Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:16]([C:18]2[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:17]=1
Reactant: CCOC(C)=NC(=O)c1ccc(C)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)cc1
Reaction time: 8 h
Yield: 54 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methyl-benzamide 429 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-(3-methyl-5-p-toly-[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide (372 mg, yield: 54%) was obtained as a solid phase.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Br:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Br:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Br)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(Br)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To 20 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-bromo-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform: methanol=10:1], to give 280 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-bromoquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[S:13])=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: S=C=Nc1cccc2ccccc12
Product: COc1ccc(NC(=S)Nc2cccc3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 1-naphthyl isothiocyanate and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 6.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>[Co]>[C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccccc1
Agent: [Co]
Solvent: OCc1ccccc1
Solvent: OCCc1ccccc1
Product: Cc1ccccc1
Yield: 50 %

Procedure:
It has long been desirable to prepare 2-phenylethyl alcohol in a low cost process. This material is a valuable intermediate in the preparation of fragrances and of styrene, a commercial chemical with widely varying uses. In the past, it has been proposed that 2-phenylethyl alcohol be prepared from benzyl alcohol. For example, the reaction has been described by Wender, I. et al., J. Amer. Chem. Soc., 71 (1949), pages 4160-4161 wherein the use of a cobalt catalyst was described. This early work is summarized by Orchin in Advances in Catalysis, Vol. V (1953), pages 393-414. This auther reports that, at 183° C., a 50-60 percent yield of toluene and a 23-35 percent yield of 2-phenylethyl alcohol is obtained. Other workers have experimented with this reaction, particularly Y. B. Kryukov et al., Neftekhimiya, 1970, 10 (1), at page 83. Here, a vapor phase reaction is described over an iron, alumina, vanadium and potassium catalyst at 430° C. and 50 atmospheres pressure. Unfortunately, in this latter reaction extremely low selectivities to the 2-phenylethyl alcohol were obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:6]([O:8]C)=[O:7])#[N:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(F)c(F)c(C#N)c1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Yield: 81.3 %

Procedure:
A solution of 156 g of methyl 3-cyano-2,4,5-trifluoro-benzoate in 960 ml of glacial acetic acid, 140 ml of water and 69 ml of concentrated sulphuric acid is heated to reflux for 8 hours. The acetic acid is then largely removed by distillation in vacuo and the residue is treated with water. The precipitated solid is filtered off with suction, washed with water and dried. 118.6 g of 3-cyano-2,4,5-trifluoro-benzoic acid are obtained as a white solid of melting point 187-190° C.
Reaction SMILES: [CH:1]1([C:7]2[NH:8][S:9](=[O:21])(=[O:20])[C:10]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO>[OH-].[Na+].[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:8][S:9](=[O:21])(=[O:20])[C:10]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Yield: 40.9 %

Procedure:
A stirred suspension of 3-cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (4.2 g; 14 mmol) and 10% Pd/C (400 mg) in abs. EtOH (100 ml) was hydrogenated at 1 bar. After consumption of the calculated amount of H2, the reaction mixture was filtered through celite. The celite was washed twice with DMF (75 ml) and the combined organic fractions were evaporated to dryness. The remanense was resuspended in EtOAc/i-PrOH and the precipitate formed, was isolated by filtration. The isolated solid was dissolved in 0.5 M NaOH (aq.) and reprecipitated with 4 M HCl (aq.). Filtration gave 1.6 g product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1Cl)[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1[O:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(F)cc1
Yield: 75 %

Procedure:
2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester (0.25 g, 0.81 mmol) and 4-fluorophenol (0.09 g, 0.81 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 61.86%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=S)=[CH:5][CH:4]=1.C1[O:24]C1CC>CO>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:24])=[CH:5][CH:4]=1
Reactant: CCC1CO1
Reactant: S=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
1.0 G. of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride is boiled in 100 ml. of methanol with 35 ml. of 1,2-butylene oxide for 14 hours under reflux. The mixture is evaporated to dryness. The residue is recrystallized from isopropanol, and 0.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[O:28][N:27]=[C:26]([C:29]3[C:30](C)=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])[N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22].C(Br)C=C.Cl.CCCC(C)C>C1COCC1.C(Cl)Cl>[CH2:9]([C:30]1[C:29]([C:26]2[N:25]=[C:24]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH:21]([CH3:22])[CH3:23])=[C:14]([Cl:13])[CH:15]=3)[O:28][N:27]=2)=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33])[CH2:10][CH:11]=[CH2:12]
Reactant: [Li]CCCC
Reactant: Cc1c(C#N)cccc1-c1noc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCc1c(C#N)cccc1-c1noc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of diisopropylamine (15.15 ml, 106 mmol) in dry THF (650 m) at −78° C. under Ar was added nBuLi (44.3 ml, 70.9 mmol) down the side of the flask and the resulting solution stirred for 1 h. A solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-methylbenzonitrile Preparation 21) (12.54 g, 35.4 mmol) in dry THF (100 ml) under Ar was added dropwise at ˜10 mlmin−1, and the resulting dark blue solution stirred at −78° C. for 45 min. Allyl bromide (6.13 ml, 70.9 mmol) was added dropwise at ˜3 mlmin−1, and the resulting dark red solution stirred for 30 min at −78° C. 1 M HCl (aq) (375 ml) was added, the mixture allowed to warm to RT then the layers separated. The aqueous was extracted with EtOAc (2×125 ml), then the combined organics washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuo to give a crude red oil (12.8 g). This was redissolved in DCM (20 ml) and added to a pre-wet (isohexane) column of silica (5 cm×5 cm). Elution with EtOAc-isohexane (1:3) and concentration of the desired fractions gave a pale orange solid 2-(3-buten-1-yl)-3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)benzonitrile (9.50 g, 20.98 mmol, 59.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (1H, d), 8.24 (1H, d), 8.05 (1H, dd), 7.79 (1H, d), 7.46 (1H, t), 7.07 (1H, d), 5.94 (1H, ddt), 5.07 (1H, dq), 5.01 (1H, dd), 4.73 (1H, sept), 3.40 (2H, t), 2.47 (2H, qd), 1.45 (6H, d); MS (ES) C22H2035ClN3O2 requires 393; found 394 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2=[O:14].[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2(=[O:15])=[O:14]
Reactant: OO
Reactant: NS(=O)(=O)c1c(Cl)nc2n1CCS2=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1c(Cl)nc2n1CCS2(=O)=O
Temperature: 100 °C

Procedure:
To a suspension of 0.80 g of 6-chloro-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonamide-1-oxide in 10 ml of acetic acid is added 4 ml of 30% aqueous hydrogen peroxide solution followed by stirring for hour 100° C. After cooling, ice water is added to the reaction mixture to precipitate crystals. The crystals are collected by filtration, washed with water and dried to give 0.30 g of the title compound as colorless crystals. mp. 246°-247° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]([OH:2])=[C:4]([C:5]([C:24]2[CH:25]=[CH:26][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:7])[CH:8]=1
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Cl)ccc2O)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 2-methoxy-5-chlorobenzoic acid (2.0 g, 10.5 mmol) in dry CH2Cl2 (10 mL) was stirred at room temperature under agron. Oxalyl chloride (2.0 g, 15.8 mmol) was added dropwise to the reaction mixture followed by DMF (0.04 mL). After stirring overnight, the volatiles were evaporated using a rotary evaporator and the residue was dissolved in dry CH2Cl2 (10 mL) at room temperature under agron. After cooling to −5° C., ethylbenzene (2.57 mL, 21 mmol) was added, followed by portionwise addition of AlCl3 (2.80 g, 21 mmol) while maintaining the reaction temperature between −5° C. and 0° C. The reaction mixture was stirred for 4 h at room temperature, and then poured into ice water and extracted with CH2Cl2 (50 mL×2). The organic layer was then washed with 1N HCl (50 mL), 1N NaOH (50 mL), water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated and the crude product was purified by column chromatography (PE:EA=10:1) to give the target compound (1.944 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)[CH:10]=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1cccc(C(=O)O)c1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of 8.6g (0.063 mole) of m-aminobenzoic acid in 200 ml of 1,2-dimethoxyethane was mixed with a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at 25° C. for one hour. The reaction mixture was then filtered. The filtrate was thereafter diluted with 300 ml of water and cooled to give the crude product as a white solid. This material was recrystallized from a mixture of ethanol and water to give 5.6g of white solid N-(3-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 279-280° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 72.0; %H, 7.3; %N, 3.7.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>O1CCOCC1>[CH2:29]([O:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCc1ccccc1
Temperature: 60 °C

Procedure:
1-[4′-(4-Hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.265 mmol) and benzyl bromide (0.031 mL, 0.265 mmol) were dissolved in dioxane. Sodium hydride (60% in mineral oil, 0.016 g, 0.398 mmol) was added and the reaction was heated to 60° C. overnight. Upon cooling the reaction was partitioned between EtOAc and H2O, acidified with 1 N HCl (aq.) and extracted with EtOAc. After drying the residue was purified by silica gel chromatography (EtOAc/hexanes) to afford the title compound.
Reaction SMILES: O1CCCC1.[Cl:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11].[NH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O>[CH:15]([NH:14][S:10]([CH2:9][CH2:8][CH2:7][Cl:6])(=[O:12])=[O:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CCCCl)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 118.6 %

Procedure:
In a three-neck round bottom flask equipped with argon inlet was charged with anhydrous tetrahydrofuran and 3-chloropropane sulfonyl chloride (500 mg, 2.82 mmol, Aldrich). The flask was cooled down to 0° C., and aminodiphenylmethane (0.49 mL, 2.82 mmol, Fluka) was added, followed by triethylamine (0.59 mL, 4.23 mmol). The reaction mixture was stirred at 0° C. and monitored by the thin layer chromatography. Upon completion, water was added the reaction mixture. It was concentrated then diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 3-chloro-propane-1-sulfonic acid benzhydryl-amide (1.083 g, light brown solid). The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:36])([CH3:35])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:35][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[O:36][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
3-(4-Trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methyl-propyl]piperazine-1-carboxylate prepared in Example 391 (13.2 g, 24.81 mmol) was dissolved in DMF (40 ml). To the solution, sodium hydride (1.19 g, 29.78 mmol) was added followed by stirring for 1.5 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (13 ml) and water (92 ml) were added in this order followed by stirring for 30 minutes. The precipitates were filtered off, washed with water and purified by silica gel column chromatography (ethyl acetate) to afford 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (10.17 g, yield 83%) as a light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCOc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: CCOc1ncc(Br)cc1N
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-(ethyloxy)-3-nitropyridine (15.5 g) in EtOAc (300 ml) was treated with tin(II) chloride anhydrate (56.6 g) then heated at reflux for 2.5 hr. The reaction was cooled to RT then evaporated to dryness. The residue was treated with 2M NaOH (aq) (500 ml) that was treated with anhydrous magnesium sulfate (˜50 g) then slurried to give a filterable sludge. The filtrate was separated and the organic phase was washed with brine, dried over magnesium sulfate then evaporated to dryness. The residue was purified by column chromatography on silica, eluting with DCM, to give the title compound.
Reaction SMILES: [O:1]1[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3](O)[C:2]1=2.ClCl.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>>[C:10]1(=[O:1])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1C2=C(O2)c2ccccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: ClCl
Agent: c1cc[nH+]cc1
Product: O=C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of epoxy indenol 6 (0.24 g, 1.42 mmol) in 40 mL of CH2 Cl2, were added 2.16 g of oven dried Celite and PDC (2.16 g, 4 eq) at rt. After stirring at rt for 18 hr, the mixture was passed through 2 cm of flash silica gel pad, washed with 5% MeOH in CH2Cl2 (50 mL). The filtrate was concentrated and chromatographed with 35% EtOAc in hexane to give 0.18 g (75%) of indene-1-one 7 as colorless oil. The compound was identical with the literature by NMR (A. R. Daniewski; J. Kiegoel, J. Org. Chem. 1988, 53, 5534-5535).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]1([C@@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:31]3[C@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:34][O:33][C:32]3=[O:35])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)nc3)CC2)c(C)c1
Yield: 4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 20 and (R)-(−)-4-phenyloxazolidin-2-one (222 mg), the title compound (25 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25](F)([F:27])[F:26])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:3]=1.FC(F)C1C=C(NC(N)=O)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([F:26])[F:27])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: NC(=O)Nc1cccc(C(F)F)c1
Product: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CCC2

Procedure:
The title compound is prepared in analogy to 4-(4-bromo-2-(methylsulfonyl)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 34), using 1-(3-(difluoromethyl)phenyl)urea (intermediate 35, 707 mg, 3.80 mmol) as starting material. Yield: 319 mg; ESI mass spectrum [(79Br)-M+H]+=525, [(81Br)-M+H]+=527, Retention time HPLC: 1.01 min (Z017_S04).