.11 (d, J=8.4, 1H), 7.83 (d, J=8.0, 1H), 7.76-7.67 (m, 3H), 7.58-7.53 (m, 2H), 7.42-7.37 (m, 3H), 7.24-7.20 (m, 1H), 7.12-7.08 (m, 1H), 7.03-6.99 (m, 2H), 5.43 (s, 2H), 5.32 (s, 2H), 3.93 (s, 3H), 3.14-3.08 (m, 2H), 2.41-2.30 (m, 4H), 1.73-1.67 (m, 2H), 1.46-1.43 (m, 2H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)(C)C>[N:26]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1

Procedure:
To a solution of 19.6 grams (53.2 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate in 54 milliliters of tertiary butyl alcohol was added 5.3 milliliters of tertiary (53 millimoles) of piperidine in 54 milliliters of tertiary butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours to obtain 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate product which crystallized from tertiary butyl alcohol-ether mixture in a yield of 13.45 grams (56 percent) as an off-white solid, m.p. 125°-128° C. A portion of this product after purification by (a) chromatographing on Silicar CC4 Special (Silica gel, product of Mallinkrodt) employing 10:1 dichloromethanemethanol as eluant, (b) recovering from the effluent and (c) recrystallizing from tertiary butyl alcohol-ether, was a white solid, m.p. 121°-122.5° C.
Reaction SMILES: Br[C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:6]=1)=[O:4].[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[P:25]([O:28][CH3:29])([O:26][CH3:27])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:6]=1)=[C:2]([CH3:24])[CH3:23])=[O:30]
Reactant: COP(OC)OC
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)nn(CC(=O)C(C)(C)C)c2c1
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
Reaction of 1-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-3,3-dimethylbutan-2-one from the above with trimethyl phosphite using the procedure as described in Method I Step B above provided the title compound identical to the one obtained with Method I.
Reaction SMILES: Cl.NCC1C=C(C(C)(C)C)C=C(I)C=1[OH:15].Cl.N[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([S:29][CH3:30])[C:20]=1[OH:31]>>[CH3:30][S:29][C:21]1[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=[C:19]([CH:18]=[O:15])[C:20]=1[OH:31]
Reactant: CSc1cc(C(C)(C)C)cc(CN)c1O
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Agent: Cl
Product: CSc1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
This compound is prepared essentially by the same procedure as described in Example 3, Step A, except that the 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride is replaced by 2-aminomethyl-4-(1,1-dimethylethyl)-6-(methylthio)phenol hydrochloride. Thereby is obtained 3-methylthio-5-(1,1-dimethylethyl)salicylaldehyde.
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25](O)=[O:26])[C:10]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCCl>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([NH:7][O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:26])[C:10]=1[Cl:28]
Reactant: CC(C)CON
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NOCC(C)C)n2)c1F
Temperature: 23 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18](/[CH:19]=[CH:20]\[CH3:21])[C:4]=2[O:3]1>C1COCC1.CO.[Pd]>[CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH2:19][CH2:20][CH3:21])[C:4]=2[O:3]1
Reactant: C/C=C\c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl (2S)-2-methyl-8-[(1Z)-prop-1-en-1-yl]-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (390 mg) in THF-MeOH (2:1, 15 ml) was added 10% palladium on carbon (50 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (366 mg, 93%) as a colorless oil.