Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:13]1([CH:11]2[CH2:12][CH:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([NH:21][C:22]5[N:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cnc(Nc2ccc3nc(C4CC(N5CCCCC5)C4)sc3c2)nc1
Temperature: 145 °C
Reaction time: 2 h

Procedure:
The product of Example 44A (trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole) (100 mg, 0.285 mmole), 2-aminopyrimidine (35 mg, 0.368 mmole), tris(dibenzylideneacetone)dipalladium (0) (10.4 mg, 0.011 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 14 mg, 0.022 mmole) and sodium tert-butoxide (38 mg, 0.400 mmole) were charged in a tube and sealed. The tube was placed on high vacuum for 2 hours and refilled with nitrogen. Toluene (2 mL) was added and the reaction vessel was placed in a microwave reactor and heated at 145° C. for 15 minutes. After cooling to room temperature, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane). The product collected was a mixture of cis and trans isomers (98 mg). 1H NMR (400 MHz, CDCl3) δ ppm 8.42-8.49 (m, 3H) 7.89 (d, 2H) 7.37-7.46 (m, 2H) 6.75 (t, J=4.76 Hz, 1H) 3.75-3.86 (m, 0.6H) 3.48-3.62 (m, 0.4H) 3.03-3.17 (m, 0.6H) 2.73-2.84 (m, 0.4H) 2.48-2.72 (m, 4H) 2.21-2.42 (m, 4H) 1.55-1.66 (m, 4H) 1.41-1.51 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[FH:13]>>[CH:11]1([F:13])[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: F
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: *C(F)(F)C(*)(F)F
Product: OC[C@H]1OC(F)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2.5 h
Yield: 94 %

Procedure:
In a distillation flask of polytetrafluoroethylene, a solution of 10 g of glucose in 100 g of hydrogen fluoride, prepared analogously to Example 1, was distilled under reduced pressure at an internal temperature of -30° C. The pressure was regulated between 100 and 130 mbar in such a way that steady distillation took place. After 2.5 hours, the residual HF content in the bottoms from the distillation was then only 5 g. The distillation was terminated, and the residue worked up in accordance with Example 1. 9.5 g of glucosyl fluoride were obtained.
Reaction SMILES: [CH2:1]([C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1)[CH:2]=C.[O:17]=[O+][O-]>ClCCl>[O:17]=[CH:2][CH2:1][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCC2)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-9-(2-propenyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.5 g of pure (±)-cis-9-(2-oxoethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:31])([C:22]([CH3:30])([CH3:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH3:21]>>[CH3:21][C:20]([OH:31])([C:22]([CH3:30])([CH3:29])[CH2:23][C:24]1[S:25][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:27][CH:28]=1)[CH3:19]
Reactant: CC(C)(O)C(C)(C)Cc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CC(C)(C)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2,3,3-trimethyl-4-thiophen-2-yl-butan-2-ol (prepared from 2,2-dimethyl-3-thiophen-2-yl-propionic acid by esterification with diazomethane and treatment with MeMgBr (Step A of Method A)).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O-:5])=[O:4].[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>CS(C)=O>[C:25]([C:21]1[CH:22]=[C:23]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[OH:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 40.5 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 100 mg (0.59 mmol) of 1,3-dinitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for one hour and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography (PTLC) and crystallization afforded 89 mg (40% yield) of 2,6-di-t-butyl-4-(2',4'-dinitrophenyl)phenol.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:35]>CC(C)=O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:35]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and MeOH (30 ml). The mixture was heated to reflux for dissolution and NaOH (0.42) was added in two portions. Precipitant was appeared at reflux temperature and wasn't dissolved after addition of another 45 ml of MeOH during 4 h. The slurry mixture was cooled to room temperature and stirred over night. The precipitant was dissolved, acetone (150 ml) was added and the mixture was stirred at room temperature for 22 h. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried at 50EC in a vacuum oven for 22.5 h to obtain 1.68 g of fluvastatin sodium crystal Form LXIV.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:25]2[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:23][CH:24]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:25]2[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[N:29]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)nc3)cn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1

Procedure:
Methanol (7 mL) was added to ethyl 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylate (343 mg), 1N aqueous sodium hydroxide solution (2.9 mL) was further added to the mixture and the resulting mixture was refluxed for 1 hour. Methanol was distilled off under reduced pressure, and the residue was neutralized by 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylic acid.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15.75 h
Yield: 97.2 %

Procedure:
Ethyl difluoroacetate (3.51 g, 28.3 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.12 g, 28.3 mmol) followed by 2-acetyl-5-chlorothiophene (4.12 g, 25.6 mmol). A pink precipitate formed after 5 minutes which was dissolved by adding ether (10 mL) and THF (10 mL) to the reaction. The reaction was stirred at room temperature overnight (15.75 hours), then treated with 3N HCl (15 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a red solid (5.94 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (2.02 g, mp 72°-77° C., 33%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H) , 7.57 (d, J=4.2 Hz, 1H), 7.01 (d, J=4.2 Hz, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.01 (d); M+ 238.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1.OC1(C2C=C(C)C=CC=2)CC(=O)C=C1C1C=CN=CC=1.CN(C1C=CC=CN=1)C.[C:50]([O:53]C(=O)C)(=[O:52])[CH3:51]>C(Cl)Cl>[C:50]([O:53][C:3]1([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][C:5](=[O:7])[CH:6]=[C:2]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:52])[CH3:51]
Reactant: Cc1cccc(C2=CC(=O)CC2(O)c2ccncc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Solvent: ClCCl
Product: CC(=O)OC1(c2cccc(C)c2)CC(=O)C=C1c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-4-pyridine-4-yl-3-m-tolyl-cyclopent-2-en-1-one, and it's regioisomer 4-hydroxy-3-pyridine-4-y1-4-m-toly1-cyclopent-2-en-1-one prepared as described in Example 8, Step E (265 mg, 1.0 mmole) in methylene chloride (5 mL) was added dimethylamino pyridine (183 mg, 1.5 mmole) and acetic anhydride (0.12 mL, 1.2 mmole) at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with 1 mL of methanol. Concentration and purification (silica, hexane/ethyl acetate) gave the title compound as the slower eluting isomer. MS (m/z): Calcd. C19H17NO3(M+): 307, found (M+H) +: 308.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38]C=CC=1C.C1(CN2C=CC(N)=N2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:38]3[CH2:39][CH2:40]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: Nc1ccn(CC2CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC3CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 410 mg, 1.23 mmol) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (615 μL, 1.23 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (293 μL, 2.46 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. 1-Cyclopropylmethyl-1H-pyrazol-3-ylamine (169 mg, 1.23 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) followed by recrystallization from 10% methylene chloride/diethyl ether afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-propionamide (162 mg, 29%) as a white crystalline solid: ESI-LRMS m/e calcd for C22H28ClN3O3S [M+] 449.15, found 450.19 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.32-0.041 (m, 2H, CH2), 0.63-0.70 (m, 2H, CH2), 1.08-1.31 (m, 3H, CH2), 1.44-1.95 (m, 8H, 4×CH2), 2.13-2.37 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 3.85 (d, J=7.0 Hz, 2H, NCH2), 6.67 (d, Jo=2.2 Hz, 1H, Ar), 7.38 (d, Jo=2.2 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Hz, Jm=1.7 Hz. 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 7.90 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2.[N+:14]([O-])([OH:16])=[O:15].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-methoxy-1-tetralone (2.26 g, 13 mmol) (prepared as described in Chatterjee, A. Tetrahedron, (1980), 36, 2513-2520) in acetic anhydride (11.5 mL) was cooled to 0° C., treated with a mixture of fuming nitric acid (0.90 mL) in acetic acid (0.70 mL) dropwise over 1 hour, stirred at 0° C. for 1.5 hours, treated with water (150 mL) and extracted with diethyl ether (300 mL). The diether ether layer was washed with water (150 mL), washed with sodium bicarbonate solution (3×), washed with brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel using a gradient of 2:1 and then 3:2 and finally 1:1 hexanes:ethyl acetate provided the desired product as the more polar isomer.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:24]3[C:25]([CH3:43])=[C:26]([NH:31][C:32](=O)[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:27]([CH3:30])=[C:28]([CH3:29])[C:23]=3[O:22][C:21]2([CH3:45])[CH3:44])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].[OH-].[Na+]>C1COCC1>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:24]3[C:25]([CH3:43])=[C:26]([NH:31][CH2:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)[C:27]([CH3:30])=[C:28]([CH3:29])[C:23]=3[O:22][C:21]2([CH3:45])[CH3:44])=[CH:18][CH:19]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a suspension of aluminum chloride (1.23 g, 9.25 mmol) in THF (40 mL) was slowly added lithium aluminium hydride (354 mg, 9.31 mmol) with ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added N-(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methoxyphenylacetamide obtained in Reference Example 365 (536 mg, 1.14 mmol), and the mixture was heated under reflux for 3 hours. The reaction mixture was added to ice-water, and the mixture was neutralized with a 8 N aqueous sodium hydroxide solution. Thereafter, the product was twice extracted with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-(4-isopropylphenyl)-N-(2-(4-methoxyphenyl)ethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine. This compound (537.9 mg, 1.18 mmol) was added to a suspension of sodium hydride (a 60% paraffin dispersion, 232.1 mg, 5.80 mmol) in DMF (25 mL) at 60° C., and the mixture was stirred for 20 minutes. Acetyl chloride (0.5 mL, 7.03 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, and a saturated sodium hydrogen carbonate solution was added to the mixture, which was twice extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the rotational isomer of the object compound (Rf=0.38; hexane:ethyl acetate=3:1) (yield 43%). Melting point: 134-136° C. (ethyl acetate-hexane).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19].C1(=O)C2C(=CC=CC=2)C(=O)C=C1/C=C(\C)/C(O)=O>CC(C)=O>[CH3:15][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(C)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Agent: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(C)=O
Product: CC1=C(/C=C(\C)C(=O)O)C(=O)c2ccccc2C1=O

Procedure:
Compound 35a was prepared from 99a (0.083 g, 0.29 mmol) as described above for 30a to give 0.048 g (0.19 mmol, 65%) of the product as a yellow solid following flash chromatography (3:17 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:18]([OH:21])[C:19]#[CH:20].O>O1CCCC1>[C:10]1([C:9]2[CH:20]=[C:19]([CH2:18][OH:21])[O:17][N:16]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCO
Reactant: ON=C(Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75 %

Procedure:
Triethylamine (7.28 ml) was added to a solution of α-chlorobenzaldehyde oxime (4.04 g) and 2-propyn-1-ol (1.66 ml) in tetrahydrofuran (130 ml) and stirred at room temperature for 4 days. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain (3-phenyl-5-isoxazolyl)methanol (3.42 g, yield 75%) as colorless crystals. m.p. 48-49° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[CH3:15][S:16]([N:19]([CH2:34][CH2:35][Cl:36])[N:20]([S:30]([CH3:33])(=[O:32])=[O:31])C(OC1C=CC=CC=1)=O)(=[O:18])=[O:17]>>[CH3:15][S:16]([N:19]([CH2:34][CH2:35][Cl:36])[N:20]([S:30]([CH3:33])(=[O:32])=[O:31])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3])(=[O:17])=[O:18]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (compound 10h) was prepared by reacting compound 2 with 4-nitrobenzyl chloroformate using a procedure similar to that employed for compound 10d. The product was recrystallized from ethanol, and the yield was approximately 22.9% by weight. The Mp was approximately 132-133° C. 1H NMR (acetone-d6): δ 8.3 and 7.8 (4H, 2d, aromatic H), 5.6 (2H, s, ArCH2), 3.6-4.2 (4H, m, CH2CH2Cl), 3.6 and 3.3 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [N:1]([CH:4]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23])=[N+]=[N-]>C(O)(=O)C.[Pd]>[NH2:1][CH:4]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23]
Reactant: [N-]=[N+]=NC1C=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: NC1C=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O
Reaction time: 2 h

Procedure:
To a solution of rac-3-azido-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (5 g, 15.2 mmole) in 300 mL of acetic acid was added 5% Pd/C (250 mg). The mixture was hydrogenated at 1 atm pressure for 2 hours. The crude material was purified on activated alumina and crystallized from ether-isopropyl ether yielding 3.4 g (74%) of solid. Melting point: 188°-191° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].[BH4-].[Na+]>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[F:14]
Reactant: O=Cc1ccc(C2OCCO2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(C2OCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a methanol solution (200 mL) of 4-[1,3]dioxolan-2-yl-3-fluoro-benzaldehyde (10 g, 50.9 mmol) described in Manufacturing Example 204-1-2 was added sodium borohydride (2.12 g, 56 mmol), which was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (2.44 g, 24%).