Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].Cl.[Cl-].[CH3:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[C:14](=[O:23])[C:15]3[C:20]([C:21](=[O:22])[C:12]=2[N+:11]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:10]1[CH3:31])=[CH:19][CH:18]=[CH:17][CH:16]=3.O>C(O)C>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]=1[N:11]([CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[C:10](=[O:1])[CH3:31]
Reactant: COCCn1c2c([n+](Cc3ccncc3)c1C)C(=O)c1ccccc1C2=O
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCCNC1=C(N(Cc2ccncc2)C(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 M Sodium hydroxide aqueous solution (5.0 ml) was added to a solution of 1-(2-methoxyethyl)-2-methyl-3-(4-pyridylmethyl)-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride monohydrochloride (1.1 g) in ethanol (30 ml) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (fraction A: elution with ethyl acetate-hexane 1:1 solution, fraction B: elution with ethyl acetate). The fraction A was crystallized from diethyl ether to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-N-(4-pyridylmethyl)acetamide (0.2 g) as a red powder. In this connection, the fraction B was crystallized from ethyl acetate to give a yellow powder (0.31 g) which was found to be the same compound, N-(2-methoxyethyl)-N-[3-(4-pyridylmethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide that will be described later in Example 37.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[CH:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1)([CH3:4])[CH3:3].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+]>>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[N:8]=[C:7]([CH:16]=[CH:17][C:18](=[N:29][OH:30])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]=1)([CH3:1])[CH3:4]
Reactant: CC(C)(C)c1nc(C=CC(=O)COc2ccccc2)nc(C(C)(C)C)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)c1nc(C=CC(COc2ccccc2)=NO)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
1-[4,6-Bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-4-phenoxy-1-butene-3-one (0.7 g, 1.9 mmol) is added to an ethanolic (50 mL) solution of hydroxylamine hydrochloride (1.3 g, 19 mmol) and sodium acetate (1.7 g, 20.9 mmol). The reaction mixture is stirred at room temperature under argon for 18 hours. The ethanol is evaporated under reduced pressure, and the remaining solid is partitioned between 20 mL of water and 20 mL of ethyl acetate. The layers are separated and the aqueous phase is washed with ethyl acetate (3×20 mL). The combined organic layers are washed with water (3×20 mL) and 20 mL of brine. Drying over MgSO4 followed by evaporation of solvent gives a yellow oil. Flash chromatography (silica, methylene chloride) followed by recrystallization from hexane gives 0.21 g (29%) of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-4-phenoxy-1-butene-3-one oxime, mp 130°-135° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([NH2:8])=S)=[O:5].[CH:9]([NH:11][NH2:12])=[O:10]>>[CH2:2]([O:3][C:4](=[O:5])[C:6]([N:11]([CH:9]=[O:10])[NH2:12])=[NH:8])[CH3:1]
Reactant: NNC=O
Reactant: CCOC(=O)C(N)=S
Product: CCOC(=O)C(=N)N(N)C=O
Temperature: 65 °C
Yield: 76.3 %

Procedure:
A mixture of ethyl thioxamate (10.55 g, 79.2 mmol) and formylhydrazine (5.00 g, 83.2 mmol) was heated at 65° C. for 30 minutes and stirred in accordance with a method described in Collect. Czech Chem. Commun., 1984, 49, p 2492. After cooling, the precipitated crystal was collected by filteration and washed with ethanol to give (N-formylhydrazino)-imino acetic acid ethyl ester (9.62 g). Yield: 76%.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:6][C:5]=1[C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4]
Reactant: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-phenyl-isoquinoline-3-carboxylic acid methyl ester (46 mg, 0.12 mmol), β-alanine (552 mg, 6.2 mmol) and NaOMe (9.3 mL, 4.65 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 47 mg of the title compound as a light yellow solid. MS: (+) m/z 429.13 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([C:25](OC)=[O:26])=[N:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH2:25][OH:26])=[N:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn(Cc2ccc(F)cc2)c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c2n(c3c(CO)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(4-fluorobenzyl)-10-methoxy-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxylate (0.10 g, 0.24 mmol) in methanol (4 mL) was treated with sodium borohydride (9 mg, 0.24 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under vacuum to half the volume. The white solid precipitated was filtered and air dried to provide the title alcohol.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+].C(O)(=O)C>>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Yield: 39.7 %

Procedure:
The title compound (77 mg) was synthesized in a yield of 38% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-[(5-{5-[4-(2,3-difluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4 ethyl-2-thienyl)methyl]azetidine-3-carboxylate (0.20 g, 0.39 mmol) that was obtained in Example 18 (18c), lithium hydroxide monohydrate (36 mg, 0.86 mmol), and acetic acid (47 μL, 0.86 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8](C(O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([NH2:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (12.5 g, 38.3 mmol) in tert-butanol (250 mL) were added triethylamine (5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). The reaction mixture was stirred at 95° C. for 16 h, then allowed to cool down to RT, and concentrated in vacuo. The resultant residue was dissolved in ethyl acetate, washed successively with water, aqueous saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (150 mL) and treated with trifluoroacetic acid (50 mL). The reaction mixture was stirred at RT for 3 h then concentrated in vacuo. The resulting residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as an off-white solid (7.94 g, 70%). LCMS (Method A): RT=3.13 min, [M+H]+=297 and 299. 1H NMR (DMSO-d6): 8.01 (1 H, d, J=8.6 Hz), 7.30-7.25 (1 H, d, J=8.6, 2.1 Hz), 7.19 (1 H, d, J=2.1 Hz), 4.27 (2 H, t, J=5.1 Hz), 3.08 (2 H, t, J=5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CI.[C:32]([O-])(=O)C.[NH4+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Reaction time: 0.17 h

Procedure:
To a solution of methyl ((8R)-8-{[(4-fluorophenyl)sulfonyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)acetate (0.46 g, 1.1 mmol) in DMF (5.5 mL) was added at 0° C. under nitrogen 60% NaH in oil (0.04 g, 1.2 mmol, 1.1 equiv.). After a period of 10 min., methyl iodide (0.076 mL, 1.2 mmol, 1.1 equiv.) was added and the reaction mixture aged 1 h at room temperature. The reaction mixture was poured over 25% aqueous ammonium acetate solution and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (hexane to 100% ethyl acetate) to provide 420 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.I[CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:15][CH:16]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: CI
Product: COc1ccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxybenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H. d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.30,(1H, m), 7.13,(1H, m), 6.94,(2H, d), 4.62-4.46,(2H, m), 3.74,(3H, s), 2.85,(3H, b), 2.55,(3H, s), 2.31,(3H, s). LCMS; retention time 3.46 min, MH+ 428.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13]Br)[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[C:17]2[CH2:24][C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:15][C:16]1[C:17]2[C@@:24]3([CH2:2][C:3]4[C:12](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=4)[CH2:13]3)[C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3,4-bis(bromomethyl)benzoate (5.0 g, 15.5 mmol) and 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (5.3 g, 31.1 mmol) in N,N-dimethylformamide (150 mL) was added cesium carbonate (10.1 g, 31.1 mmol). After 10 min, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) then a second silica gel purification (100% dichloromethane→>75% dichloromethane/EtOAc gave the title compound as a racemic mixture. Chiral separation of the individual enantiomers was accomplished by use of HPLC using a 10 cm ChiralPak® AD column (60% EtOH/hexanes with 0.1% diethylamine to give the title compound as the 1st eluting enantiomer. MS: m/z=330.1 (M+1).
Reaction SMILES: N1[C:6]([C:7](OCC)=O)=[N:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-].[NH2:23]C(=[NH2+])C>CN(C=O)C>[CH2:15]([O:14][C:12]([C:4]1[N:3]=[C:2]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([NH2:23])=[CH:6][N:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Reactant: CC(N)=[NH2+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(N)c(C(=O)OCC)n1
Temperature: 100 °C

Procedure:
To a stirred solution of triethyl 1,3,5-triazine-2,4,6-tricarboxylate (J. Org. Chem. 59, 4950, 1994) (2.02 g, 6.80 mmol.) in DMF (15 mL) is added 1-aminoethaniminium chloride (1.29 g, 13.60 mmol). After the addition, the mixture is heated at 100° C. for 18 hours then the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=3:1) to give diethyl-aminopyrimidine-2,4-dicarboxylate; HPLC Retention time 0.89 minutes (condition C); MS 240.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=S)[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]1=2.[CH3:37][O:38][NH3+:39].[Cl-]>N1C=CC=CC=1>[CH3:37][O:38][N:39]=[C:7]1[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:3]=2[N:2]1[CH3:1]
Reactant: CO[NH3+]
Reactant: CN1C(=S)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C1COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N1C
Yield: 20.5 %

Procedure:
In a round-bottomed flask was added tert-butyl 1-(4-(1-methyl-7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (0.1 g, 0.199 mmol) and o-methylhydroxylamine hydrochloride (0.067 g, 0.797 mmol) in Pyridine (Volume: 2 ml). The resulting solution was stirring and heating at 70 degree for 18 h. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was separated and washed with water (2×15 ml), brine (15 ml) concentrated to give the crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to give product (21 mg) 1H NMR (500 MHz, CDCl3) 7.20-7.29 (m, 9H), 7.10 (s, 1H), 5.19 (s, 2H), 4.95 (s, 1H), 3.81 (s, 3H), 3.31 (s, 3H), 2.2-2.6 (m, 4H), 1.95-2.15 (m, 1H), 1.75-1.85 (m, 1H), 1.2-1.4 (br, 9H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccccc4)cc3)nc2c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 2-(4-benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide (Example 3,18 mg, 0.05 mmol) in anhydrous methanol (2.0 mL) was added sodium borohydride (2.0 mg, 0.05 mmol) in one portion. The reaction mixture was stirred under N2 for 1 h. The solvent was removed under reduced pressure, and the residue was re-dissolved in 1:1 ethyl acetate/H2O (40 mL). The solution was washed with H2O (20 mL) then brine (20 mL) and dried (Na2SO4). Solvent was removed under reduced pressure, and purification by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 15 mg (83%) of the title compound. TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.13. HPLC (Method A): Rt=6.36. MS (ESI+): mass calculated for C21H17N3O2, 343.1; m/z found, 344.1 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.17 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.82–7.80 (dd, J=8.4, 1.4 Hz, 1H), 7.63 (br d, J=6.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.42–7.40 (dd, J=8.5, 1.4 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.26–7.22 (m, 1H), 5.85 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][O:24]C3CCCCO3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(#Cc1cnc(-c2ccccc2)c(-c2ccccc2)n1)CCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: OCCCC#Cc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
To a solution of 1.79 g of 5,6-diphenyl-2-[5-(2-tetrahydropyranyloxy)-1-pentyn-1-yl]pyrazine in methanol, 1.13 g of pyridinium p-toluenesulfonate was added and the mixture was heated at reflux for 30 minutes. The reaction solution was poured into ice water while stirring, extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting crystal was recrystallized from diisopropyl ether to obtain 1.00 g of the desired compound as a yellow crystal having a melting point of 88 to 90° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[OH:14])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(F)(F)F)c1O
Reaction time: 4 h
Yield: 71.5 %

Procedure:
2-Nitro-6-trifluoromethyl-phenol (1.8 g) (J. Org. Chem. 1962, 27, 4660-4662) was dissolved in MeOH (20 ml) prior to the addition of 10% Pd/C (1.0 g). The reaction was placed on a Parr aparatus under hydrogen at 60 psi for 4 h. The palladium was filtered off and the solution was concentrated to give 2-amino-6-trifluoromethyl-phenol (1.1 g): 1H NMR (CD3OD, δ ppm, 300 mHz) 6.78 (m, 2H), 6.90 (d, 1H). (22b) A portion (200 mg) of the above derivative (22a) was dissolved in p-xylene prior to the addition of diethyl malonate (0.9 ml) and p-toluenesulfonic acid (22 mg). The reaction was heated to reflux with azeotropic removal of the water. After cooling to rt, the solution was concentrated. Flash chromatography of the resulting residue gave (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid ethyl ester (130 mg). 1H NMR (CDCl3, δ ppm, 300 mHz) 1.30 (t, 3H), 4.09 (s, 2H), 4.25 (q, 2H), 7.41 (t, 1H), 7.60 (d, 2H), 7.90 (d, 1H). (22c) The above derivative (22b) (130 mg) was dissolved in THF (1 ml) prior to the addition of a solution of LiOH in water (1 ml). A couple drops of MeOH were added until the solution became clear. After 2 h at rt, the reaction was partially concentrated and 1N HCl was added to neutralize the reaction. This was exacted with EtOAc. The organic layer was dried, filtered and concentrated to provide (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid (85 mg). 1H NMR (CD3OD, δ ppm, 300 mHz) 4.13 (s, 2H), 7.54 (t, 1H), 7.70 (d, 2H), 7.95 (d, 1H). (22d) (±)(1S*,2R*,4R*)—N4-Isopropyl-N4-methyl-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexane-1,4-diamine TFA salt, from example (19g), (65 mg) was dissolved in DMF (2 ml) prior to the addition of 4-methylmorpholine (74 μl) and example (22c) (39 mg). After cooling to 0° C., BOP reagent (77 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (28 mg). MS found: (M+H)+=598.5
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C@@H:7]([CH:18]([CH3:20])[CH3:19])[CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.BrC1C=CC(O[C@@H](C(C)C)[C@@H](O)CCC2C=NC=CC=2)=CC=1.BrC1C=CC(O[C@@H](C(C)C)[C@H](O)CCC2C=NC=CC=2)=CC=1>C(OCC)(=O)C.[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH:18]([CH3:19])[CH3:20])[CH:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:21][CH:22]=1
Reactant: CC(C)[C@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Agent: [Rh]
Agent: CC(C)[C@H](Oc1ccc(Br)cc1)[C@@H](O)CCc1cccnc1
Agent: CC(C)[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](Oc1ccc(Br)cc1)C(O)CCc1cccnc1
Reaction time: 144 h

Procedure:
(3RS, 4S)-4-(4-Bromophenoxy)-5-(methyl)-1-pyridin-3-yl-hex-1-yn-3-ol (13.6 g) was dissolved in ethyl acetate (350 ml) and hydrogenated at 3 atmospheres for 6 days using 10% rhodium on charcoal (2.1 g) as catalyst. The catalyst and solvent were replaced 5 times during this period. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to give a. The mixture was purified by HPLC eluting with dichoromethane:2-propanol (97:3) to give a mixed fraction containing reduced and unreduced (6.0 g), pure (3S, 4S)-4-(4-bromophenoxy)-5-(methyl)-1-pyridin-3-yl-3-hexanol (1.73 g) and pure (3R,4S)-4-(4-bromophenoxy)-5-(methyl)-1-pyridin-3-yl-3-hexanol (2.73 g).