Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10](C(O)=O)[C:11]#[N:12])=[O:7])[CH3:4].C([O-])(=O)C.[Na+].Cl>O>[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([Br:1])[C:11]#[N:12])=[O:7])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(C)C(C#N)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)C(Br)C#N
Temperature: 20 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
40 g (0.25 mol) of bromine were added dropwise to a solution of 42.6 g (0.2 mol) of 3-carboxy-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester and 41 g of sodium acetate in 400 ml of water at 20° C. The mixture was subsequently stirred at 20° C. for 5 hours. It was then acidified with dilute HCl and extracted twice with 100 ml of methylene chloride each time. The organic solutions were dried over sodium sulphate and then concentrated. The residue was first introduced dropwise into a flask, which was heated to 200° C., whereupon continuous evolution of CO2 started, and was then twice subjected to fractional distillation. 38 g (76.5% of theory) of 3-bromo-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 92°-95° C./2.5 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=C=O)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:37])=[CH:26][CH:27]=1)(=[O:32])=[O:33])=[O:12]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2[N+](=O)[O-])cc1

Procedure:
A catalyst amount (ca. 10 gm) of N,N-dimethylaminopyridine (available from the Aldrich Chemical Co. Ltd.) was added to a stirred mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (260 gm, 0.72 moles) in 350 ml toluene under nitrogen. A solution of para-toluenesulfonylisocyanate (available from the Aldrich Chemical Co., Ltd., 180 gm, 0.94 moles) in toluene (150 ml) was then added dropwise to the above solution with stirring. After the addition was complete the mixture was brought to reflux for six hours. Toluene in the cooled solution was then removed in vacuo. The resulting waxy solid was further recrystalized from toluene to yield 170 gm (0.33 moles, 46%,) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>C1COCC1.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 159C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) in a mixture of THF (6 mL) and water (1 mL) was stirred at room temperature for 6 hours. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 159D as an oil (30 mg, 100%); 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08 (m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45 (m, 2H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[CH3:18][OH:19]>>[CH3:18][O:19][C:7]1[S:8][C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(C)c1
Reactant: CO
Product: COc1nc(C(=O)O)c(-c2cccc(C)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-m-tolyl-thiazole-4-carboxylic acid methyl ester with MeOH. LC-MS: tR=0.88 min; [M+H]+=250.3.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=O.C[N:17](C)CCCN=C=NCC>C(O)C>[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([NH2:17])=[O:15]
Reactant: O=C(O)c1c[nH]c2ccc(O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1c[nH]c2ccc(O)cc12

Procedure:
In general, a beta-ketoester (e.g. ethyl acetoacetate) is treated with an amine (e.g. 2-thiophenemethyl amine) in the presence of an organic acid (e.g. para-toluenesulfonic acid) and 1,4-benzoquinone to produce a 5-hydroxyindole-3-carboxylic acid (e.g. 5-hydroxy-2-methyl-1-(2-thiophenemethyl)indole-3-carboxylic acid) after hydrolysis of the ester with a strong base such as sodium hydroxide in a suitable solvent such as ethanol. The carboxylic acid is further reacted with an amine in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodimide (EDC) to produce 5-hydroxyindole-3-carboxamide (e.g. 3,4-difluorophenylmethyl 5-hydroxy-2-methyl-1-(2-thiophenemethyl)indole-3-carboxamide). The carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C.O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][N:10]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CNC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(N2CC(c3cccc(Br)c3)(c3cccc(Br)c3)C2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
A mixture of 3,3-bis(3-bromophenyl)azetidine (60 mg, 0.163 mmol), 1-tert-butyl-4-iodobenzene (85 mg, 0.327 mmol), xantphos (9.46 mg, 0.016 mmol), Pd2(dba)3 (3.74 mg, 4.09 μmol) and tert-butoxide (18.85 mg, 0.196 mmol) in dioxane (5 mL) was stirred at 110° C. for 12 h. After the reaction was cooled to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous phase was extracted with dichloromethane (15 mL×3). The combined organic layers were dried and concentrated. The residue was purified by prep-HPLC (Instrument waters 2767 PHW004 Column YMC-Triart C18 150*20 mm S-5 um 12 nm Mobile Phase A: water (0.05% NH4HCO3) B: ACN Gradient 95-95% B in 8 min stop in 14 min Flow Rate(ml/min) 20.00 Detective Wavalength(nm) 214\254 Retention Time(min) 7.4 to afford 26 mg of the title compound (0.052 mmol, 31.8% yield). LC/MS: [M+1]=500.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[CH:4][C:3]=1[N:11]([CH3:20])[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:8][CH2:7][C:5]1[S:6][C:2]([CH3:1])=[C:3]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1cc(N(C)S(=O)(=O)c2cccs2)c(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(CO)cc1N(C)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of methyl 5-methyl-4-[methyl(2-thienylsulfonyl)amino]thiophene-2-carboxylate (37.5 g) in tetrahydrofuran (200 mL) was slowly added lithium aluminum hydride (4.4 g) in small portions. The reaction mixture was stirred at room temperature for 1 hr, and water (4.4 mL), 15% aqueous sodium hydroxide solution (4.4 mL) and water (13.2 mL) were successively added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated and crystallized from diethyl ether to give N-[5-(hydroxymethyl)-2-methyl-3-thienyl]-N-methylthiophene-2-sulfonamide (31.1 g, yield 91%) as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:23]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][NH:22][CH2:2][CH2:1][C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=Cc1ncccn1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(C(CCNCCc2ncccn2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of 2-vinylpyrimidine (0.373 g, 3.51 mmol) in EtOH (6 mL) at room temperature was added AcOH (1 mL) and 3,3-diphenylpropan-1-amine (2.21 g, 10.5 mmol). The reaction mixture was heated to reflux for 1 d, cooled to 0° C., and the solids were removed by filtration. The filtrate was concentrated and diluted with 5 M NaOH, brine, and EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% MeOH in DCM) gave 3,3-diphenyl-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=2)[N:7]=1)=[O:5])C.[Li+].[OH-].O>C1COCC1>[C:11]1([C:9]2[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:21][CH:22]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of compound 3b (0.37 g, 1 mmol) in THF (10 mL) was added LiOH (35 mg, 1.5 mmol) followed by 2 mL of water at room temperature. The reaction mixture was stirred overnight. The reaction was quenched by adding 1N HCl. The solvent was evaporated in vacuo. The resulting white solids were collected by suction filtration and washed with water. The crude product was recrystallized from MeOH to give the titled compound (0.33 g, 96% yield) as a white solid. mp 188.5-190.9° C. 1H NMR (300 MHz, DMSO-d6): δ 13.10 (s, 1H), 7.87 (d, J=8 Hz, 2H), 7.55-7.48 (m, 4H), 7.44-7.37 (m, 3H), 7.34-7.26 (m, 2H), 7.10 (s, 1H).
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O-:27])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3].[Na+].[C:31]([O:34][CH2:35]Br)(=[O:33])[CH3:32]>CN(C=O)C.O>[F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O:27][CH2:35][O:34][C:31](=[O:33])[CH3:32])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3]
Reactant: CC(=O)OCBr
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(C(C)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CSC(F)(F)F)C(=O)N12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of sodium 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (738 mg, 1.5 mmol) in dry DMF (10 ml) is added a solution of bromomethyl acetate (253 mg, 1.65 mmol) in DMF (1 ml). The reaction is stirred for 30 minutes at 0°C and 90 minutes at room temperature. The reaction is diluted with water and the aqueous mixture is extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to give acetoxymethyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The product is dissolved in ethyl acetate and is precipitated by the addition of petroleum ether.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:17][C:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a suspension of methyl 6-chloro-5-nitronicotinate (0.108 g, 0.499 mmol), 1-Boc-pyrrole-2-boronic acid (0.210 g, 0.997 mmol), and trans-Dichlorobis(triphenylphosphine)palladium (II) (0.350 g, 0.499 mmol) in Dioxane (Volume: 2.3 mL) was added 2M Sodium carbonate (0.798 mL, 1.596 mmol) at 23° C. The reaction was stirred at 100° C. for 1 hr. The resulting suspension was filtered and rinsed with dioxane and H2O. The filtrate was diluted with EtOAc (20 mL) and the layers were separated. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, rinsed with EtOAc, and dried in vacuo. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation to provide methyl 6-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5-nitronicotinate (0.0738 g, 0.212 mmol, 42.6% yield) as an orange gummy solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 3.96 (s, 3 H) 6.41 (t, J=3.28 Hz, 1 H) 6.65 (dd, J=3.28, 1.77 Hz, 1 H) 7.50 (dd, J=3.28, 1.77 Hz, 1 H) 8.82 (d, J=1.77 Hz, 1H) 9.33 (d, J=1.77 Hz, 1 H). ESI-MS: m/z 348.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[NH2:31][OH:32]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:31][OH:32])[CH2:13]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and hydroxylamine hydrochloride (40 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-propionamide (150 mg, 77%) as a yellow foam: mp 100-106° C.; (ES)+-HRMS m/e calcd for C19H20BrClN4O4S (M+H)+ 515.0150. found 515.0154.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH3:26].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([CH2:4][CH2:3][CH2:2][C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
A solution of 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 1.97 g of n-butyl iodide in 10 ml of N,N-dimethylformamide was added dropwise thereto, and the mixture was heated at 50° C. for 13 hours. The reaction solution was poured into a mixed solution of 70 g of dilute hydrochloric acid and 70 g of ethyl acetate for extraction. The resulting organic layer was washed twice with water, dried, and then concentrated under reduced pressure to obtain 2.59 g of crude ethyl 3-(N-n-butylbutyrylamino)-4-nitrobenzoate. Then, 0.81 g of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (94) were formed in the same manner as in Example 24.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].N1CCCCC1>C(O)C>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([CH3:10])[CH2:9]2)#[N:13]
Reactant: CC(=O)C1CC(C)CCC1=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(C)CC2

Procedure:
To the total amount of the crude 2-acetyl-4methylcyclohexanone prepared in (1), 35 ml of ethanol, 3.36 g of cyanoacetamide and a small amount of piperidine were added and the obtained reaction mixture was heated under reflux for four hours. The crystals thus precipitated were filtered and recrystallized from a mixture of methanol and water to give 4.22 g of 4-cyano-1,7-dimethyl-2,3,5,6,7,8hexahydro-3-oxoisoquinoline. m.p. >290° C. NMRδTMSCF3COOH : 1.23 (3H, d), 2.60 (3H, s) and 1.8-3.3 (7H,m).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH2:11][C:12](OCC)=[O:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)CCc1cc(OC)ncc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1cc(CCCO)c(Br)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To solution of ethyl 3-(5-bromo-2-methoxypyridin-4-yl)propanoate (1 eq.) from step 3 in THF (0.18M) at −78° C. was added DIBAH (2.5 eq.). The reaction mixture was stirred at −78° C. for 30 min then at 0° C. for 2 h. The reaction was quenched with HCl (1N) at 0° C. and then was diluted with Et2O. The organic extract was washed with water, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)OCC[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:7]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([OH:23])[C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:16][CH:17]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(O)c1ccc(C2(c3ccccc3)OCCO2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C

Procedure:
14.2 gr. of the above 2-phenyl-2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane is dissolved in 500 milliliters 25% acetic acid and 5 milliliters of concentrated hydrochloric acid are added. The solution is heated on a water bath at about 60° C. for two hours. The mixture is then treated with 300 ml. of saturated sodium chloride and extracted three times with ether. The combined ether layers are washed with saturated sodium chloride solution, 2N sodium hydroxide and then dried over anhydrous magnesium sulfate and filtered. The solvent is removed and the solid recrystallized from ether-petroleum ether to give 1-(p-benzoylphenyl)-2,2-dimethylpropanol (m.p. 103°-105° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=[S:22])[CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Yield: 99.7 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one (40 g) was dissolved in chloroform (600 ml) and phosphorus pentasulfide (117 g) was added thereto with stirring. The mixture was refluxed for 3 hours. After the reaction, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and precipitated crystals were collected by filtration with diisopropyl ether and recrystallized from ethanol-chloroform to give 42 g of 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione having a melting point of 198°-199° C. The thione compound obtained (42 g) was suspended in methanol (300 ml) and 100% hydrazine hydrate (19 ml) was added thereto under cooling. The mixture was stirred at room temperature for 2 hours. After the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol-dimethylformamide to give 34 g of 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-hydrazine, melting point 214°-216° C. The hydrazone compound (20 g) was dissolved in chloroform (200 ml) and cyclohexylcarbonyl chloride (10 g) was added thereto with stirring. The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in toluene (200 ml) and acetic acid (5.4 ml) was added thereto. The mixture was refluxed for 3 hours. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The objective fraction was concentrated under reduced pressure to give 15 g of 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine, melting point 116°-119°πC.