Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:13][OH:14].[OH-:15].[Na+]>CCO>[OH:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:15][CH2:2][O:3][C:4]=2[CH:9]=1)=[NH:11]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)OCO2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2c(c1)OCO2

Procedure:
To a solution of Benzo[1,3]dioxole-5-carbonitrile (5.0 g, 33.9 mmol) in EtOH (100 mL) was added hydroxylamine hydrochloride (4.68 g, 67.90 mmol) and NaOH (2.71 g, 67.9 mmol). The resulting reaction mixture was refluxed for 12 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 4.8 g, 78.68%).
Reaction SMILES: COC(=O)[CH2:4][CH:5]([N:7]([CH2:9][CH2:10][C:11]([O:13]C)=O)[CH3:8])[CH3:6].CCN(CC)CC.O>C(Cl)Cl.[Cl-].[Na+].O.Cl[Ti](Cl)(Cl)Cl>[CH3:8][N:7]1[CH2:9][CH2:10][C:11](=[O:13])[CH2:6][CH:5]1[CH3:4]
Reactant: COC(=O)CCN(C)C(C)CC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CC(=O)CCN1C
Temperature: -15 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A 1 M solution of TiCl4 in CH2Cl2 (23 mL, 23 mmol, 1.0 equiv) was added to a flask under Ar and cooled to −15° C. with a MeOH/ice water bath. 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric acid methyl ester (5 g, 23 mmol, 1.0 equiv) was added dropwise over a 25 min period as a solution in 75 mL of dry CH2Cl2 to give a dark red mixture that was difficult to stir with a magnetic stir bar. Stirring was continued an additional 1 h and then Et3N (5.1 g, 50.6 mmol, 2.2 equiv) was added dropwise over a 30 min period and then the reaction was stirred an additional 1.5 h at −15° C. The reaction mix was poured into 150 mL of brine and 150 mL of CH2Cl2 was added. After thorough mixing, the pH of the water was brought to 8-9 with Et3N. The mix was filtered and the gel-like solid was washed 3×100 mL CH2Cl2. The filtrate layers were separated and the aqueous layer was washed 3×50 mL CH2Cl2. All of the organic layers were combined and concentrated to a thick red oil. The residue was taken up in 150 mL of concentrated HCl and the solution was refluxed 4 h. The cooled reaction solution was evaporated to dryness and the residue was dissolved in 200 mL of saturated sodium bicarbonate solution. The product ketone was extracted with 2×100 mL of EtOAc. The organic layers were combined and dried over Na2SO4. The product was purified by flash chromatography on SiO2 using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluent. The product was isolated as an orange oil (1.23 g, 42%); MS, m/z 128=M+1.
Reaction SMILES: [C:1]([CH2:4][C:5]([OH:15])([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7])([OH:3])=[O:2].[CH:16](O)=O.C(OCC)(=O)C.O>CO>[CH3:16][O:2][C:1]([CH2:4][C:5]1([C:6]([OH:8])=[O:7])[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[O:15]1)=[O:3]
Reactant: CC(C)=CCCC(O)(CC(=O)O)C(=O)O
Reactant: O=CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)CC1(C(=O)O)CCCC(C)(C)O1
Temperature: 25 °C

Procedure:
The solution obtained from the previous stage and containing 5 kg of 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid 100% is charged into an enameled reactor. This residue is then cooled to 20-30° C. and 15 kg of formic acid 99% are added. The mixture is then heated to 70-75° C. and kept under stirring at that temperature for at least 4 hours. It is then cooled to 50-60° C. and the water is removed by vacuum distillation until an oily residue is obtained. The oily residue is cooled to 30-35° C. and 15 kg of ethyl acetate and 5 kg of demineralised water are added. The mixture obtained is stirred always at 30-35° C. and left under rest until the phases separate, eliminating the aqueous phase, while the solvent is removed from the organic phase by vacuum distillation until an oily residue is obtained. This residue is then cooled and 10.0 kg of methanol are added.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.O.C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1sc(N)c(C(=O)O)c1C

Procedure:
A mixture of 15 parts of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate and 75 parts by volume of 2N solution of sodium hydroxide in 50 % aqueous ethanol is refluxed for 2.5 hours. After cooling the solution is diluted with 75 parts by volume of water and neutralized with acetic acid under cooling with ice. The resulting precipitate is collected by filtration to give 2-amino-4,5-dimethylthiophene-3-carboxylic acid as crystals. Recrystallization from chloroform with charcoal gives colorless needles melting at 136°-138°C (decomposition).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:58]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:58][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5CC6CCC(C5)O6)c5cnn(C)c5n4)cc3)cc2)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(4-methylpiperazino)aniline as the aniline component. (13%, MS=554.3 (M+H))
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([Cl:35])=[CH:14][CH:15]=2)[N:10]=1)=O)(C)(C)C.F[C:37](F)(F)C(O)=O.C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:6]([NH:8][C:9]1[CH:18]=[C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])[CH2:23][CH2:24]2)[C:16]2[C:11](=[CH:12][C:13]([Cl:35])=[CH:14][CH:15]=2)[N:10]=1)(=[O:5])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reaction time: 3 h

Procedure:
2-tert-Butoxycarbonylamino-7-chloro-4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]quinoline (110 mg, 0.22 mmol) in CH2Cl2 (1 mL) is treated with trifluoroacetic acid (1 mL) for 2 h at room temp. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (9 mL). Triethylamine (154 μL, 1.1 mmol), acetyl chloride (26 μL, 0.24 mmol), and DMAP (10 mg) are added. The reaction mixture is stirred at room temp. for 3 h, washed with water, dried (MgSO4), and concentrated. Purification of the residue by column chromatography with CH2Cl2-MeOH affords the title product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](=[O:18])(=O)(O)[OH:15]>C1(S(O)(=O)=O)C=CC=CC=1.ClC1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([S:14]([C:11]3[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)(=[O:18])=[O:15])[CH:10]=[CH:9][C:8]=2[OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(O)c(-c2ccccc2)c1)c1ccc(O)c(-c2ccccc2)c1
Reaction time: 10 h
Yield: 85 %

Procedure:
To a mixture of 391 g (2.3 mol) of o-phenylphenol, 100 g (1 mol) of 98% by weight sulfuric acid, and 100 g of chlorobenzene was added 9.5 g (0.05 mol) of benzenesulfonic acid and heated with stirring. While the generated water was distilled away with chlorobenzene and the organic phase of the distillate was refluxed into the reaction vessel, the reaction was carried out for 10 hours. At the time when the distilled water amounted to 36 milliliters and the temperature in the reaction vessel rose to 165° C., the reaction mixture was cooled by adding 500 milliliters of xylene to precipitate crystals. The crystals were recrystallized from acetone-cyclohexane mixture solution to obtain 340 g of a product (yield: 85%). The melting point of the product was between 251° to 252° C. and the results of 1H-NMR (acetone d6) were as follows.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClC(Cl)C>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3

Procedure:
A 5.80 gm (0.0211 mole) quantity of the compound of Example 15 was dissolved in 100 ml of dichloroethane, and 380 mg (0.003 mole) of dimethylaminopyridine and 3.1 gm (0.03 mole) of triethylamine were added, followed by 2.38 gm (0.030 mole) of acetyl chloride. This mixture was refluxed overnight and evaporated. The resulting mixture was partioned between dilute aqueous NaHCO3 and CH2Cl2. The organic layer was dried and evaporated. The residue was triturated with ether and the resulting solid was collected to give 4.40 g of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1, 2,4-triazolo[3,4-a]phthalazin-3yl)acetamide; mp 147-149° C. (toluene-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]2[C:16]([F:27])=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]3[C:16]([F:27])=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)([OH:14])[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:29])[CH:3]=2)=[CH:32][C:31]=1[F:30])=[O:38]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cc2c(cc1F)OCC(=O)N2C)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cc4c(cc3F)OCC(=O)N4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=570.3 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=[O:15].[OH2:18].C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:18])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 85.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 13.1 g (0.24 mol) of methanesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at 40° C. without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. And then after the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 85.9%) was obtained.
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].CO[CH:16](OC)[CH2:17][C:18](=O)[CH3:19].Cl>C(O)C>[CH3:19][C:18]1[CH:17]=[CH:16][N:1]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[N:2]=1
Reactant: COC(CC(C)=O)OC
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1ccn(-c2nc3ccccc3c(=O)[nH]2)n1

Procedure:
35.2 g (0.2 mole) of 2-hydrazino-4(3H)-quinazolinone, 500 ml of ethanol and 31.68 g (0.24 mole) of 4,4-dimethoxy-butan-2-one are boiled under reflux for 4.5 hours. The initial suspension has then dissolved. The same volume of 2 N HCl at 50° is added at 50°, whereupon a precipitate soon forms. After warming at 50° for a total of 40 minutes, the 2-(3-methyl-1H-pyrazol-1-yl)-4(3H)-quinazolinone is isolated by filtration with suction. The crude product (35.9 g of melting point 162° to 165° C.) is recrystallized from ethanol and then has a melting point of 165° to 166° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:30])C(=O)C1>>[Br:30][CH2:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2occc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrCc1ccc2occc2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 1.46 g (11.0 mmol) of 5-methylfuro[3,2b]pyridine (from Step 2) and 100 mg AIBN in 35 mL of CC14 was added 2.1 g (11.6 mmol) of NBS. The mixture was stirred at 75° C. under radiation from a 150 W spot light for 1 hr. Another portion of NBS was added (1.0 g) and the reaction was allowed to proceed for another 1.5 hr. The reaction was allowed to cool to r.t., diluted with aqueous NH4OAc 25% w/v (150 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography on silica gel eluted with 20-25 % EtOAc in hexane to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[Cl-].[NH4+]>CCO.O.ClCCl.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[C:4]([CH:3]=1)[NH2:11]
Reactant: COc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1c(N)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
5-Bromo-1-fluoro-2-methoxy-3-nitrobenzene (1.0 g, 4.0 mmol), zinc (2.62 g, 40.0 mmol) and ammonium chloride (2.14 g, 40.0 mmol) in EtOH (20 mL) and water (12 mL) were heated at 80° C. for 10 minutes and then stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (100 mL) and water (60 mL), and filtered through CELITE®. The organic phase was dried over sodium sulfate and filtered and then concentrated to afford Intermediate 25A (723 mg, 82% yield) as a gray solid. HPLC: Rt=1.3 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=222.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[OH:17])[C:12]#[N:13])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[S:25][C:24]=2[CH:32]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([OH:17])=[C:9]([CH:10]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:25][C:24]3[CH:32]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[CH:27]=2)(=[O:30])=[O:29])[C:4]1=[O:18])#[N:13]
Reactant: N#Cc1ccc(O)c(CN2CCC(N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: N#Cc1ccc(O)c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile hydrochloride as described in EXAMPLE 17, Part G substituting 6-chlorobenzo[b]thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulonyl chloride. The crude product is triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1>CC(O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Sodium borohydride(95 mg) was added to a tetrahydrofuran(60 ml)-2-propanol(30 ml) solution of ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(2.93 g) at 0° C. After stirring for 30 minutes, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-hydroxyacetate(2.20 g, 75%). This was recrystallized from acetone-ethyl acetate to give colorless prisms. mp 197-198° C. (degradation)
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:14].[Na+].C(O[CH2:20][CH3:21])(=O)C>CS(C)=O>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([C:12]([N:11]3[C:20]4[C:21](=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:8][CH2:9][CH2:10]3)=[O:14])[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(N1CCC(c2ccccc2)CC1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
4-Nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate obtained in 1) above was dissolved in DMSO (10 ml), and 4-phenylpiperidine hydrochloride (1.58 g, 7.97 mmol) and 4 N aqueous sodium hydroxide (2.09 ml, 8.36 mmol) were added thereto and stirred at room temperature for 22.5 hours. 60 ml ethyl acetate was added to the reaction solution which was then washed with an aqueous potassium carbonate solution and a saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resultant residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1), whereby 2.10 g of the title compound was obtained as pale yellow liquid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[F:17])=[N:6][O:7][C:8]=1[CH3:9])([OH:3])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.CN(C)C=O>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([NH:34][C:32](=[O:33])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:1]([C:4]3[C:5]([C:10]4[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=4[F:17])=[N:6][O:7][C:8]=3[CH3:9])=[O:3])[CH:26]=2)[CH:36]=[C:37]([O:45][CH3:46])[C:38]=1[O:43][CH3:44]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: Cc1onc(-c2ccc(Br)cc2F)c1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4ccc(Br)cc4F)noc3C)c2)cc(OC)c1OC
Yield: 65.9 %

Procedure:
In a fashion similar to that described for preparation 35, 4-carboxy-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (119 mg, 0.40 mmol), oxalyl chloride (0.070 ml, 0.80 mmol), dimethylformamide (0.010 ml), dichloromethane (5 ml), 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (110 mg, 0.35 mmol), triethylamine (0.111 ml, 0.80 mmol), DMAP (5 mg), dimethylformamide (1 ml), dichloromethane (5 ml) gave the title compound (138 mg, 66%) after column chromatography (silica gel, hexanes/ethyl acetate gradient).
Reaction SMILES: O[C@H](C1C=CN=CC=1)[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]>[OH-].[K+].CO.C1COCC1.O>[CH3:4][C@H:3]1[C@@H:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:7][C:6](=[O:15])[NH:5]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1

Procedure:
A solution of benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate in 7.5N aq. KOH/MeOH/THF (1:2:4, 7 mL) was stirred at room temperature overnight. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one. LCMS calc.=179.1; found=179.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:18]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1cccnc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(2-methoxy-3-pyridinyl)alaninate (0.877 g, 3.91 mmol), N-α-t-Boc-glycine (0.753 g, 4.30 mmol, Aldrich, St. Louis, Mo.), HATU (1.784 g, 4.69 mmol, Aldrich, St. Louis, Mo.) and N,N-diisopropylethylamine (2.05 mL, 11.73 mmol, Aldrich, St. Louis, Mo.) in DMF (8 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give ethyl N-(tert-butoxy carbonyl)glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.38 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:37]([O:39][C:40](=[O:43])[CH2:41]Br)[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][O:36][C:31]1[CH:30]=[C:29]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[C:17]([F:27])[C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:34]=[CH:33][C:32]=1[F:35])[CH3:38]
Reactant: CC(c1ccc(-c2ccc(F)c(O)c2)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1cc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 1, step 5, 6-[2-(3-chloro-4′-fluoro-3′-hydroxy-biphenyl-4-yl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless foam. MS (m/e)=614.2 [M+H+].