Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[C@H:10]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:38][C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid benzyl ester (2 g, 5 mmol) in DMF (10 mL) was added over 10 min to a slurry of NaH (240 mg 60% dispersion in mineral oil, 6 mmol) in DMF (10 mL) at 0° C. The resultant solution was stirred at this temperature for 30 min. BnBr (1.128 g, 0.785 mL, 6.5 mmol) in DMF (5 mL) was then added slowly to the solution at 0° C. and then mixture warmed to room temperature over 1.5 h. After stirring overnight the reaction was quenched and the solvent removed. The residue was taken up into EtOAc and washed with water, brine and dried with MgSO4. Filtration and removal of the solvent yielded crude material which was subject to column chromatography (silica gel, 50% EtOAc/petroleum ether, Rf 0.85) to give the ester (2.276 g, 92%). 13C NMR (CDCl3) δ 172.0, 155.2, 137.4, 136.5, 135.4, 128.7, 128.5, 128.3, 127.5, 127.4,126.9, 126.9, 126.6, 121.9, 119.4, 119.1, 109.7, 109.2, 79.7, 66.9, 54.5, 49.8, 28.3, 27.9. ISMS: 485 (M+H),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.O.NN.C(O)COCCO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)C(=O)CCC2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cnc2c(c1)CCCC2
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the 3-methyl-7,8-dihydro-5(6H)-quinolone as a colorless crystalline solid b.p. 80° (7.5 g. 48%). A mixture of 3-methyl-7,8-dihydro-5(6H)-quinolone (20 g.), hydrazine hydrate (14 ml), diethylene glycol (150 ml.) and sodium hydroxide (14 g) was heated at reflux with stirring for 1 hour. The condenser was replaced by a Dean and Stark Water Separator and the heating continued for a further 3 hours. The cooled reaction mixture was diluted with water (200 ml.) and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled at 15 mm Hg to give the title compound as a colourless oil b.p.116° (17 g, 93%) G.L.C. (3% SE30, T=150°) RF =3.5 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][C:16]3[C:21]([C:9]=2[CH2:8][CH2:7]1)=[CH:20][CH:19]=[CH:18][CH:17]=3>CS(C)=O>[N:1]([CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][C:16]3[C:21]([C:9]=2[CH2:8][CH2:7]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N+:2]=[N-:3]
Reactant: O=C1Nc2ccc3ccccc3c2CCC1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2c(ccc3ccccc23)NC1=O
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a suspension of sodium azide (0.55 g, 8.4 mmol) in DMSO (17 ml) was added 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (1.6 g, 6.7 mmol) and the suspension was heated at 80° C. for 2.5 h. The hot reaction mixture was added on ice (30 g) and the precipitate was filtered and purified by chromatography on silica gel (200 g) using initially heptane as eluent and subsequently a mixture of heptane and ethyl acetate (1:1) to afford 1.1 g of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH3:12])=[C:7]([CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:14]>>[NH2:14][C:9]1[C:8]([CH3:12])=[C:7]([CH3:13])[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=1
Reactant: CCCCc1nc(C)c(C)c(Cl)n1
Reactant: N
Product: CCCCc1nc(C)c(C)c(N)n1

Procedure:
The title compound is prepared form 2-n-butyl-4-chloro-5,6-dimethylpyrimidine (from Example 22) upon treatment with alcoholic ammonia as described by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1.[CH3:18]O>>[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(O)c(O)c1
Temperature: 10 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
Twenty 20 ml of concentrated sulfuric acid was added dropwise to a solution of 200 g of gallic acid in 600 ml of methanol at room temperature with stirring for 6-8 hours. After approximately 2/3 of the methanol was removed, the residue was cooled to 10° C., poured into 1.2 kg of water and allowed to stand overnight. The white precipitate which formed was filtered and washed with water to give 178 g of product methyl gallate, m.p. 200°-204° C. (yield 82%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[N:26]12CCN(CC1)C[CH2:27]2>C(#N)C.[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:27]#[N:26])=[CH:16][CH:15]=1
Reactant: C1CN2CCN1CC2
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CC#N
Product: N#Cc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (200 mg, 0.49 mmol) was dissolved in acetonitrile (5 ml) and stirred at 0° C. Tetrabutylammonium cyanide (236 mg, 0.98 mmol) and 1,4-diaza-bicyclo[2.2.2]octane (173 mg, 1.5 mmol) were added to the reaction mixture and stirring was continued at 0° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and then purified by flash chromatography using 30% ethyl acetate/hexanes as the eluant to obtain the desired product I-(16A-1)a (215 mg, quant): +ESI MS (M+1) 400.2; 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.45–7.39 (m, 4H), 7.21 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 2-methyl-4-oxo-4H-chromene-8-carbaldehyde (200 mg, 1.062 mmol) and ethyl acetoacetate (138 mg, 1.062 mmol). 309 mg (97% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O1CCOCC1>[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:37]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2-methylbenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 70° C. for 30 minutes. The reaction liquid is cooled and triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the oily residue is purified by column chromatography on silica gel (elution solvent: chloroform). The The purified oily substance is dissolved in about 15 ml of dimethyl sulfoxide and the solution is added dropwise to about 400 ml of ice water under vigorous agitation whereupon a precipitate is formed. The resultant precipitate is collected by filtration, washed with water and dried at room temperature under reduced pressure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[N:23]=1)[CH2:16][CH3:17]
Reactant: CCCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCN(Cc1ccc(COc2ccc(C3CC3C(=O)OC)cc2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), {4-[(propyl{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]phenyl}methanol (0.303 g, 0.745 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 m1) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.366 g, yield 77%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:29][N:28]=[N:27][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of 3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-1,2,4-triazole (1.5 g, 4.33 mmol) in DMF (35 ml) was added sodium azide (NaN3, 0.84 g, 13 mmol) and ammonium chloride (NH4Cl, 0.69 g, 13 mmol). The mixture was stirred at 100° C. for four days whereupon an additional 0.3 g NaN3 and 0.23 g NH4Cl were added. Stirring was continued 2 days further at 100° C. The solvent was removed (rotary evaporation) and the residue was partitioned between ethyl acetate and water (100 ml ea). The organic phase was dried (MgSO4), filtered and concentrated to a viscous light brown oil (1.5 g) which was purified by flash chromatography on silica gel to give 350 mg (21%) of an off-white solid; m.p. 201°-205° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([NH:7][OH:8])=[NH:6].[CH2:18](S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:17])[C:11]=1[NH:12][S:13]([CH2:16][CH3:18])(=[O:15])=[O:14])[C:5]([NH:7][OH:8])=[NH:6]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1c(C)cc(C(=N)NO)cc1Cl

Procedure:
The title compound is prepared in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine using ethanesulfonylchloride; LC-MS**: tR=0.27 min, [M+1]+=292.13; 1H NMR (D6-DMSO): δ 1.36 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 3.22 (q, J=7.5 Hz), 5.88 (s, 2H), 7.57 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 9.18 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:11](=[O:36])[CH2:12][N:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44](O)[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:11](=[O:36])[CH2:12][N:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([O:22][CH2:44][CH3:45])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(±)-1-[N-[3-(Benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline (1.17 g., 2 mmole), prepared as set forth in Example 109 (d), is taken into tetrahydrofuran (2 ml.) with stirring in an ice-bath. To this is added absolute ethanol (2.3 ml., 40 mmole) followed by 4-dimethylamino pyridine (122 mg., 1 mmole) and dicyclohexylcarbodiimide (412 mg., 2 mmole). The reaction is allowed to run overnight at room temperature. The dicyclohexylurea is filtered off, the filtrate is concentrated to dryness, the residue is taken into ethyl acetate and washed neutral with 10% potassium bisulfate and saturated sodium carbonate. The crude product (1.2 g.) is purified on silica gel column in benzene: acetic acid (8:2) to yield 1.0 g. of (±)-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-proline, ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[N:11]=2)=[CH:5][C:4]([C:17]2[C:22]([CH:23]=[O:24])=[C:21]([N:25]3[CH2:36][CH2:35][N:34]4[C:27](=[CH:28][C:29]5[CH2:30][C:31]([CH3:38])([CH3:37])[CH2:32][C:33]=54)[C:26]3=[O:39])[N:20]=[CH:19][CH:18]=2)=[CH:3]1.[BH4-].[Na+]>CO.ClCCl>[OH:24][CH2:23][C:22]1[C:21]([N:25]2[CH2:36][CH2:35][N:34]3[C:33]4[CH2:32][C:31]([CH3:37])([CH3:38])[CH2:30][C:29]=4[CH:28]=[C:27]3[C:26]2=[O:39])=[N:20][CH:19]=[CH:18][C:17]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)n1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 179a (262 mg, 0.50 mmol) in methanol/dichloromethane (10/10 mL) was added NaBH4 (57 mg, 1.5 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) and dichloromethane (20 mL. The water phase was separated and extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 179 (180 mg, 69%) as white solid. MS-ESI: [M+H]+ 526. 1H NMR (500 MHz, CDCl3) δ 8.93 (d, J=2.0 Hz, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.28 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 6.86 (s, 1H), 6.60 (d, J=6.0 Hz, 1H), 5.18-5.16 (m, 1H), 4.70-4.67 (m, 1H), 4.55-4.53 (m, 1H), 4.33-4.31 (m, 1H), 4.18-4.16 (m, 2H), 3.91-3.90 (m, 1H), 3.74 (s, 3H), 2.60 (s, 3H), 2.58 (d, J=5.5 Hz, 2H), 2.52 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(Br)C1C=CC=CC=1>>[CH2:31]([O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reactant: CCCCCCBr
Agent: BrCc1ccccc1
Product: CCCCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O

Procedure:
The title compound (388 mg) was prepared by the method of Example 18 substituting the title product of Example 1 (406 mg; 1.00 mmol) for the title product of Example 2, and further substituting 1-bromohexane (198 mg, 1.20 mmol for benzyl bromide.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>C(O)(=O)C.O>[Br:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1cccc(C=O)c1O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
The solution of 2-hydroxy-3-methoxybenzaldehyde (10.0 g, 65.79 mmole) in acetic acid (50 mL) was cooled to 0° C. (ice bath). Bromine (12.55 g, 78.95 mmole) was added dropwise to above solution, which was allowed to stir for 2 hours. The reaction was warmed to room temperature and diluted with water (100 mL). A light brown precipitate was formed. The solid was filtered and washed with water (50 mL). The filtrate was dried on high vacuum to give a light brown solid (12.2 g, 80.0%): GCMS m/z 231.0 (M+). 1H NMR (CDCl3/400 MHz) 10.97 (s, 1H), 9.82 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 3.89 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:31]1[C:40]2[CH2:39][CH2:38][N:37]=[CH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:37]5[CH2:38][CH2:39][C:40]6[N:31]=[CH:32][CH:33]=[CH:34][C:35]=6[CH2:36]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C1=NCCc2ncccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ncccc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 7,8-dihydro-[1,6]naphthyridine following a procedure analogous to that described for Intermediate 42. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(F)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1O
Temperature: 40 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 3-fluoro-2-hydroxy-benzoic acid (5.0 g, 32 mmol) in methanol (20 mL) was added thionyl chloride (5.0 g, 42 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours, then heated at 50° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo and resulting residue was purified by silica gel column chromatography using 0-50% ethyl acetate/hexanes mixtures as eluant to give methyl 3-fluoro-2-hydroxy-benzoate (5.1 g, 94%) as white crystals. ESI-MS m/z calc. 170.0. Found 170.9 (M+1)+; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[S:26][C:25]([C:23]([NH:22][C@@H:17]([CH:16]([CH3:39])[CH3:15])[C:18]([O:20][CH3:21])=[O:19])=[O:24])=[N:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 9.860 (s, 1H), 8.747-8.720 (d, 2H), 8.687 (s, 1H), 8.495-8.465 (d, J=9 Hz, 1H), 8.376 (s, 1H), 7.892 (s, 1H), 7.769-7.741 (d, J=8.4 Hz, 2H), 7.718-7.688 (d, J=9 Hz, 1H), 7.611-7.582 (d, J=8.7 Hz, 2H), 4.351-4.301 (t, J=7.5 Hz, 1H), 3.682 (s, 3H), 2.285-2.262 (m, 1H), 0.967-0.924 (t, J=6.6 Hz, 6H); MS (ESI) m/z 555 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:24])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g, 0.0015 mol) (Aldrich Cat. #495484) and triethylamine (0.31 mL, 0.0022 mol) in methylene chloride (2 mL) was added p-nitrophenyl chloroformate (0.33 g, 0.0016 mol) (Acros Organics, Cat. #17080). The mixture was stirred at r.t. for 2 h. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography on a silica gel with ethyl acetate in hexanes (0-20%) to afford the desired product (0.32 g, 58%). Analytic LCMS (M+Na)+: m/z=389.0.