Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1F.Cl>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]([F:23])([F:24])[F:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[O:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Temperature: 60 °C
Yield: 56 %

Procedure:
Sodium hydride (60% in oil, 0.44 g, 11.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.98 g, 10.0 mmol) and 3-chloro-4-fluoro-5-nitrobenzotrifluoride (1.5 g, 10.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 60° C. for 7 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (80 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/3), to give a yellowish solid of 3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole (1.8 g, yield: 56.6%). mp: 120-123° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.29 (s, 3H), 5.79 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.65-9.30 (br s, 1H).
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: NC(CO)Cc1ccccc1
Solvent: CCO
Product: NC(COB(c1ccccc1)C(OC(B(OCC(N)Cc1ccccc1)c1ccccc1)c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
The entitled compound (9 mg) was obtained by allowing 41 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 10 mg of 2-amino-3-phenylpropanol to act in 1 mL of ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Yield: 87.4 %

Procedure:
1,1-dimethylethyl 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3.25 g) was hydrogenated for 3 h under atmospheric pressure at 25° C. in the presence of 10% Pd/C (0.32 g) in MeOH (130 ml). The catalyst was removed by filtration, the solvent evaporated under reduced pressure and the resulting residue was purified by flash chromatography over silica gel (eluting with 40% ethyl acetate in hexane) to give the title compound (2.55 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([F:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12](C=O)C.CCOC(C)=O>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.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>[NH2:8][C:5]1[C:4]([F:9])=[C:3]([C:2]([Cl:1])=[CH:7][N:6]=1)[C:11]#[N:12]
Reactant: Nc1ncc(Cl)c(I)c1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1c(Cl)cnc(N)c1F
Temperature: 175 °C
Yield: 69 %

Procedure:
To a 200 mL round bottom flask was added 5-chloro-3-fluoro-4-iodopyridin-2-amine (9.7 g, 5.5 mmol, 1.0 equiv), zinc cyanide (4.6 g, 6.1 mmol), tetrakis(triphenylphosphine)palladium(0) (4.1 g, 0.56 mmol), and DMF (80 mL). The reaction mixture was heated to 175° C. for 40 minutes. The reaction was then poured into a mixture of EtOAc (300 mL) and brine (150 mL). The organic layer was separated, washed with brine (150 mL), dried over Na2SO4, and concentrated. The residue was dissolved in CH2Cl2 and purified by silica gel chromatography (5-30% EtOAc/hexanes) to yield 4.1 g of the title compound (69%) as an off-white solid.
Reaction SMILES: [CH2:1]([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[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][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[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cncc(Br)c2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10]([O:12]CC)=O.[CH3:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)[N:28]=1>>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][CH:26]=3)[CH:30]=2)[C:10](=[O:12])[CH:9]([CH3:15])[CH2:8]1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: Cc1nc(-c2cccc(CN3C(=O)C(C)CC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 439.03 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2]
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Reaction time: 0.25 h

Procedure:
To 2 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 20 ml. dry ethanol, is added with ice cooling under nitrogen with exclusion of moisture and stirring, portionwise over 15 minutes, 206 mg. NaBH4. The mixture is stirred 15 minutes more and 0.325 ml. glacial acetic acid is added dropwise thereto. The mixture is poured into 50 ml. of water. Solvent is removed by distillation and the residue is extracted three times with 15 ml. amounts of diethyl ether. The organic phase is washed with water and dried over Na2SO4. Solvent is removed to obtain as residue 9β,15-dihydroxy-12-prostenoic acid ethyl ester which, after chromatographic purification twice (first silica gel/dichloromethane:acetone = 10:1; then silica gel/petroleum ether:ethanol = 9:1), can be separated into the two 15-epimers:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([N:9]2[CH2:15][CH2:14][C:13]3[C:16](O)=[N:17][CH:18]=[N:19][C:12]=3[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)Cl.CCO[C:31]([CH3:33])=O>CC#N>[C:3]([C:31]1[CH:33]=[CH:13][C:12]([NH:19][C:16]2[C:13]3[CH2:14][CH2:15][N:9]([C:4]4[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][CH2:11][C:12]=3[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:8])[CH3:2]
Reactant: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 90 °C
Yield: 33 %

Procedure:
To a solution of 7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (185 mg, 0.60 mmol) in CH3CN (2 mL) was added POCl3 (0.11 mL, 1.19 mmol). The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and quenched slowly with saturated (satd.) aq. NaHCO3. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg, 33%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]([Cl:27])([Cl:26])[Cl:28])=[O:22])=[C:16]([CH3:18])[CH2:20][S:17][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (500 mg.), chloroform (10 cc) and pyridine (170 mg.) was heated under reflux for 10 hours. After cooling, the reaction mixture was washed with water, dilute phosphoric acid and water in order, dried and then concentrated. The residue was subjected to chromatography on silica gel and eluated to yield an oil. The oil was crystallized from a mixture of acetone and petroleum ether to yield 2,2,2-trichloroethyl 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 111°-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([CH:17]1[CH2:19][CH2:18]1)[OH:16].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:23](=[O:24])[O:16][C:15]([CH:17]4[CH2:19][CH2:18]4)([CH:20]4[CH2:21][CH2:22]4)[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(O)(C1CC1)C1CC1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C(C2CC2)(C2CC2)O1

Procedure:
The title compound was prepared according to Example 41 from (4-amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol and 1,1′-carbonyldiimidazole. Yellow solid: mp 198-200° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.72 (bs, 1H), 7.67 (bs, 1H), 7.62 (m, 2H), 7.48 (t, 1H, J=7.88 Hz), 7.40 (d, 1H, J=8.04 Hz), 6.94 (d, 1H, J=8.27 Hz), 1.55 (m, 2H), 0.5 (m, 6H), 0.28 (m, 2H); MS (EI) m/z 339 (M+, 40%); Anal. Calc. For C20H18ClNO2: C, 70.69; H, 5.34 N, 4.12. Found: C, 69.38; H, 5.07; N, 4.02.
Reaction SMILES: [CH:1]1([N:10]2[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH3:36])[C:31](O)=[O:32])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[CH:1]1([N:10]2[CH:14]=[C:13]([NH:15][C:31](=[O:32])[C@@H:30]([NH:29][C:27](=[O:28])[CH2:26][C:21]3[CH:22]=[C:23]([F:25])[CH:24]=[C:19]([F:18])[CH:20]=3)[CH2:34][CH2:35][CH3:36])[N:12]=[CH:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cn(C2CCc3ccccc32)cn1
Reactant: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCc3ccccc32)cn1

Procedure:
1-(2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-imidazole was reduced and coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 453 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>CN(C)C=O.O>[CH2:16]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:17]
Reactant: Nc1cccc(S)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 3-aminobenzenethiol (5.0 g, 39.9 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.62 g, 47.9 mmol) and iodoethane (3.19 mL, 39.9 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-30% ethyl acetate/hexanes) to afford 3-(ethylthio)aniline (5.12 g, 84% yield). MS (m/z) 154.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].ClCI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:18][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Agent: ClCI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a solution of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (480 mg, 2.0 mmol) and K2CO3 (1.38 g, 10.0 mmol) in DMF (50 mL) stirring at 100° C., chloroiodomethane (386 mg, 2.2 mmol) in DMF (10 mL) was added dropwise. After addition, the mixture was allowed to stir for another 0.5 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL*3). The organic layer was washed with brine (100 mL*3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide the product 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (260 mg, yield: 50.7%). 1H-NMR (CDCl3, 400 MHz) δ 7.63 (d, J=8.0 Hz, 1H), 7.22˜7.27 (m, 3H), 7.19 (d, J=2.4 Hz, 1H), 7.08˜7.12 (m, 2H), 5.86 (s, 2H). MS (M+H)+: 257/259.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline (5 g, 0.024 mole) was added to chlorosulfonic acid (50 ml, Aldrich) and stirred for 12 hours at room temperature. The reaction mixture was poured over ice (750 g). and the dark brown solid collected by filtration. The solid was washed with water, suspended in water (500 ml), and the pH of the suspension adjusted to 5.00 by addition of sodium bicarbonate. The suspension was filtered, the product washed with H2O and dried under high vacuum at room temperature to give 1,2,5,6-tetrahydro-3-methyloxobenzo[f]quinazolin-9-sulfonyl chloride as a light brown solid (3.054 g, 41%). 1H NMR (DMSO-d6, 300 MHz) δ: 2.60 (s, 3H, CH3); 2.90 (s, 4H, Ar CH2); 7.22 (d, J=9 Hz, 1H, Ar); 7.53 (d, J=9 Hz, 1H, Ar); 8.75 (s, 1H, Ar).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(CC)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cs1
Yield: 84 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (650 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (524 mg, yield 81%). melting point: 168-169° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:41][O:42][CH3:43])[C:4]([CH3:40])=[C:5]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[C:7]=1[C:8]([O:10]COC(=O)C(C)(C)C)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:41][O:42][CH3:43])[C:4]([CH3:40])=[C:5]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])=[O:30])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:26])[F:27])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2ccccc2C(F)(F)F)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)C(c2ccccc2C(F)(F)F)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 83 %

Procedure:
In 10 ml of isopropyl ether saturated with water was dissolved 613 mg of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinedicarboxylate obtained in Example 8, and 50 mg of Lipase B was added thereto, followed by stirring at room temperature for 7 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC (acetate/hexane=1/1), and the spot of the desired product was extracted with ethyl acetate. The extract with concentrated under reduced pressure to obtain 414 mg (yield: 84%) of (+)-1,4-dihydro-2,6-dimethyl -1-methoxymethyl-4-(trifluoromethylphenyl)-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[CH2:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>C1COCC1>[CH3:2][C:3]([CH3:4])=[CH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8]2
Reactant: [Li]CCCC
Reactant: O=Cc1ccc2c(c1)CCC2
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
In a flamed dried flask under argon isopropyltriphenylphosphonium iodide (6.48 g, 15 mmol) in 30 mL of dry THF was cooled to 0° C. Then n-BuLi (2.5 M) in hexanes (6.0 mL) was added via syringe. The reaction mixture was stirred 0° C. for 45 min. Then a solution of the 2,3-dihydro-1H-indene-5-carboxaldehyde (J. Med. Chem. 1993, 36, 3700–3706) was added (1.7, 12.0 mmol) in THF (20 mL) was added drop-wise and the reaction was stirred under Argon at RT overnight. The reaction was filtered, the filtrate was concentrated in vacuo and the residue purified by flash colum chromatography (ethyl acetate/hexane, 1:99) to yield the above titled compound as a pale yellow oil (1.7 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Product: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 3-Bromo-phenylamine to produce N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 13A, 13B and 13C to provide the title product.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:12](=N)([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16]>CCO>[C:1]([NH:9][N:10]=[C:12]([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=N)OCC
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCC(=NNC(=O)c1ccccc1)OCC
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A solution of 2.2 g (15.9 mmol) of benzoic hydrazide in 50 ml of dry EtOH was stirred under N2 at -10° C. as a solution of 2.5 g (15.1 mmol) of ethyl valerimidate hydrochloride [prepared by method of A. H. Hill and I. Rabinowitz, J. Am. Chem. Soc. 48, 734 (1926)] in 50 ml of dry EtOH was added dropwise over about 15 minutes. Stirring was continued at -10° C. for 3 hours, during which time a white precipitate separated. The cold mixture was filtered through Celite, and the filtrate was co-evaporated with CHCl3 at 10° C. The residue was chromatographed twice on silica gel columns (gradient elution with 0.3-5% MeOH in CH2Cl2) to give 951 mg (25%) of the title compound as a cream-colored semi-solid, suitable for use without further purification (TLC in 97:3 CH2Cl2 -MeOH). 1H NMR (CDCl3, 400 MHz) was complex, suggesting that the product is a mixture of syn- and anti-isomers.