Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[CH3:17])#[N:2].[CH3:18][Li].[BH4-].[Na+].Cl>C1COCC1.CCOCC>[NH2:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:10][CH2:11][S:12][CH2:13][CH2:14]2)=[CH:5][C:4]=1[CH3:17])[CH3:18]
Reactant: Cc1cc(C2(C#N)CCSCC2)ccc1C#N
Reactant: [Li]C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
4-(4-Cyano-3-methylphenyl)tetrahydro-2H-thiopyran-4-carbonitrile (983 mg, 4.06 mmol) is stirred in THF (40.0 mL) at −78° C. under nitrogen as a 1.6 M solution of methyllithium in Et2O is added slowly via syringe to the vessel. The contents are stirred for 3 hours at −20° C. before being quenched with MeOH (40.0 mL) and warmed to room temperature. NaBH4 (460 mg, 12.2 mmol) is slowly added at 0° C. in an ice bath and the mixture is warmed to room temperature and stirred for 16 hours. 1.0 N aqueous HCl is added until a pH of 3.0 is reached and the solvent is removed by rotary evaporator. To the residue is added concentrated aqueous HCl (3.0 mL) and the mixture is stirred for 16 hours. The contents are neutralized with 1.0 M aqueous NaOH and EtOAc (40.0 mL) is added. The layers are separated and the organic is dried with Na2SO4 and concentrated to a residue that is purified by silica get column chromatography (10% MeOH in DCM) (253 mg, 1.05 mmol, 26%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=12)=[O:5].[CH2:29]([Mg]Cl)[C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH3:29][C:30]([CH3:33])([CH3:32])[CH2:31][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C:10]=12)=[O:5]
Reactant: CON(C)C(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Compound 26A (0.10 g, 0.26 mmol) was dissolved in THF and cooled to 0° C. and neopentylmagnesium chloride (1M in diethyl ether, 0.35 mL) was added and the mixture was stirred for 2 hours. The mixture was quenched with NH4Cl saturated solution and extracted with EtOAc. The residue was purified by preparative flash chromatography on silica, eluting with 20-80% gradient of ethyl acetate in hexanes to provide intermediate 26B (0.08 g, 77%).
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6]1>[Pd].C(O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:8]2[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:6][N:5]([CH3:4])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Yield: 101.9 %

Procedure:
Hydrazine hydrate (3 ml, 60% solution) is added to a well stirred mixture of 1-methyl-4-(p-nitrophenoxy)-3,5-diphenylpyrazole (2.56 g, 0.0069 mole), 5% Pd on carbon (0.4 g) and absolute ethanol (40 ml). Gas bubbles form immediately and an exotherm (ca. 50°C) is observed. After the reaction subsides, the reaction mixture is refluxed for 2 hours. The reaction mixture is cooled slightly and filtered to remove the catalyst. The filtrate is stripped in vacuo to give a white solid 2.4 g (100%), m.p. 167° to 169°C. Recrystallization from benzene (20 ml) affords a white solid m.p. 167° to 168°C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(O[CH:10]=[C:11]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])C>CC(N(C)C)=O>[C:15]1([S:12]([C:11]([S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:10][NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1nccs1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1nccs1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 44.3 %

Procedure:
A solution of 2-aminothiazole (0.5 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (1.76 g) in dimethylacetamide (20 ml) was heated at reflux for 3.5 hours. The solution was cooled and poured onto ice (200 g) and then the resulting buff precipitate was filtered off, washed with water and dried in vacuo over phosphorous pentoxide. Recrystallisation from ethyl acetate gave 1,1-bis(phenylsulphonyl)-2-(thiazol-2-ylamino)ethene (0.9 g), m.p. 189°-191° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([O:17]C)=[O:16])[CH3:2].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 69.1 %

Procedure:
A mixture of methyl 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.636 g, 2.42 mmol), sodium methoxide (0.393 g, 7.27 mmol), methanol (10 mL) and water (2.5 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.600 mL, 7.27 mmol) was added to adjust the pH to 4. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.415 g, 69%) as an orange solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14].C([O:17][CH:18]=[C:19](C(OCC)=O)[C:20](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[NH:7][CH:20]=[CH:19][C:18]2=[O:17]
Reactant: COCCOc1cc(N)ccc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCCOc1cc2[nH]ccc(=O)c2cc1OC
Temperature: 240 °C
Yield: 7.9 %

Procedure:
A solution of 4-methoxy-3-(2-methoxyethoxy)aniline (5 g, 25.3 mmol) and diethyl ethoxymethylenemalonate (6 ml, 30 mmol) was heated at 110° C. for 30 minutes. Phenyl ether (5 ml) was added and the mixture was heated at 240° C. for 6 hours. The mixture was allowed to cool and diluted with petroleum ether. The resulting solid was collected by filtration and purified by reverse phase chromatography on a Diaion (trade mark of Mitsubishi) HP20SS resin column eluting with acetonitrile/water (40/60) to give 6-methoxy-7-(2-methoxyethoxy)-1,4-dihydroquinolin-4-one (500 mg, 8%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][CH:5]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)Cc1c(Br)[nH]c2cccc([N+](=O)[O-])c12
Reactant: Cc1ccccc1B(O)O
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccccc2C)[nH]c2cccc([N+](=O)[O-])c12

Procedure:
To a deoxygenated solution of ethyl (2-bromo-4-nitro-1H-indol-3-yl)acetate from Step B (250 mg, 0.76 mmol), 2-methylphenylboronic acid (156 mg, 1.15 mmol), and Na2CO3 (202 mg, 1.91 mmol) in EtOH (10 mL), toluene (10 mL) and H2O (0.5 mL) was added tetrakis(triphenylphosphine)palladium (44 mg, 0.038 mmol) and the resulting mixture was heated at reflux for 18 h. The cooled mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=339 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NC1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with cyclopentylamine (1.90 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-cyclopentylamino-cyclopentanecarboxylic acid ethyl ester (1.48 g, 6.57 mmol, 34.2%), as a light yellow oil. LC-MS (ESI) calcd for C13H23NO2 225.17, found 226.2 [M+H+].
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[OH:23])[C:16]([O:18][CH3:19])=[O:17])=O.Cl>C1COCC1>[OH:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[CH:11]=[CH2:1]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (8 mL) in a 0° C. ice bath is added methyl triphenylphonium bromide (1.92 g, 5.38 mmol). The mixture is allowed to warm to rt and stir for 10 min. A solution of methyl 3-formyl-4-hydroxybenzoate (200 mg, 1.11 mmol) in THF (3 mL) is added to the above solution. The mixture is stirred at rt for 5 h. The reaction mixture is acidified to pH=5 with 1N HCl, and extracted with ether (3×). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to a yellow oil. The crude product is purified by chromatography on SiO2. Elution with hexanes-EtOAc (80:20) gives 130 mg (66%) of methyl 4-hydroxy-3-vinylbenzoate as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.12, 7.86, 6.93, 6.85, 5.84, 5.50, 5.46, 3.92.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([OH:29])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:7]=1[N+:30]([O-])=O)([CH3:4])[CH3:3]>[Pd]>[NH2:30][C:7]1[CH:8]=[C:9]([C:12]2([OH:29])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]2[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:10]=[CH:11][C:6]=1[NH:5][C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Yield: 56.7 %

Procedure:
A solution of 3-{4-[(1,1-dimethylethyl)amino]-3-nitrophenyl}-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (1.8 mg, 4.17 mmol) in a mixture of terahydrofuran-ethyl acetate (1:1, 20 mL) was hydrogenated over 10% Pd—C (50 mg) at 40 psi for 18 h. The catalyst removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford 3-{3-amino-4-[(1,1-dimethylethyl)amino]phenyl}-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (950 mg, 57%). MS (EI) for C25H27N3O2: 402 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:53][C:54]1[C:62]([NH2:63])=[CH:61][CH:60]=[CH:59][C:55]=1[C:56]([NH2:58])=[O:57]>CN(C=O)C>[NH2:53][C:54]1[C:55]([C:56](=[O:57])[NH2:58])=[CH:59][CH:60]=[CH:61][C:62]=1[NH:63][C:21]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22]
Reactant: O=C(O)C1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1N
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-1: To a solution of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (560 mg, 1.8 mmol) in anhydrous DMF (7 ml) was added EDC.HCl (1.035 g, 5.4 mmol), HOAt (367 mg, 2.7 mmol) and triethylamine (0.375 ml, 2.7 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (302 mg, 2 mmol) was added and heated to 55° C. over night. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum to yield benzyl 1-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 445.22 [M+H]+
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:39]1[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:48]([O:47][C:45]([C@@H:41]1[CH2:42][CH2:43][CH2:44][N:39]([CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:40]1)=[O:46])[CH3:49]
Reactant: OCCCOCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
A solution of the above alcohol (4.2 g, 14.3 mmol) in dry THF (30 ml) was placed under an atmosphere of nitrogen and placed on an ice-bath. A solution of n-butyllithium in hexanes (5.7 ml, 2.5 M) was added dropwise within 15 minutes and the mixture was stirred for another 15 minutes. p-Toluenesulfonyl chloride (2.7 g, 14.0 mmol) was added in one portion and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo keeping a low bath temperature. The oily residue was dissolved in acetone (25 ml) and ethyl (R)-3-piperidinecarboxylate (3.3 g, 21.0 mmol) and potassium carbonate (3.5 g, 25.0 mmol) were added. The mixture was stirred at room temperature for 120 h. The mixture was filtered and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (100 g) using a mixture of ethyl acetate and n-heptane (2:3) as eluent. Collecting the proper fractions afforded 3.0 g of (R)-N-(3-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)ethoxy)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.19 (SIC2 ; ethyl acetate/n-heptane=1:1).
Reaction SMILES: [F:1][C:2]1([F:18])[CH:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([CH3:10])[NH:8][O:9][CH:5]2[CH2:4][CH2:3]1.CCCCCCC>C(O)C>[F:18][C:2]1([F:1])[C@H:6]2[C@@:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([CH3:10])[NH:8][O:9][C@H:5]2[CH2:4][CH2:3]1
Reactant: CC1(c2ccccc2F)NOC2CCC(F)(F)C21
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@@]1(c2ccccc2F)NO[C@H]2CCC(F)(F)[C@H]21
Yield: 30 %

Procedure:
Intermediates IX-1: The rac-(3S,3aR,6aR)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole was resolved by high-performance liquid chromatography (HPLC) on a chiral phase (Chiralpak AD) using a 90:10-mixture of n-heptane and ethanol as the eluent to give the (3R,3aS,6aS)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole (intermediate IXb-1) as the faster eluting enantiomer (30% yield) and the desired (3S,3aR,6aR)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole (intermediate IXa-1) as the slower eluting enantiomer (27% yield) both as light yellow oils.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([N:20]1[C:24]2[N:25]=[CH:26][C:27]3[N:28]([C:29]([C@@H:32]4[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]4)=[N:30][N:31]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O=O>C(Cl)Cl.CC#N.O.C(O[Cu]OC(=O)C)(=O)C>[S:10]([N:20]1[C:24]2[N:25]=[CH:26][C:27]3[N:28]([C:29]([C@@H:32]4[CH2:36][CH2:35][C@@H:34]([NH:37][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:33]4)=[N:30][N:31]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](N)C4)n23)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](Nc5ccccc5)C4)n23)cc1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A 100 mL round bottom flask was sequentially charged with phenylboronic acid (0.123 g, 1.01 mmol), diacetoxycopper monohydrate (0.010 g, 0.05 mmol), powdered 4 {acute over (Å)} molecular sieves (0.375 g) and DCM (4 mL). The reaction mixture was stirred for about 10 min then a suspension of (1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.20 g, 0.50 mmol) in DCM (2 mL) and MeCN (2 mL) was added. The flask was fitted with an oxygen balloon. The flask was purged with oxygen and then heated at about 40° C. for about 18 h. Additional diacetoxycopper monohydrate (0.010 g, 0.05 mmol) was added and the reaction mixture was heated at about 45° C. under an atomosphere of oxygen for about 3 days. DCM (50 mL) was added and the reaction mixture was filtered through a pad of Celite® while washing with DCM (20 mL). The filtrate was concd under reduced pressure and the residue was purified using silica gel chromatography (20 g) eluting with a gradient of 30-80% EtOAc in DCM to give N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (0.106 g, 45%): LC/MS (Table 1, Method b) Rt=2.39 min; MS m/z: 473 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[OH:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10]>O.O1CCOCC1>[NH2:4][OH:1].[OH:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9]([NH:4][OH:1])=[O:10]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)NO)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.5 %

Procedure:
An hydroxylamine solution was prepared by addition of aqueous sodium hydroxide (393 mg, 9.82 mmol)/water (1.6 ml) to a stirred solution of hydroxylamine hydrochloride (292 mg, 4.21 mmol) in water (3.5 ml). Immediately slowly added a solution of methyl 2-hydroxy-4-methoxybenzoate (511 mg, 2.81 mmol) in 1,4-dioxane (1.5 ml). The resulting reaction mixture was stirred at room temperature for 18 hours, under an argon atmosphere. The reaction mixture was concentrated on a rotary evaporator to half the original volume, and the product precipitated by addition of concentrated hydrochloric acid, keeping flask cool in an ice bath. Filtered the suspension to give 2-hydroxy-4-methoxybenzohydroxamic acid (476 mg, 92%) as a pale brown solid.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
To a solution of (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol)) in 1,4-dioxane (7.0 mL) were added 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic amount) and K2CO3 (0.28 g, 2.0 mmol). The reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 20° C. then diluted with CHCl3. The solution was filtered to remove excess K2CO3 and the filtrate was concentrated in vacuo and chromatographed (silica gel, CHCl3:MeOH 98:2) to give the title compound (0.22 g, 58%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.75-2.20 (m, 7H), 2.20-2.35 (m, 1H), 2.35-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.60-2.78 (m, 3H), 2.78-2.90 (m, 1H), 2.99 (t, J=7.2 Hz, 2H), 3.05-3.15 (m, 1H), 3.18-3.32 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.90-8.08 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:12]C(=O)OCC)=S)=[N:7][CH:8]=1.[Cl-].O[NH3+].C([N:24](CC)C(C)C)(C)C.C(O)C>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:24]=[C:10]([NH2:12])[N:9]=2)[CH:8]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc2nc(N)nn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of ethyl [(5-methoxypyridin-2-yl)carbamothioyl]carbamate (1.34 g, 5.25 mmol), hydroxylammonium chloride (2.55 g, 36.7 mmol), N,N-diisopropylethylamine (4.57 mL, 26.2 mmol), ethanol (15 mL) and methanol (15 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration, and washed with ethyl acetate-hexane to give the title compound (790 mg, 92%) as a yellow oil.