Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39]C(OCC3C=CC=CC=3)=O)=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCNC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole (0.3 g) was dissolved in tetrahydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.24 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.13 g) was dissolved in dichloromethane (2.6 mL). To the solution were added triethylamine (0.042 mL) and 4-nitrophenyl chloroformate (52 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A ¼ amount of the reaction mixture was separated. To the part of the reaction mixture were added triethylamine (0.028 mL) and L-threonine amide hydrochloride (23 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-ethyl acetate/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-(3-[(1S,2R)-1-carbamoyl-2-hydroxypropyl]-ureido)ethyl)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (30 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.006 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.005 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (21 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)CCCCC(=O)c1ccc(O)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 0.1 %

Procedure:
The title compound is prepared from the methyl ester as follows. 1-Bromohexane (1.65 g, 10 moles) is heated under reflux for four hours with methyl 5-(4-hydroxybenzoyl)pentanoate (2 g, 8.5 moles) in a mixture of acetone (50 ml) and anhydrous potassium carbonate (2.35 g). The reaction mixture is filtered and evaporated under reduced pressure. The residue (3.3 g) is heated under reflux in 2N sodium hydroxide (26 ml) for four hours. The reaction mixture is partitioned between water (200 ml) and ether (300 ml). The ether phase is discarded and the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted with ether (2×250 ml). The ether extract is dried over magnesium sulfate and evaporated under reduced pressure to a tan crystalline solid. Recrystallization from aqueous ethanol gives 5-(4-n-hexyloxybenzoyl)pentanoic acid (2.3 g) as colorless crystals, m.p. 95°-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.3 mol of 1-(2,4,6-trimethylphenyl)-1-ethanone are dissolved in 200 mi of glacial acetic acid and 31.8 g of bromine are added dropwise, while maintaining the reaction medium at a temperature below 10° C. After the addition, the reaction medium is allowed to return to room temperature and is left at this temperature for 2 hours. The reaction medium is then poured into 500 ml of ice-water and the aqueous phase is extracted with ethyl ether. The organic extracts are washed with saturated aqueous sodium bicarbonate solution end then with salted water, end are dried over anhydrous magnesium sulphate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:60][CH2:59][N:51]2[C:52]3[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=3[CH:58]=[C:50]2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, tert-butyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 158c (300 mg, mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (352 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.035 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), and 1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 166a.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(Cl)Cl>O1CCOCC1>[CH2:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CC(=O)Nc1c(-c2ccccc2)sc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCNc1c(-c2ccccc2)sc2ccccc12
Reaction time: 1 h

Procedure:
10.7 g (40 mmol) of 3-acetamido-2-phenyl-benzo(b)thiophene and 3.8 g (0.1 mol) of LiAlH4 in 200 milliliters of absolute dioxan is refluxed with stirring for 1 hour. The cooled reaction mixture is mixed with water to decompose the excess LiAlH4 and, after the addition of 300 milliliters of CH2Cl2, it is stirred for a further 15 minutes. After centrifuging with the addition of hyflo, the organic phase is dried over potassium carbonate and evaporated: 3-ethylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product. It is dissolved in a little chloroform and converted into the hydrochloride by hydrochloric gas: 10.9 g (94% of theory) of colourless sticks in ethanol, decomposition from 205° C. (in sealed tube).
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([C:19]([C:21]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[C:22]=2[O:33][CH2:34][CH3:35])=O)[CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[O:5][N:4]=[C:19]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[C:22]=3[O:33][CH2:34][CH3:35])[C:17]=2[CH:18]=1
Reactant: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1c(-c2noc3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Acetone oxime (172 mg, 2.35 mmol) was added to a solution of potassium t-butoxide (264 mg, 2.35 mmol) in 10 ml of THF. This was stirred for 30 min. at ambient temperature under a nitrogen atmosphere, then a solution of (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone (800 mg, 1.96 mmol) in THF was added. After 2 hrs., the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ether (2×20 mL). The organic layers were combined, dried over MgSO4 and evaporated. The residue was dissolved in ethanol (10 mL) and 1N HCl solution (10 mL) and refluxed for 1 h. The reaction mixture was portioned between ether and water after cooling to room temperature. The organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel column (10% ethyl acetate in hexanes) to give 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole as a clear oil (313.2 mg, 40%).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:27][CH2:26][CH2:25][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12])=[O:8])=[O:4]>Cl.O1CCOCC1>[NH:1]1[CH2:27][CH2:26][CH2:25][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CNC(=O)CNC(=O)[C@@H]1CCCN1)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-Pro-Gly-Gly-Gly-OCH2Ph (SEQ ID NO.: 1) (0.2 g, 0.42 mmol) was dissolved in a 4N HCl solution in dioxane (10 mL) at 5° C. and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated and the residue carefully dried at high vacuum and then crystallized from MeOH/Et2O to give Pro-Gly-Gly-Gly-OCH2Ph (SEQ ID NO.: 1) (0.18 g, 100%) as a colorless solid, mp 145–146° C. 1H-NMR (300 MHz, δ, CD3OD): 2.00–2.25 (4H, m), 3.35–3.45 (2H, m), 3.90–4.05 (6H, m), 4.30–4.40 (1H, m), 5.18 (2H, s), 7.30–7.40 (5H, m). 13C-NMR (75 MHz, δ, CD3OD): 25.2, 30.9, 42.1, 43.3, 43.7, 47.6, 61.4, 68.1, 129.5, 129.6, 129.9, 137.5, 170.9, 171.4, 171.8, 172.4.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO.O>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1ccc(CCCCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc(CCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 22.5 %

Procedure:
To a mixture of 4-(4-phenylbutyl)phenyl acetate (8.29 g) in methanol (112 ml) and water (97 ml) was added sodium carbonate (13.10 g). The reaction was refluxed. After 3.5 hours, the reaction mixture was allowed to cool to room temperature. After 25 minutes at room temperature, the reaction mixture was treated with 5N HCl (50 ml). It was then concentrated in vacuo to remove the majority of the methanol present. Diethyl ether (250 ml) was added to the residue, then the material was treated with 1N HCl (3×100 ml) and the phases were separated. The material was dissolved in diethyl ether, then the denied compound was isolated by flash silica-gel filtration, eluting with hexane/ethyl acetate (20:1, 92×13 ml). The fractions containing the denied compound were combined and concentrated in vacuo to give 1.57 g of 4-(4-phenyl butyl)phenol an oil. Upon standing at room temperature the oil crystallized out.
Reaction SMILES: ClC1C=NC(N2CC(NC3C=CC(F)=CC=3F)C2)=C(C=1)C([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=O.[F:37][C:38]1[CH:39]=[N:40][C:41]([O:44][CH:45]2[CH2:48][N:47]([C:49]3[N:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:50]=3[C:51]([OH:53])=O)[CH2:46]2)=[N:42][CH:43]=1.Cl.NC1(C2C=CC(C(OC)=O)=CC=2)CC1>>[F:37][C:38]1[CH:43]=[N:42][C:41]([O:44][CH:45]2[CH2:48][N:47]([C:49]3[N:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:50]=3[C:51]([NH:9][C:10]3([C:13]4[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=4)[CH2:12][CH2:11]3)=[O:53])[CH2:46]2)=[N:40][CH:39]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ncc(F)cn2)C1
Agent: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1

Procedure:
The title compound (D182) (36 mg) was prepared according to the experimental procedure described in Description (D169) starting from 2-(3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D131) (42 mg, 0.117 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (27 mg, 0.117 mmol).
Reaction SMILES: C([O:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH2:13]([O:18][CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH3:17]>>[OH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([O:18][CH:19]=[CH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)OC=Cc1ccccc1
Agent: CCCCCOC=Cc1ccccc1
Product: OC=Cc1ccccc1

Procedure:
The polymer used herein may be synthesized by any desired methods, for example, by dissolving acetoxystyrene and amyloxystyrene monomers in an organic solvent, adding a radical initiator thereto, effecting heat polymerization, and subjecting the resulting polymer to alkaline hydrolysis in the organic solvent to deprotect the acetoxy group, thereby obtaining a hydroxystyrene-amyloxystyrene copolymer. Examples of the organic solvent which can be used for polymerization include toluene, benzene, tetrahydrofuran, diethyl ether and dioxane. Examples of the polymerization initiator used herein include 2,2′-azobisisobutyronitrile (AIBN), 2,2′-azobis(2,4-dimethylvaleronitrile), dimethyl 2,2-azobis(2-methylpropionate), benzoyl peroxide, and lauroyl peroxide. Preferably the system is heated at 50 to 80° C. for polymerization to take place. The reaction time is 2 to 100 hours, preferably 5 to 20 hours. For the alkaline hydrolysis, aqueous ammonia, triethylamine or the like may be used as the base. The reaction temperature is −20° C. to 100° C., preferably 0° C. to 60° C., and the reaction time is 0.2 to 100 hours, preferably 0.5 to 20 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C=O)C.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1>CCOC(C)=O.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncccc1OCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To the mixture of 2-aminopyridin-3-ol (500 mg) and DMF (dry) (15 mL) was added NaH (60%, 200 mg) at room temperature and the mixture was stirred at room temperature for 20 min. 1-(Bromomethyl)-3-chlorobenzene (933 mg) was added and the mixture was stirred at the same temperature for 1 hr. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.01 g) as a brown crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nc(-c3ccccn3)co2)c1
Yield: 24.7 %

Procedure:
Using the procedures of Kelly et al., J. Org. Chem., (1996) 61:4623–4633, a solution of 2-bromoacetylpyridine (120 mg, 0.6 mmol) in toluene (5 mL) was treated with 3-chlorobenzamide (300 mg, 1.9 mmol) and the mixture heated in a sealed vial at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 38 mg (9%) of 2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole as a pale yellow solid. 1H-NMR (CDCl3), δ (ppm): 8.62 (d, 1H), 8.35 (s, 1H), 8.15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=O.[CH2:10]([O:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH3:11].C(O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH2:8][N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:26])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=CC1=C(Br)CCCC1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(Br)CCCC3)CC2)cc1

Procedure:
A 100 mL round bottom flask was charged with 2-bromocyclohex-1-enecarbaldehyde, (prepared as described by Arnold, A. et. al. Collect. Czech. Chem. Commun., 1961, 26, 3059-3073.), (42 mmol), 4-piperazin-1-yl-benzoic acid ethyl ester (42 mmol) and ethanol (50 ml). The mixture was stirred and sodium cyanoborohydride (42 mmol) was added. Acetic acid was used to adjust pH to 5-6. The reaction mixture was stirred under N2 at room temperature overnight. The reaction mixture was filtered and washed with ethanol. The filtered solid was discarded and the combined organic layers were concentrated under vacuum. The mixture was purified by silica gel chromatography eluting with 5-10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]([CH2:24][OH:25])[N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]([CH:24]=[O:25])[N:21]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C=O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.3 h
Yield: 24.7 %

Procedure:
To a solution of oxalyl chloride in DCM (2 M, 3 mL, 6 mmol) and DCM (5 mL) at −78° C. under nitrogen was added, dropwise with stirring, a solution of DMSO (1.0 mL, 1.09 g, 14 mmol) in DCM (5 mL) and mixture was stirred at −78° C. for 0.4 h. A solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.12 g, 3.5 mmol) in DCM (5 mL) was added dropwise over 0.2 h and mixture stirred at −78° C. for 0.6 h. Triethylamine (3.9 mL, 2.83 g, 28 mmol) was added dropwise over 0.2 h and stirring was continued for a further 0.3 h. Water (10 mL) was added and mixture was warmed slowly to 20° C. over 16 h. Organic phase was separated and aqueous phase was extracted with DCM (2×10 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a paste. This was partitioned between 1:1 Et2O+40-60 petroleum ether (50 mL) and water (3×50 mL) and organic phase was dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-20% EtOAc in 40-60 petroleum ether) gave the title compound (0.275 g) as an oil. MS: [M+H]+=319.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
69.3 Using general method H, 5-chloro-1H-indole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 5-chloro-1H-indole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. Pale yellow solid. MS 506.1 ([M−H]−)
Reaction SMILES: N[C:2]12[CH:17]([OH:18])[CH2:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+]>Cl.O>[CH:17]([C:2]12[CH2:16][CH:9]([C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=31)[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NC12c3ccccc3C(CC1O)c1ccccc12
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=CC12CC(c3ccccc31)c1ccccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.4 %

Procedure:
To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (50 mg) in conc. hydrochloric acid (2 ml) and water (2 ml) was added a solution of sodium nitrite (112 mg) in water (1.0 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (35 mg).