Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:20][C:14]1([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CN(C)CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 50 °C
Yield: 20.3 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added 2-dimethylamino-ethanol (0.114 mL, 1.14 mmol), TFA (0.130 mL, 1.17 mmol), and the mixture heated to 50° C. for 8 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 14 mg (20%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.21 (d, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.35 (dd, J=8.6, 2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 5.67 (m, 1H), 3.83-3.66 (m, 4H), 3.30-3.15 (m, 4H), 2.76 (s, 6H), 2.26-2.20 (m, 2H), 2.12-1.94 (m, 6H), 1.51 (t, J=6.3 Hz, 2H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O3, 492.3 (M+H). found 492.0.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)([O-:23])=[O:22].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:2][O:1][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Cc1cccc(OC[C@H](CO)NC(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cccc(OC[C@H](COCc2cccc([N+](=O)[O-])c2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To t-butyl (1S)-2-hydroxy-1-[(3-methylphenoxy)methyl]ethylcarbamate (300 mg) obtained in Step 1 of Example 118 were added 3-nitrobenzyl bromide (254 mg), tetrabutylammonium sulfate (91 mg), benzene (2.3 ml) and 50% aqueous sodium hydroxide solution (2.3 ml), and the mixture was stirred at room temperature for 1.5 hrs. The mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (340 mg).
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[F:19][C:20]1[C:21](=[O:27])[NH:22][C:23](=[O:26])[NH:24][CH:25]=1>C([O-])(=O)C.[NH4+]>[F:19][C:20]1[C:21](=[O:27])[NH:22][C:23](=[O:26])[N:24]([CH:25]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reaction time: 5 h
Yield: 30 %

Procedure:
An assay mixture containing 2 g (wet weight) of Bacillus stearothermophilus cells, 5 mM 2′-deoxyinosine and 5 mM 5-fluorouracil was made in 10 ml of 50 mM ammonium acetate buffer (pH 5.5). The conversions were run at 55° C. for 5 hour. The reaction mixture was centrifuged and then filtered using an Amicon Ultrafiltration device (YM-3 membrane) and the products were separated and analyzed by HPLC (C-18 column) in 5% methanol and 5 mM phosphate buffer at pH 4.6 using a flow rate of 0.5 ml/min. Blanks were run to check the authenticity of the reaction. No undesirable side reactions were detected. 5-fluoro-2′-deoxyuridine was obtained in 30% yield (62% conversion).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2 g (11.6 mmol) 5-chloro-2-nitro-phenylamine, 2.14 g (11.6 mmol) piperazine-1-carboxylic acid tert-butyl ester and 1.3 g (11.6 mmol) 1,4-diazo-bicyclo[2.2.2]octane in 20 ml DMSO was heated to 150° C. for 16 h. The mixture was poured onto 200 ml water and extracted with 250 ml ethyl acetate. The emulsion was filtered through decalite and the aqueous phase was extracted with 2×200 ml. The combined organic phases were washed with 2×100 ml water, dried with MgSO4 and evaporated to dryness. The residue was purified with column chromatography on silica eluting with ethyl acetate/hexane to yield the title compound as a yellow solid. MS(ISP): 321.2 (M−H)−.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:6](=[O:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)OCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
A tetrahydrofuran (6 L) solution of 140 g of 2-isopropoxyacetic acid and 540 mL of triethylamine was cooled to −20° C., to which a tetrahydrofuran (100 mL) solution of 145 g of 2,2-dimethylpropanoyl chloride was added dropwise, followed by stirring the reaction mixture at −10 to −20° C. for 3 hours. The reaction mixture was cooled to −30° C., to which 80 g of anhydrous lithium chloride and then 225 g of (4S)-4-benzyl-1,3-oxazolidin-2-one was added, followed by stirring the reaction mixture overnight at room temperature. The reaction mixture was filtered and subjected to vacuum concentration. The residue was dissolved in 3 L of ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution (1.5 L), and dried with anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was purified using silica gel column chromatography to obtain 196 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (5:1→2:1)-eluted fraction.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)O
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a cooled solution (0-5° C.) of D-leucine (200 g, 1.5 mol) in sulfuric acid (3 L, 1 M) was added dropwise a solution of sodium nitrite (240 g, 3.5 mol) in water (1 L) while maintaining the temperature between 0-5° C. The reaction mixture was stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted with tert-butyl methyl ether (3×). The combined organic layers were dried over Na2SO4 and filtered, and the solvent was removed in vacuo. (R)-α-hydroxyisocaproic acid was isolated as a white solid in a yield of 67% (132 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[NH:13])=[CH:10][CH:9]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[NH:14][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:13]=2)=[CH:10][CH:9]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc(-c3ccc(Cl)cc3)c[nH]2)cc1
Reaction time: 1 h

Procedure:
To a two-phase mixture of 30% K2CO3 solution (5 ml) and chloroform (5 mL) containing 276 mg of 4-fluorobenzamidine was added a solution of 468 mg of 2-bromo-4'-chloroacetophenone in chloroform (3 mL). After stirring for 1 hr, the reaction mixture was filtered. The white crystallinesolid was washed with distilled water and dried in a vacuum oven overnight to afford 2-(4-fluorophenyl)4-(4-chlorophenyl)imidazole (Compound 1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=2)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: CCCc1cccc(O)c1
Reactant: O=Cc1ccc(F)cc1Cl
Product: CCCc1cccc(Oc2ccc(C=O)c(Cl)c2)c1

Procedure:
3-Propylphenol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a pale brown oil.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:19]=3[N:18]([CH2:28][CH:29]([OH:44])[CH2:30][N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH3:43])[CH2:33][CH2:32]3)[N:17]=2)=[CH:12][C:11]=1[N+:45]([O-])=O.Cl.C(=O)(O)[O-].[Na+]>O.C1COCC1>[NH2:45][C:11]1[CH:12]=[C:13]([C:16]2[C:20]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:19]=3[N:18]([CH2:28][CH:29]([OH:44])[CH2:30][N:31]3[CH2:32][CH2:33][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH3:43])[CH2:35][CH2:36]3)[N:17]=2)[CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(N)c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a solution of sodium hydrosulfite (1.28 g, 7.3 mmol) in 30 mL water was added 1-{3-(4-chloro-3-nitro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone (810 mg, 1.5 mmol) in 15 mL THF. The reaction mixture was stirred at room temperature for 5 min. The color of the solution changed from light yellow to colorless. Hydrochloride solution (1 N, 10 mL) was added to the reaction mixture. This solution was stirred at room temperature for 30 min, and treated with saturated sodium bicarbonate until the pH of the solution between 7 to 8. The product was extracted with dichloromethane (3×80 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to a residue. This residue was purified by column chromatography (silica, 5-20% MeOH/CH2Cl2) to afford 644 mg (84.1%) of the title compound. MS (electrospray): m/z 523.3 (523.3, calculated for C28H35ClN6O2, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.30-6.70 (m, 7H), 4.80-4.60 (m, 1H), 4.55 (s, 1H), 4.20-4.05 (m, 4H), 3.95-3.90 (m, 2H), 3.80-3.60 (m, 2H), 2.90-2.30 (m, 9H), 2.20 (s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:32])[CH2:6][N:7]([CH2:27][C:28]([O:30]C)=[O:29])[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:10]=1>>[C:5]([CH2:6][N:7]([C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:10]=1)[CH2:27][C:28]([OH:30])=[O:29])([OH:32])=[O:4]
Reactant: CCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCOc1cccc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-methoxy-2-oxoethyl)-N-[3-(decyloxy)benzoyl]glycine methyl ester as in Example 4 gave N-(carboxymethyl)-N-[3-(decyloxy)benzoyl]glycine, mp 87°-90°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1/[CH:11]=[CH:21]/[CH:22]=[O:23]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cn1c(C=O)nc2ccccc21
Product: Cn1c(/C=C/C=O)nc2ccccc21

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-methyl-1H-benzimidazole-2-carboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 187 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:34])[CH:17]([C:19]4[CH:33]=[CH:32][C:22]5[N:23](C6CCCCO6)[CH:24]=[N:25][C:21]=5[CH:20]=4)[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:23]1[C:22]2[CH:32]=[CH:33][C:19]([CH:17]([N:16]([CH3:34])[C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH3:18])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: CC(c1ccc2c(c1)ncn2C1CCCCO1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(c1ccc2[nH]cnc2c1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 50 °C
Yield: 45.1 %

Procedure:
To a solution of 86 (68 mg, 0.148 mmol) in MeOH (50 mL) and water (10 mL) was added TsOH.H2O (44 mg, 0.148 mmol). The reaction mixture was heated at 50° C. for 18 h. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 25 mg (45%) of (±)-N2-(1-(1H-benzo[d]imidazol-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine (88) as white solid: MS (ESI) m/z=375.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]([O:22][CH3:24])=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Yield: 64.2 %

Procedure:
To a solution of 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylic acid (45 mg, 0.132 mmol) in MeOH (2649 μl) was added TMS-diazomethane (132 μl, 0.265 mmol, 2M in Et2O). Additional TMS-diazomethane aliquots were added until no more gas evolution was observed. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 12 g, 0 to 50% EtOAc in hexane), to give methyl 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate (30 mg). methyl 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate was reduced using DIBAL, using a similar procedure as described in the preparation of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE B1.1), to provide {5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}methanol. MS: M+H=326.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[S:19][C:20](Br)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([O:15][C:16]([C:18]1[S:19][C:20]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)OC(C)(C)C)s2)cc1
Temperature: 70 °C
Yield: 87.7 %

Procedure:
To the mixture of 4-methylbenzeneboronic acid (38.0 mg, 0.279 mmol) and 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (40 mg, 0.0925 mmol) in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A°) using ethyl acetate/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 81% yield). 1H NMR (CDCl3, 300 MHz) 9.94 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.44-7.25 (m, 6H), 7.18 (d, J=8.1 Hz, 2H), 2.71 (s, 3H), 2.36 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([O:22]CC)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Si:1]([O:18][CH2:19][C:20]1([OH:22])[CH2:25][C:26]1([CH3:28])[CH3:27])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(C)CC1(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 10 g (29 mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 100 ml of tetrahydrofuran (THF) and 6.0 ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37 ml of isobutylmagnesiumbromide (2.0M in THF) at −10° C., and the reaction solution was stirred for 12 hours at room temperature. 50 ml of saturated ammonium chloride was added to stop the reaction. The tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500 ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 5.0 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[C:22](Cl)([CH3:24])=[O:23]>C1([N+]([O-])=O)C=CC=CC=1>[C:22]([C:14]1[CH:13]=[CH:12][C:10]2[C:11]3[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[C:6]=3[CH:7]=[CH:8][C:9]=2[CH:15]=1)(=[O:23])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c3c(ccc2c1)N(C(=O)C(F)(F)F)CC3CCl
Yield: 33 %

Procedure:
Acylation of 108 (0.88 g, 2.8 mmol) with AlC3 and AcCl in PhNO2 at 0° C., stirring at room temperature for 16 h, and workup as above, gave a crude product. Chromatography on silica gel, eluting with EtOAc/petroleum ether (from 0:1 to 1:3) gave 7-acetyl-1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (110) (196 mg, 33% based on consumption of starting material): mp (EtOAc/petroleum ether) 168-170° C.; 1H NMR (CDCl3) δ 8.52 (d, J=8.9 Hz, 1H), 8.51 (s, 1H), 8.14 (dd, J=8.8, 1.7 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.8H, 1H), 4.68-4.62 (m, 1H), 4.49-4.41 (m, 1H), 4.28-4.19 (m, 1H), −3.99-3.93 (m, 1H), 3.61-3.55 (m, 1H), 2.74 (s, 3H); 13C NMR δ 197.6, 182.8, 154.9 (q, JC-F 38.4 Hz), 142.1, 134.1, 132.2, 131.3, 131.1, 125.7, 125.5, 131.1, 118.1, 116.0 (q, JC-F 288 Hz), 52.7, 45.4, 42.6, 26.6. Anal. (C17H13ClF3NO2) C, H, N. Further elution gave recovered 108 (360 mg, 40%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:16]=[CH:15][CH2:14][NH2:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: NCC=NC1CCC(c2ccccc2)CC1

Procedure:
A mixture of 4-phenylcyclohexanone (4.00 g, 22.96 mmol) and ethylenediamine (1.66 g, 27.5 mmol) and p-toluenesulfonic acid (437 mg) in benzene (200 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Tlc analysis indicated the completion of the reaction. Solvent was evaporated and the product was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH: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])=[C:4]([F:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[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:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[CH:3][C:4]=2[F:24])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 48.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (783 mg) described in Preparation Example 4 and oxazolidin-2-one (174 mg), the title compound (383 mg) was obtained.