Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C@@H:9]12[C:18](=O)[O:17][C:15](=[O:16])[C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:15](=[O:16])[C@H:10]3[C@H:9]([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:18]2=[O:17])=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Temperature: 170 °C
Yield: 69.5 %

Procedure:
A mixture of 4-aminophenol (5.46 g, 50.0 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (7.71 g, 50.0 mmol) was heated in a round bottom flask at 170° C. for 2 h. After cooling to room temperature the solid material was dissolved in hot ethanol (200 ml), activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was partially evaporated. The solids were collected by filtration, washed quickly with a small amount of ethanol and dried in vacuo at 40° C. yielding the title compound (8.52 g, 69% yield, pink solid).
Reaction SMILES: NC(C(O)CCCCC)C(O)=O.C(OC(=O)C)(=O)C.[C:20]([NH:23][CH:24]([CH:28]([OH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:25](O)=[O:26])(=[O:22])[CH3:21].COC(=O)C(NC(=O)C)C(O)CCCCC.[H-].C([Al+]CC(C)C)C(C)C>CO>[C:20]([NH:23][CH:24]([CH:28]([OH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:25]=[O:26])(=[O:22])[CH3:21]
Reactant: CCCCCC(O)C(NC(C)=O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: CCCCCC(O)C(N)C(=O)O
Agent: CCCCCC(O)C(NC(C)=O)C(=O)OC
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(O)C(C=O)NC(C)=O

Procedure:
Protect the amino function in the 2-amino-3-hydroxy-octanoic acid by conversion thereof to an acetamido function by reaction with acetic anhydride, then esterify the resultant 2-acetamido-3-hydroxyoctanoic acid with methanol; reduce the resultant 2-acetamido-3-hydroxyoctanoic acid methyl ester with di-isobutylaluminum hydride according to known procedures to obtain 2-acetamido-3-hydroxyoctanal.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].N([O-])=O.[Na+].Cl.NC(N)=O>S([O-])([O-])(=O)=O.[Cu+2].O.CO>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[C:8]([Cl:12])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: [Cu+2]
Agent: Cl
Agent: NC(N)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
206 parts of 2-amino-3,5-dichlorobenzoic acid is introduced into 1000 parts of water, then 180 parts of 50% by weight caustic soda solution and 70 parts of sodium nitrite are added and the mixture is allowed to flow while cooling into a mixture of 200 parts of water and 600 parts of concentrated hydrochloric acid (25% by weight strength). The mixture is stirred for another hour, 20 parts of urea is added and the whole is allowed to flow at 65°C with vigorous evolution of nitrogen into a mixture of 70 parts of methanol, 400 parts of water and 3 parts of copper(II) sulfate. The mixture is stirred for another 25 minutes, cooled to ambient temperature and suction filtered. 183 parts (96% of theory) of 3,5-dichlorobenzoic acid is obtained having a melting point of 179° to 181°C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH:30]=[CH:31][C:32](OCC)=[O:33])=[CH:28][CH:27]=1.Cl>C1(C)C=CC=CC=1>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:26]1[CH:38]=[CH:37][C:29](/[CH:30]=[CH:31]/[CH2:32][OH:33])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A toluene solution of diisobutylaluminum hydride (1.5M, 67 ml) was added dropwise at 0° C. to a suspension of ethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate (15.0 g) in toluene (200 ml). The mixture was stirred for 2 hours at room temperature, to which was added 2N HCl (200 ml) under ice-cooling. The organic layer was washed with water, dried (MgSO4) and concentrated to give (E)-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propen-1-ol (12,0 g, 90%), which was recrystallized from ethyl acetate to give colorless prisms, m.p.127°-128° C.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:23]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][NH:35][CH2:34]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][N:35]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][C:3]=2[F:14])[CH2:34]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1CNC1)OCc1ccccc1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc2ncc(F)c(N3CC(NC(=O)OCc4ccccc4)C3)c2n1
Temperature: 85 °C
Yield: 85 %

Procedure:
An oven-dried vial was charged with 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (commercial; 2.0 g, 7.78 mmol), palladium(II) acetate (70 mg, 0.31 mmol), DPEphos (335 mg, 0.62 mmol), K3PO4 (4.13 g, 19.45 mmol) and azetidin-3-yl-carbamic acid benzyl ester (1.68 g, 8.17 mmol). The resulting mixture was purged with argon for several min. Dioxane (25 mL) was then added via syringe and the resulting suspension was purged with argon for 3 min. The mixture was then heated at 85° C. overnight. The solvent was removed in vacuo and the residue was extracted with EA/water. The org. layer was washed with brine, dried over MgSO4 and concentrated. To the resulting solid TBME and a few drops of DCM and MeOH were added and the mixture was sonicated for 5 min and filtered to afford the title intermediate as a beige solid (2.53 g, 85%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 64 %

Procedure:
Into a 500 mL single-neck flask fitted with a stirrer and thermometer, 10.0 g. of 4′-iodoacetophenone, 1.0 g. of PdCl2(dppf), and 17 mL triethylamine were placed in Dioxane (160 mL) and stirred at room temperature under a nitrogen atmosphere. This solution was then degassed with nitrogen for 15 minutes, followed by the addition of 8.8 mL pinacol borane syringe wise. Addition was exothermic and the solution turned dark immediately. The reaction was then heated at 85° C. for 6 h. The mixture was then cooled to room temperature and poured into H2O and the desired product was extracted with ether. This organic layer was washed with H2O, dried over MgSO4, and concentrated under reduced vacuum to yield a white solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with hexane/ethyl acetate 19:1 to yield intermediate title compound, acetophenone derivative, (6.4 g, 64%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH:23]=1>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:7]/[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH:23]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: COc1ccc(COc2cc(I)ccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(/C=C/c3ccc(F)cc3)ccn2)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 61 %

Procedure:
4-Fluorostyrene (3.0 mL), dichlorobis(triphenylphosphine)palladium (870 mg) and potassium carbonate (5.2 g) were added to DMF (70 mL) solution of 4-iodo-2-(4-methoxybenzyloxy)pyridine (4.25 g) and stirred at 100° C. for 19 hours. Saturated brine was added to the reaction liquid, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-200; ethyl acetate:hexane=1:19-1:9-1:4) to provide the title compound (2.55 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH:7]([OH:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(=O)C[C@@H](NC(C)=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])cc(Cl)c2c1C(O)C[C@@H](NC(C)=O)CC2
Reaction time: 0.25 h

Procedure:
N-((S)-4-Chloro-1-methoxy-2-nitro-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide (100 mg; 0.3 mmol), of Example 632f, in Methanol (10 mL) was treated with Sodium tetrahydroborate (30 mg, 0.8 mmol) neat at rt. After 15 minutes, a second portion of Sodium tetrahydroborate (30 mg, 0.8 mmol) was added to the reaction mixture. After 30 minutes the reaction mixture was treated with water, then extract with Et2O followed by CH2Cl2 (2×). The aqueous phase was treated with 1N KOH and re-extracted with CH2Cl2. The organics were combined, dried over MgSO4, filtered and concentrated to give 210 mg (TW 100 mg) of whitish, crude N-((S)-4-Chloro-9-(R,S)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide, which was used without further purification; MS (m/e) 328.97 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23](Cl)[N:22]=1)([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[N:22]=[C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)Nc1nc(NC2CCC(NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 170 °C
Yield: 64.5 %

Procedure:
To a suspension of cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (122 mg, 0.57 mmol) in 2-propanol (2 mL) were added tert-butyl-(2-chloro-quinazolin-4-yl)-amine (100 mg, 0.42 mmol) and diisopropylethylamine (180 μL, 1 mmol) and the mixture was heated at 170° C. for 1 hr using a Smith Microwave Synthesizer. The resulting solution was concentrated and purified by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give [4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (112 mg, 65%) as a yellow solid. To a suspension of cis-[4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (95 mg, 0.23 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 hr. The solution was concentrated, alkalized with saturated aqueous NaHCO3 and 1 M aqueous sodium hydroxide (pH=9), and the aqueous layer was extracted with CH2Cl2 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The solid was collected by filtration to give cis-N2-(4-amino-cyclohexyl)-N-tert-butyl-quinazoline-2,4-diamine (44.6 mg, 53%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([O:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH2:16]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ncc(-c3ccc(NC(=O)c4ccccc4)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A N,N-dimethylformamide (1 mL) solution of Example 24B (0.025 g, 0.079 mmol), benzoic acid (0.011 g, 0.087 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.015 g, 0.079 mmol), 1-hydroxybenzotriazole hydrate (0.011 g, 0.079 mmol), and N-methylmorpholine (0.345 mL, 0.314 mmol) was heated to 55° C. for 16 h. The solution was cooled to room temperature and diluted with ethyl acetate (2 mL) and H2O (2 mL). The layers were separated, and the organic was washed with brine (1×1 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL) and 2.5M NaOH (0.95 mL, 0.237 mmol) was added. The reaction was stirred at room temperature for 16 h, concentrated under reduced pressure, and purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a white solid. 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.83-1.93 (m, 1 H), 1.95-2105 (m, 1 H), 2.53-2.67 (m, 5 H), 3.99 (s, 2 H), 7.49-7.60 (m, 4 H), 7.63-7.67 (m, 2 H) 7.81 (m, 2 H), 7.92-7.94 (m, 2 H), 7.97 (s, 1 H); MS (ESI) m/z 409 [M+H]+.
Reaction SMILES: C(O[CH:5]([C:7]1[CH:12]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[C:9]([O:17][C:18](=[O:20])[CH3:19])[CH:8]=1)[CH3:6])(=O)C>C1(C)C=CC=CC=1>[C:14]([O:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([O:17][C:18](=[O:20])[CH3:19])[CH:10]=1)[CH:5]=[CH2:6])(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(C)OC(C)=O)c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Temperature: 500 °C
Yield: 42.2 %

Procedure:
20 g of 1-(1-acetoxyethyl)-3,5-diacetoxy-benzene (71 mmol) were dissolved in 20 ml toluene and placed into a feed vessel connected to a pyrolytic tube filled with Raschig rings. The tube was heated to 500° C. and the neat mixture was immediately added. Conversion of the alcohol was achieved within two minutes. The column was rinsed with toluene. Work-up was conducted by extracting the crude material in toluene twice with 200 ml water. The aqueous solutions were reextracted with toluene, the organic layers were combined, dried over magnesium sulfate and the solvent removed under reduced pressure giving 6.6 g 3,5-diacetoxystyrene (42%).
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.Cl.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24]CC)[N:20]=[C:19]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:18]=[C:17]2[N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH3:50])[CH:46]=3)[N:41]([CH3:51])[C:40]2=[O:52])[CH2:35][CH2:34]1)[CH3:12].Cl>CN(C=O)C.O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[OH:24])[N:20]=[C:19]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:18]=[C:17]2[N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH3:50])[CH:46]=3)[N:41]([CH3:51])[C:40]2=[O:52])[CH2:35][CH2:34]1)[CH3:12]
Reactant: CCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Agent: Cl
Agent: Sc1ccccc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
In 10 ml of DMF was suspended 1.19 g (30.0 mmol) of 60% sodium hydride, and 3.07 ml (30.0 mmol) of thiophenol in 20 ml of DMF was dropwised under ice-cooling. After the mixture was stirred at ice-cooling for 10 minutes, 5.74 g (10.0 mmol) of Compound 10 obtained in Example 10 in DMF (50 ml) was added at ice-cooling, then the reaction mixture was stirred at 150° C. for 20 hours. After the reaction mixture was cooled to room temperature, water was added, pH of the reaction mixture was adjusted at 5 by concentrated hydrochloric acid and was subjected to extraction with chloroform. The organic layer was washed with sodium chloride solution and dried, concentrated to give residue which was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). The more polar product obtained was recrystallized from ethanol/ether to give 2.67 g (yield: 49%) of Compound 47 as white crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:18][OH:19])[C:13]=2[O:14][CH2:15][O:16][CH3:17])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH:18]=[O:19])[C:13]=2[O:14][CH2:15][O:16][CH3:17])=[CH:7][CH:8]=1
Reactant: COCOc1c(CO)csc1-c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COCOc1c(C=O)csc1-c1ccc(C(F)(F)F)cc1
Yield: 58.1 %

Procedure:
2-(4-trifluoromethylphenyl)-3-methoxymethyloxy-4-hydroxymethylthiophene (1.4 g, 4.3 mmol) in chloroform (22 ml) was stirred with manganese dioxide (3.7 g, 43 mmol) at room temperature for 20 hours and at 50° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as a colorless oil (0.79 g, yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(F)ccc1OCc1ccccc1Cl

Procedure:
10.0 g (58 mmol) of methyl 5-fluoro-2-hydroxybenzoate [CAS 391-92-4], 13.3 g (64.5 mmol) of 2-chlorobenzyl bromide [CAS 611-17-6], 40.6 g (293 mmol) of potassium carbonate and 14.6 g (88 mmol) of potassium iodide are dissolved in 50 ml of acetone, and stirred under reflux for 12 h. The solvent is distilled out in vacuo, and the residue is taken up in ethyl acetate and washed twice each with 10% strength sodium hydroxide solution, 1 N hydrochloric acid and water. Drying over magnesium sulfate, filtration and washing with ethyl acetate are followed by concentration. The residue is stirred with petroleum ether, and the solid is filtered off with suction and dried on a clay dish. 10.0 g (33.9 mmol, 59% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>[Pd].CCO.CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2c(C)nsc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (0.19 mmol), 10% Pd/C (33 mg), ammonium formate (9.7 mmol), and EtOH/EtOAc (1:1, 1.9 mL) was refluxed with stirring for 4 h. After cooling to r.t. the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (35.4 mg) as a white solid: MS (m/z) 267.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36](C(=O)C2C=CC=CC=2)[CH:35]=1)(=O)C1C=CC=CC=1>>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([CH2:33][N:6]2[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)=[CH:35]1
Reactant: CCOC(=O)c1cc(C(C)C)n[nH]1
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOC(=O)c1cc(C(C)C)nn1Cc1c[nH]c2ccccc12
Reaction time: 0.75 h

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (0.044 grams, 0.24 mmol, 0.1 in anhydrous 1,4 dioxane). While stirring at room temperature KHMDS (0.3 mL, 0.261 mmol, 0.87 M in toluene) was added. After stirring for 45 minutes, a solution of (1-benzoyl-1H-indol-3-yl)methyl benzoate (0.02 grams, 0.056 mmol, in 1.0 mL of anhydrous 1,4 dioxane) was added and the reaction mixture stirred over night. The next day, the reaction was quenched with 0.1M HCl and the organic material extracted with ethyl acetate. The aqueous solution was then salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification using a Teledyne ISCO chromatography on silica gel (hexanes/ethyl acetate gradient) followed by a Teledyne ISCO chromatography using C18 reverse phase (water with 0.1% formic acid, acetonitrile gradient) afforded the desired compound. Yield, 63%. 1H NMR δ 8.29 (bs, 1H), 7.58 (d, 1H), 7.36 (d, 1H), 7.20 (t, 1H), 7.11 (t, 1H), 6.96 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H), 4.41 (q, 2H), 3.03 (m, 1H), 1.39 (t, 3H), 1.16 (d, 6H). Calculated mass for C18H21N3O2, 311.16. Observed 334.1 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:27]>>[ClH:27].[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1COc2ccccc2NC1=O
Reaction time: 3 h

Procedure:
In 30 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 5 g of 3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, and the mixture is allowed to stand at room temperature for 3 hours. The deposited crystals are collected by filtration to give 3.8 g of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride as a colorless needles, melting at 230°-240° C. (decomposition).