Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12].[BH4-].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[F:28][C:8]1[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=[C:6]([CH2:2][O:1][CH2:5][CH2:4][OH:3])[C:7]=1[F:29])[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12]
Reactant: O=C(NOCCO)c1cc(C2OCCO2)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCCO)c1cc(COCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 5-[1,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (21.69 g) obtained in Step G in anhydrous THF (100 ml) were added sodium borohydride (4.21 g, 111.4 mmol) and trifluoroacetic acid (5.08 ml, 66.8 mmol) with ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2 600 g, 100% AcOEt to AcOEt/MeOH (50:1 to 20:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide (13.9 g, 80%) as a white powder.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C(F)(F)F)cc(C#N)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)cc(C(N)=O)n1
Reaction time: 12 h
Yield: 84.3 %

Procedure:
To 10 ml of ethanol were added 0.86 g of sodium bicarbonate and 0.71 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.8 g of 6-methyl-4-trifluoromethylpyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 12 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.74 g of 6-methyl-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: Cl[C:2]1[N:6]2[C:7]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:8]=3[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][CH:11]([CH2:12][CH3:13])[C:5]2=[N:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:7]2[N:6]3[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:3][N:4]=[C:5]3[CH:11]([CH2:12][CH3:13])[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]=2[CH:20]=1
Reactant: C1CNCCN1
Reactant: CCC1N=C(c2ccccn2)c2cc(Cl)ccc2-n2c(Cl)nnc21
Product: CCC1N=C(c2ccccn2)c2cc(Cl)ccc2-n2c1nnc2N1CCNCC1

Procedure:
In the manner given in Example 1, 1,8-dichloro-4-ethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with piperazine to give 8-chloro-4-ethyl-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39]COC)=[O:32])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[OH:39])=[O:32])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A 60 ml quantity of trifluoroacetic acid was stirred with ice cooling, 12.3 g of the compound obtained in Example 231 was added thereto, and stirring was conducted for one hour. At the completion of the reaction, the reaction mixture was neutralized by addition of an aqueous saturated sodium bicarbonate solution, and ethyl acetate was added to the obtained mixture. The organic layer was washed twice with water, separated, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethanol, thereby yielding 5.9 g of white powdery 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1ccc(OCc2ccccc2)cc1
Yield: 58.4 %

Procedure:
A mixture of N-[3-(4-benzyloxyphenoxy)propyl]phthalimide (3.87 g) and hydrazine hydrate (0.55 g) in ethanol (40 ml) was heated at reflux for 3 hours. The reaction mixture was allowed to cool, filtered and the filtrate evaporated. Sodium hydroxide solution (2M, 20 ml) was added to the residue, the aqueous mixture extracted with ethyl acetate and the ethyl acetate extract dried. The solid collected by filtration of the cooled reaction mixture was suspended in sodium hydroxide solution (2M, 20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried, combined with the dried ethyl acetate derived from the filtrate and the combined extract evaporated to give 3-(4-benzyloxyphenoxy)propylamine as a solid (1.5 g), m.p. 115° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:22]=1[CH:23]([OH:27])[C:24](Cl)=[O:25]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:24](=[O:25])[CH:23]([C:22]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:21]=2[CH2:20][Cl:19])[OH:27])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: COc1ccc(C(O)C(=O)Cl)c(CCl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(COC(C)=O)CSC23)c(CCl)c1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1.2 g of 2-chloromethyl-4-methoxymandelic acid chloride in 200 ml of ethyl acetate is refluxed for 50 minutes after which the solvent is removed under high vacuum. The resulting product is chromatographed on silica gel using benzene-actone as the eluant. The product obtained is triturated with ether to give 3-[(acetyloxy)methyl]-7-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 140°-142°C (dec.).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Na]>C(O)CCC>[CH2:4]([O:5][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:3][CH2:7][CH3:8]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1ncccc1C(=O)O
Yield: 192 %

Procedure:
2-Chloronicotinic acid (10.0 g, 63.5 mmol) was added to a solution of sodium (3 g, 130 mmol) in butanol (100 ml) at 80° C., and the resulting mixture heated under reflux for 4 hours. The reaction was allowed to cool, and partitioned between EtOAc and 2M HCl (to give pH 3-4), and the layers separated. The organic phase was washed with brine, concentrated under reduced pressure, redissolved in EtOAc, dried (MgSO4), filtered and evaporated under reduced pressure, to give the desired product as a solid (11.9 g).
Reaction SMILES: Br.C[O:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:15])(=[O:14])[N:6]([CH3:16])[C:5]=1[C:17]([NH:19][C:20]1[S:21][C:22]([CH3:25])=[CH:23][N:24]=1)=[O:18]>C(O)(=O)C>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:15])(=[O:14])[N:6]([CH3:16])[C:5]=1[C:17]([NH:19][C:20]1[S:21][C:22]([CH3:25])=[CH:23][N:24]=1)=[O:18]
Reactant: COC1=C(C(=O)Nc2ncc(C)s2)N(C)S(=O)(=O)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)s1
Reaction time: 24 h

Procedure:
0.5 ml of 48% hydrobromic acid and 1 ml of glacial acetic acid were added to 0.2 gm (0.55 millimols) of 4-methoxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-caboxamide-1,1-dioxide. After standing for 24 hours, the reaction mixture was heated for two hours on a water bath and was subsequently evaporated in vacuo to dryness. The residue was dissolved in methylene chloride, and the solution was washed with water. After drying and evaporating of the organic phase, 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide was obtained with a yield of 0.1 gm (52% of theory).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:45](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:20]=[N:19][N:18]([CH3:45])[N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 0.5 g, 0.85 mmol), methyl iodide (0.3 g, 2.1 mmol) and potassium carbonate (0.29 g, 2.1 mmol) were stirred at 50° C. in acetonitrile (20 ml) for 2 hours. Concentrated in vacuo then partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 20, 50 and 75% ethyl acetate/iso-hexanes to afford the title compounds: isomer A (0.25 g, 49%) and isomer B (0.17 g, 33%).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].CS(C)=O.BrC1C=[N:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=1.C(OCC)(=O)C>C(OCC)C.O>[CH3:20][S:17]([C:14]1[N:13]=[CH:2][C:1]([OH:4])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(O)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6.6 g of bis(pinacolate)diboron, 5.9 g of potassium acetate and 980 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane complex were added to a dimethylsulfoxide (80 ml) solution of 4.72 g of 3-bromo-6-methanesulfonyl-pyridine, and the reaction liquid was stirred at 80° C. for 2 hours. Ethyl acetate and water were added to the reaction liquid, the insoluble substance was removed through filtration through Celite, and the organic layer was separated. The organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. 60 ml of aqueous 5 N sodium hydroxide solution and 30 ml of aqueous 30% hydrogen peroxide solution were added to a tetrahydrofuran (200 ml) solution of the resulting residue at 0° C., and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with diethyl ether, and washed with water. The aqueous layer was made acidic with 5 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was washed with a mixed solvent of chloroform and hexane to obtain the entitled compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[NH2:6].[C:18]([CH:21]=[C:22]=[O:23])(=[O:20])[CH3:19]>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[CH2:21][C:18](=[O:20])[CH3:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 3-trifluoromethyl-4-morpholinoaniline (4.0 g, 16.2 mmol), EtOAc (30 mL) and acetyl ketene (2.73 g, 32.5 mmol) was stirred at 90° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (4.0 g, 75%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:47][C@H:46]([C:45]([OH:44])=[O:51])[CH:48]([CH3:50])[CH3:49])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N[C@H](C(=O)O)C(C)C)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and L-valine methyl ester hydrochloride (34 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.03-12.85 (br.s, 1 H), 8.95 (s, 1 H), 7.96 (d, 1 H), 7.23 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.68 (dd, 1 H), 6.49 (m, 2 H), 4.14 (dd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.92 (t, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.31 (m, 2 H), 2.02 (m, 1 H), 1.90 (m, 2 H), 0.86 (s, 3 H), 0.85 (s, 3 H); MS (APCI+) m/z 674.7 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(CCCCl)c1cc(C(C)C)c(OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c(C(CCCCl)C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoate (7.7 g) was dissolved in a mixed solvent of methanol (25 mL) and tetrahydrofuran (25 mL). A 5 N sodium hydroxide solution (22 mL) was added and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure and water was added, followed by washing with heptane. The aqueous layer was made acidic with 5 N hydrochloric acid, followed by extraction with tert-butyl methyl ether. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain 5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid (6.2 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@@H:22]([CH3:26])[C@@H:23]1[O:25][CH2:24]1)[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.O>C(OCC)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@@H:22]([CH3:26])[C@@H:23]([OH:25])[CH3:24])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@H](O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 74.7 %

Procedure:
84 mg (2.16 mmole) of lithium aluminum hydride were added, under an atmosphere of nitrogen, to a solution of 320 mg (1.08 mmole) of (2R*,3S*,4S*)-2-(2,4-difluoro-phenyl)-4,5-epoxy-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-pentanol (stereoisomer A) [prepared as described in step (a) above] in 20 ml of diethyl ether, whilst ice-cooling and stirring. Ten minutes later the reaction mixture was heated under reflux, and this was continued for hour. At the end of this time, the mixture was cooled, and 2 ml of water were slowly added; the mixture was then stirred for 10 minutes. The insoluble materials in the reaction mixture were removed by filtration using a Celite filter aid, and then the residue was washed with ethyl acetate. The combined filtrate and washings were dried and freed from the solvent by distillation under reduced pressure. The resulting oily residue was subjected to column chromatography through silica gel, using a 5:5:1 by volume mixture of ethyl acetate, chloroform and hexane as the eluent, to afford 240 mg of the title compound.
Reaction SMILES: C([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.OS(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[C:17](=[O:26])[NH:16][C:15](=[O:27])[NH:14][CH:19]=2)[CH:21]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1cccnc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(-c2cccnc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 3), starting from 1-benzhydryl-5-(3-pyridyl)pyrimidine-2,4-dione (0.085 g, 0.239 mmol). Herein, anisole (0.163 g, 1.5 mmol) was added together with the triflic acid/TFA mixture, and the orange reaction mixture was here stirred for 1 hr at 0° C. TFA was removed by a stream of nitrogen and remaining TFA removed by co-evaporating with diethyl ether (40 mL). Water (15 mL) and acetonitrile (15 mL) was added, solidified in a dry ice-acetone bath, and the crude title compound was obtained by lyophilization. The crude was purified by column chromatography using a Teledyne ISCO apparatus (Dichloromethane:20% methanol in dichloromethane 30:70) to afford the title compound as, a triflic salt (0.067 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.91 (dd, J=6.2, 5.8 Hz, 1H), 8.07 (d, J=6.1 Hz, 1H), 8.60 (dt, J=8.2, 1.6 Hz, 1H), 8.72 (dd, J=5.4, 1.4 Hz, 1H), 9.06 (d, J=2.1 Hz, 1H), 11.55 (s, 1H), 11.58 (d, =5.5 Hz, 1H). MS (ESI) m/z: 190 [M-H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH:33]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(c3cc(C)c(C)nc3OC)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added, followed by stirring at room temperature for 15 min, and then 2-iodopropane(42 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Yield: 71.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (700 mg) obtained from Reference Example 1 was suspended in 1,2-dichloroethane (20 ml). Pyridine (237 mg) and pivaloyl chloride (362 mg) were added thereto, and the mixture was refluxed for two hours. After the reaction mixture was allowed to cool, crystals that precipitated were collected by filtration, to thereby obtain 650 mg of the title compound (yield: 71%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.[CH3:39][C@H:40]1[CH2:45][NH:44][C@H:43]([CH3:46])[CH2:42][N:41]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=1)=[O:48]>C(N(CC)CC)C>[CH3:46][C@H:43]1[CH2:42][N:41]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:40]([CH3:39])[CH2:45][N:44]1[C:27]([C@@H:11]1[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[O:29]
Reactant: C[C@@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 23.9 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 1.79 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.54 ml of pivaloyl chloride, 0.61 ml of triethylamine and 1.29 g of trans-2,5-dimethyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 577 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(-n2ccnc2)cc1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(=O)Nc1ccc(-n2ccnc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1-Ethoxalylamino-4-(1H-imidazol-1-yl)-benzene (16 g; 61.8 mmol) was added gradually to 100 ml nitric acid (d=1.52) at 0° C. Stirring was continued at 0° C. for 1 h, and then the reaction mixture was poured into ice-water to give the title compound (18 g; 80%) as a nitric acid salt. M.p. 180° C. (decomp.).