Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C>[Br:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:4]
Reactant: O=C(O)C(Br)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C(Br)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10.1 g (44.1 mmol) of 2-bromo-3-phenylpropionic acid in tert-butyl acetate (150 ml) was cooled in an ice/water bath. 0.5 ml of perchloric acid was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution (200 ml) and the organic phase was separated off. The aqueous phase was extracted twice with 60 ml of ethyl acetate each time, the combined organic phases were washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 20% acetic acid in cyclohexane). Yield: 6.76 g (54%) of colorless oil
Reaction SMILES: Cl[C:2]1[C:3]([O:19][CH2:20][CH2:21][CH2:22]CN(CCC)CCC)=[C:4](/[CH:8]=[CH:9]/[C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=[C:35](/[CH:52]=[CH:53]/[C:54]2O[C:56]3[CH:62]=[CH:61]C=C[C:57]=3[N:58]=2)C=C(OC)C=1OCCCN(CCC)CCC.CC1C=C(/C=C/C2OC3C=CC=CC=3N=2)C=C(C)C=1OCCCN(CCC)CCC>>[CH2:54]([N:58]([CH2:57][CH2:56][CH2:62][CH3:61])[CH2:22][CH2:21][CH2:20][O:19][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:8]=[CH:9]/[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:53][CH2:52][CH3:35]
Reactant: CCCN(CCC)CCCCOc1c(Cl)cccc1/C=C/c1nc2ccccc2o1
Reactant: CCCN(CCC)CCCOc1c(OC)cc(/C=C/c2nc3ccccc3o2)cc1OC
Agent: CCCN(CCC)CCCOc1c(C)cc(/C=C/c2nc3ccccc3o2)cc1C
Product: CCCCN(CCCC)CCCOc1ccccc1/C=C/c1nc2ccccc2o1

Procedure:
A compound of claim 1 selected from the group consisting of (E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole, (E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole and (E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole and acid addition salts thereof.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[O:1]=[C:2]1[CH:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4][N:3]1[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(NC1CCNC1=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1CCC(NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.92 h

Procedure:
To a stirred solution of benzyl N-(2-oxopyrrolidin-3-yl)carbamate (which may be prepared as described in Description 39) (0.5 g, 2.13 mmol) in dry DMF (6 mL) was added in 3 equal portions a 60% dispersion of NaH in oil (90 mg, 2.25 mmol) over 5 minutes under N2. After stirring for 55 minutes, 2-(chloromethoxy)ethyl-trimethyl-silane (0.42 mL, 2.35 mmol) was added dropwise over 12 minutes. The solution was stirred under N2 at ambient temp for 19 hours. The reaction was quenched by addition of saturated aqueous NH4Cl solution (2 mL). The mixture was evaporated and re-evaporated from toluene (3×100 mL). The residue was partitioned between DCM (30 mL) and water (30 mL). The organic phase was dried (MgSO4) and evaporated to an oily solid. The material was purified by silica column chromatography: it was dissolved in toluene (6 mL) and the solution was applied to a 50 g cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane (30-100%). Relevant fractions were pooled and evaporated to give benzyl N-[2-oxo-1-(2-trimethylsilylethoxymethyl)pyrrolidin-3-yl]carbamate (D40) as a colourless oil, dried under vacuum for 2 hours at room temperature to afford 170 mg;
Reaction SMILES: C[Mg]I.[CH3:4]I.[Mg].[CH3:7][Si:8]([CH3:36])([CH3:35])[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH:25]([CH:26]=[CH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][C:18]21[O:22][CH2:21][CH2:20][O:19]2.[Cl-].[NH4+]>C(OCC)C>[OH:34][C:28]([CH3:4])([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]1[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][Si:8]([CH3:7])([CH3:35])[CH3:36]
Reactant: CI
Reactant: CCCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A solution (2.86 ml.) of methyl magnesium iodide in diethyl ether [prepared, in the manner well known in the art, from methyl iodide (6 g.), magnesium (1.07 g.) and diethyl ether (20 ml.)] was added dropwise to a stirred solution of 6-(7-trimethylsilyloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (2.1 g.) in diethyl ether (80 ml.) at room temperature. The mixture was stirred for 30 minutes and a further quantity (1.09 ml.) of the solution of methyl magnesium iodide in diethyl ether was then added dropwise. The mixture was stirred for a further 30 minutes and then added to saturated aqueous ammonium chloride solution (250 ml.) at 0° C. and stirred for 15 minutes. The ether layer was separated and the aqueous layer extracted with diethyl ether. The combined ether layers were concentrated in vacuo to give crude 7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsilyloxyheptyl)-1,4-dioxaspiro[4,4]nonane (1.9 g.), ν max 845 cm-1, 1250 cm-1, 3400 cm-1, pure enough to use in the next stage.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([CH2:12][C:13](O)=[O:14])=[C:4]2[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[CH3:22][N:24]([CH3:25])[C:13](=[O:14])[CH2:12][C:11]1[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9][N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)n2nc(-c3ccccc3)c(CC(=O)O)c2n1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(-c3ccccc3)c(CC(=O)N(C)C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A suspension of 3.0 g (0.011 mole) of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 1.73 g (0.011 mole) of 1,1'-carbonyldiimidazole in 120 ml of anhydrous tetrahydrofuran was stirred for 4 hours at room temperature while a stream of nitrogen was bubbled through the mixture. The solution was treated with a solution of dimethylamine in tetrahydrofuran (11.2 ml; 0.033 mole; 2.95M) and the mixture was stirred at room temperature for 17 hours under nitrogen. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, extracted with aqueous 7% sodium bicarbonate, and with water, dried over magnesium sulfate and evaporated under reduced pressure (4.5 g). The residue was recrystallized from isopropanol to give 2.1 g (62%) of product, mp 171°-172° C.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:6][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CCNC(C(=O)N2CCCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCNC(CN2CCCC2)C1
Yield: 71.7 %

Procedure:
By reducing 5.4 g (0.027 moles) of 2-(pyrrolidin-1-yl) carbonyl-4,4-dimethyl piperidine with 1.1 g (0.027 moles) of LiAlH4 in 100 ml of dry THF, using an alkaline work-up, 3.8 g of the title compound were obtained.
Reaction SMILES: [CH:1]1([CH2:4][C@:5]2([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)[CH3:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O.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>[CH:1]1([CH2:4][C@:5]2([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17]([C:35]4[CH:36]=[CH:37][C:38]([C:41]5([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]5)=[N:39][CH:40]=4)=[CH:16][CH:15]=3)[CH3:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Reactant: NC(=O)C1(c2ccc(Br)cn2)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: CCO
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nc2)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 100 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (3.3 mg) was added to a solution of (S)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (150 mg), 1-(5-bromopyridin-2-yl)cyclopropanecarboxamide (94 mg), and Na2CO3 (348 mg, 3.28 mmol) in ethanol (8 mL), toluene (12 mL), and H2O (4 mL) at room temperature. The reaction mixture was heated to 100° C. for 2 h. After cooling to room temperature, the formed mixture was concentrated to afford an oil which was diluted with H2O (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was concentrated to afford an oil which was purified by preparative TLC and preparative HPLC to give the title compound. Yield: 30 mg (19% of theory); LC (method 4): tR=0.95 min, Mass spectrum (ESI+): m/z=492 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 0.01 (d, 2H), 0.40-0.50 (m, 2H), 0.69 (m, 1H), 1.27 (m, 2H), 1.33 (s, 3H), 1.39 (s, 3H), 1.61 (d, 3H), 1.78 (m, 1H), 1.82 (m, 2H), 1.89-2.05 (m, 4H), 2.21 (m, 1H), 2.80 (m, 1H), 3.19 (m, 1H), 5.51 (1H), 5.85 (m, 1H), 7.29 (m, 1H), 7.48 (d, 2H), 7.58 (d, 2H), 7.82 (1H), 7.89 (d, 1H), 8.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.N1C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9]1)[CH3:25]
Reactant: Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1

Procedure:
2.2 g of 3-(2-aminophenyl)-1-(trifluoroacetyl)-piperidine in 100 ml of methylene chloride, 3 ml of pyridine and 1 ml of ethyl chloroformate were stirred for one hour, washed with 2N hydrochloric acid and then with water, dried, taken to dryness under reduced pressure to obtain 2.8 g of an oil which was used as is for the following step.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (63.6 mmol) of trans-4-aminomethylcyclohexane-1-carboxylic acid, 25.1 g (132 mmol) of 4-toluenesulfonic acid, 50 mL (482 mmol) of benzyl alcohol, and 75 mL of toluene was heated to reflux under a N2 atmosphere using a Dean-Stark trap to collect water formed during the reaction. During reflux, all solids dissolved to leave a colorless solution. After 3 hours at reflux, the solution began to turn yellow. Heat was removed, and the flask allowed to cool to room temperature. The solids which separated out were collected and washed with diethyl ether. There was obtained 24.5 g (58.4 mmol, 92% yield) of product as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[C:18](=O)(O)[O-].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc(O)c(I)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(I)c1

Procedure:
A solution of 3-iodo-4-hydroxybenzoic acid (28.76 g, 0.11 mol) and sulphuric acid (6.6 ml) in methanol (160 ml) is refluxed for 6 h. 300 ml of water are added and the mixture is basified with sodium bicarbonate until neutral. It is extracted with ethyl ether (600 ml). The organic phase is washed with twice 400 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on the column of silica (10% ethyl acetate, 90% CH2Cl2).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:27]1[CH:11]2[CH:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CC(c2ccccc2)CCC1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(C2CCC(c3ccccc3)C3OC23)cc1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
3,6-Diphenylcyclohex-1-ene (50 mg, 0.21 mmol), m-chloroperbenzoic acid (55%, 200 mg, 0.64 mmol), and K2CO3 (150 mg, 1.09 mmol) were stirred in CH2Cl2 (10 mL) for 24 hours. The reaction mixture was filtered and washed with CH2Cl2 (40 mL). The filtrate and aqueous Na2S2O3 solution (10%, 10 mL) were stirred for 2 hours. The organic phase was washed with saturated NaHCO3 solution and H2O and dried over anhydrous magnesium sulfate. Preparative thin-layer chromatography (silica gel, 2 mm, developed with 10:1 hexane/EtOAc) gave 1,2-epoxy-3,6-diphenylcyclohexane (32 mg, 60% yield) as a colorless oil along with recovery of starting material (10 mg, 20%). 1,2-Epoxy-3,6-diphenylcyclohexane: 1H NMR (200 MHz, CDCl3) δ 7.20-7.45 (m, 10 H), 3.45 (s, 2 H), 3.37 (t, J=6.4 Hz, 2 H), 1.67-1.88 (m, 2 H), 1.37-1.58 (m, 2 H); 13C NMR (50 MHz), 143.2, 128.6, 128.0, 126.5, 56.2, 39.9, 25.0.
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][CH:15]([CH3:38])[CH2:16][CH2:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20].Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41]>CN(C)C=O>[CH3:14][CH:15]([CH3:38])[CH2:16][CH2:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:40](=[O:41])[O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20]
Reactant: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Yield: 101.7 %

Procedure:
N,N-dimethylformamide (30 ml), pyridine (0.52 ml, 6.4 mmol) and triethylamine (1.35 ml, 9.69 mmol) were added to N1-(3-methylbutyl)-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (0.81 ml, 6.4 mmol) was added at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (2.0 g) of phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.4 g of the mixture was dissolved in N,N-dimethylformamide (4 ml); 4-tetrahydro-1H-1-pyrrolylpiperidine (0.43 g, 2.8 mmol) was added thereto; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (275 mg, 0.53 mmol).
Reaction SMILES: [CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6]C)=O)[CH3:2].[C:11](#[N:13])[CH3:12].[H-].[Na+]>O1CCCC1>[C:11]([CH2:12][C:4]([C:3]([CH2:1][CH3:2])([CH3:10])[CH2:8][CH3:9])=[O:6])#[N:13]
Reactant: CC#N
Reactant: CCC(C)(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(CC)C(=O)CC#N

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH2:13][CH:14]([CH2:16][NH2:17])[O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:17][CH2:16][CH:14]1[CH2:13][C:12]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1Cc2c(cccc2-c2ccccc2)O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(cccc2-c2ccccc2)O1)OCc1ccccc1
Yield: 70.3 %

Procedure:
Treatment of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.622 g, 2.38 mmol) with diisopropylethylamine (0.447 g, 3.57 mmol) and benzyl chloroformate (0.462 g, 2.62 mmol) generally according to the procedure described for Intermediate 12 provided 0.601 g (70%) of (±)-benzyl(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 132-134° C.; Anal. calcd. for C23H21NO3: C, 76.86H, 5.89; N, 3.90. Found: C, 75.98H, 5.80; N, 3.72. Chiral HPLC separation of (±)-benzyl(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, ethanol:water 15:85) provided two fractions. Fraction 1 (Rt=6.651 min Chiralcel OD, ethanol:water 1:3); Fraction 2 (Rt=7.395 min, Chiralcel OD, ethanol:water 1:3).
Reaction SMILES: C[O:2][CH:3]([O:19]C)[C:4]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][O:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:12][O:11][C:9]([C:8]1[O:7][N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[C:3]([OH:19])=[O:2])=[O:10]
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(OC)OC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)c1onc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(dimethoxymethyl)-3-phenylisoxazole-5-carboxylate, 12-B, (144 mg, 0.519 mmol) in acetone (3 mL) at rt was added Jones' Reagent (0.539 mL, 0.727 mmol) and the resulting mixture was allowed to stir at rt for 1 hr. Three additional aliquots of Jones' Reagent (0.539 mL, 0.727 mmol) were added portion wise over 1 hr and stirring was continued at rt for 2 hr. At this time, the reaction mixture was partitioned between EtOAc (30 mL) and 2% NaHSO3 solution (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford 5-(methoxycarbonyl)-3-phenylisoxazole-4-carboxylic acid (108 mg, 0.437 mmol, 84% yield) as a light yellow solid. HPLC retention time=1.30 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=248.13. 1H NMR (400 MHz, chloroform-d) δ ppm 4.16 (s, 3H), 7.50 (m, 3H), 7.66 (dd, J=8.2, 1.4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[NH:19]C(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[NH2:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cccc2ccc(OCc3ccccc3)cc12
Reaction time: 0.25 h

Procedure:
A solution of 7-benzyloxy-1-(tert-butoxycarbonylamino) naphthalene, as described above in Step I, (100 mg, 0.29 mmol) in EtOAc (10 mL) at 0° C. was saturated with HCl (g). After 15 min, the mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous Na2CO3 (5 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield the desired amine as a pale solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:27])=[N:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:34](OC(=O)C)(=O)[CH3:35].C(O)(=O)C.O>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[N:27]=[C:34]([CH3:35])[O:26][N:25]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=NO)cc12
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(C)n3)cc12
Yield: 45.4 %

Procedure:
A solution of tert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.46 g, 1 mmol), acetic anhydride (0.14 ml, 1.5 mmol) and a catalytic amount of acetic acid in tetrahydrofuran (10 ml) was refluxed under heating for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give tert-butyl[4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 45.8%) as crystals.