Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[NH:31][C:25]3=[N:26][CH:27]=[C:28]([F:30])[CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19]CC)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH2:17][CH2:18][OH:19])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[C:22]2[NH:31][C:25]3=[N:26][CH:27]=[C:28]([F:30])[CH:29]=[C:24]3[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(CCO)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-ethyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (210 mg, 0.47 mmol) in dichloromethane (10 mL) at 0° C. was added a solution of boron tribromide (0.22 ml, 2.36 mmol) in dichloromethane (10 ml). The mixture was stirred at 0° C. for 1 h. The reaction was quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (2×50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL) and brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (2-{4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzenesulfonyl}-ethanol (40 mg, 20%) as a white solid: LC/MS m/e calcd for C22H25FN2O3S [M+H]+ 417.52, observed 417.0; 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (t, J=2.3 Hz, 1H), 7.83-7.88 (m, J=8.3 Hz, 2H), 7.56-7.65 (m, 3H), 6.38 (s, 1H), 4.89-4.99 (m, 1H), 4.68-4.84 (m, 1H), 4.59 (br. s., 1H), 4.29 (t, J=8.0 Hz, 1H), 3.82 (t, J=6.2 Hz, 2H), 3.37 (t, J=6.2 Hz, 2H), 2.22-2.30 (m, 1H), 2.05-2.13 (m, 1H), 1.58-1.85 (m, 4H), 1.42-1.54 (m, 2H), 1.13-1.34 (m, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.I[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O1CCCC1.CCOCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1.C([N:19](CC)CC)C>ClCCl>[O:1]=[C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]c1=O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Reaction time: 2 h

Procedure:
A mixture of 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxylic acid (1.92 g) ethyl chloroformate (1.1 g) and triethylamine (2.0 ml) in 50 ml of dichloromethane is allowed to stir at 25°-30° C. for 2 hours. Ammonia gas is then bubbled into the mixture for 15 minutes. Water (50 ml) is added and the dichloromethane is separated and concentrated on the rotary evaporator. The residue is chromatographed on silica gel with 2% methanol and chloroform to give 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxamide.
Reaction SMILES: [C:1]1([C:7]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[CH2:14]3)[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([OH:28])[CH:9]([OH:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>CO.[Zn]>[C:38]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:27])[CH2:17][C:18]4[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:14]3)[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([OH:28])[CH:9]([OH:37])[CH2:8]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc([N+](=O)[O-])cc3)CC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(N)cc3)CC21
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a solution of 1 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-nitrophenyl)acetyl]perhydro-4,5-isoindolediol in 3.3 cm3 of methanol, maintained at a temperature of 50° C., are added 33 cm3 of water, 4.6 g of ammonium chloride and 2.2 g of zinc powder. The reaction mixture is brought to reflux for 30 minutes, cooled to room temperature and then washed with twice 50 cm3 of dichloromethane. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 70 cm3 of 1N hydrochloric acid. The organic phase is extracted with twice 50 cm3 of ethyl acetate. The aqueous phase is basified with 1N sodium hydroxide and the organic phase is then extracted with 3 times 100 cm3 of ethyl acetate. It is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The meringue-like product obtained is crystallized in 20 cm3 of isopropyl ether. 0.71 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-aminophenyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 188° C.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:48]([CH3:50])[CH3:49])[C:10]([O:12][CH:13]([N:15]1[C:19]2=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:23]=[C:18]2[C:17]([C:31](=[O:47])[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]=2[F:46])=[CH:16]1)[CH3:14])=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:30].[NH2:8][CH:9]([CH:48]([CH3:49])[CH3:50])[C:10]([O:12][CH:13]([N:15]1[C:19]2=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:23]=[C:18]2[C:17]([C:31](=[O:47])[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:41])=[O:42])[C:33]=2[F:46])=[CH:16]1)[CH3:14])=[O:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C(N)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 114.9 %

Procedure:
A mixture of 1-(5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (0.29 g, 0.39 mmol) and a saturated solution of HCl in EtOAc (4 mL) was stirred at rt for 2 h. The mixture was filtered to give the title compound as a white solid (0.15 g, 57%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]2[CH2:14]1)([O:11][CH3:12])=[O:10].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:51])(=O)=O)=CC=1>C1COCC1>[CH:35]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]3[CH2:14][C:13]([C:9]([O:11][CH3:12])=[O:10])([F:51])[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=23)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)OC)Cc1ccccc1-3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of LDA in THF (0.7 mL of 0.5 N, 0.35 mmol) was added to a solution of methyl (±)-6-carbomethoxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (100 mg, 0.23 mmol) in THF (1 mL) at −78° C. Stirring was continued at −78° C. for 15 min and N-fluorobenzenesulfonimide (110 mg, 0.35 mmol) was added in one portion. The mixture was then slowly warmed to −0° C. and Stirring was continued for 1 hr at 0° C. The solution was quenched with MeOH. The solution was extracted with ethyl acetate and the extract washed with dilute HCl (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (30 mg, 29%). ESI-MS m/z 449 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.O>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:1][CH:2]2[CH2:3][CH2:4][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[N:28][CH:29]=1
Reactant: CCOC(=O)C1(C)CCC(N)CC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C)CCC(Nc2ncc(Br)cn2)CC1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
To an ice-cold solution of ethyl 4-amino-1-methylcyclohexanecarboxylate (0.18 g, 0.97 mmol) in EtOH (5.0 mL) was added DIPEA (0.52 mL, 2.91 mmol) followed by the addition of 5-bromo-2-chloropyrimidine (0.185 g, 0.97 mmol). The mixture was heated to 80° C. for 6-8 h after then cooled to rt, water added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 4% EtOAc:hexane to obtain the desired product (0.064 g, 19%). MS: 342.01 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:16][C:15]#[CH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C#CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (1.56 g) in DCM (25 mL) benzyltrimethylammonium chloride (0.18 g) was added. To this solution aqueous 50% NaOH (30 g) and propargyl bromide (1.05 mL of 80% solution in toluene) were added and the mixture was vigorously stirred at room temperature for 3 h. Phases were diluted and separated; the organic phase was washed with water (2×15 mL), dried and evaporated under reduced pressure. The residue was purified by chromatography (silica gel, 0-5% methanol in DCM) to give the title compound as a pale-orange oil (1.53 g); ESMS m/z 222.4 [M+Na]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>ClCCl.C(=O)(O)[O-].[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][C:30]1[N:31]=[CH:32][N:33]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:34]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1cn(-c2ccccc2)cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 52 %

Procedure:
Phenylboronic acid (2.44 g, 20 mmol), copper acetate (2.72 g, 15 mmol), 4 Å molecular sieves (3 g) and pyridine (1.62 ml, 20 mmol) were added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-4-yl)propanoate (2.69 g, 10 mmol) in dichloromethane (60 ml), and the reaction mixture stirred at room temperature whilst bubbling through compressed air, for 2 days. A solution of ethylenediaminetetraacetic acid (5 g, 17 mmol) in saturated sodium bicarbonate solution (200 ml) was added and the mixture stirred at room temperature for 20 minutes. The phases were separated, the aqueous layer extracted with dichloromethane (2×100 ml), and the combined organic extracts dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was azeotroped with toluene (300 ml), and then purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 40:60), to afford the title compound as a yellow gum, 1.87 g, 52% yield.
Reaction SMILES: [OH-].[Na+].CO.[Cl:5][C:6]1[N:7]=[C:8]([CH3:33])[N:9]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([O:31]C)=[O:30])[C:10]=1[Cl:11]>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH3:33])[N:9]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([OH:31])=[O:30])[C:10]=1[Cl:11]
Reactant: COC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)O)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (7.3 ml of 1M aqueous solution) followed by methanol (4 ml) were added to a solution of the product of step c) (2.28 g) in tetrahydrofuran (50 ml) and stirred at room temperature for 3 h. The solution was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 2-5% ethanol in dichloromethane to give the sub-title compound as a white solid (1.68 g). MS (APCI) 445/447 [M+H]+. δ 1HCDCl3 0.96 (6H,d), 2.22 (1H, septet), 2.37 (3H,s), 3.51 (3H,s), 3.78 (2H,d), 5.78 (2H,s), 15.51 (1H,br.s).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][OH:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][O:20][CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a slurry of sodium hydride (60%) (1.623 g, 40.5 mmol, 1.3 eq) in THF (15 mL) was added (S)-2-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.760 g, 31.1 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (100 mL) and the mixture was stirred at room temperature for 1 hr. Methyl iodide (3 mL, 48.2 mmol, 1.5 eq) was added and the reaction was stirred at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (10/90) as an eluent to give the title compound as a colorless oil (3.863 g, 47% ). NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:17](O)[CH3:18]>COC1CCCCCN=1>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:14]=[C:18]2[CH2:17][CH2:4][CH2:5][CH2:6][CH2:7][NH:14]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CCO
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: COC1=NCCCCC1
Agent: Cl
Product: Clc1ccc(C(N=C2CCCCCN2)c2ccccc2)cc1
Reaction time: 72 h

Procedure:
A slurry of 12.0 g of 4-chlorobenzhydrylamine hydrochloride in 23 ml of O-methylcaprolactim was allowed to stand at room temperature for 3 days and was stirred occasionally with a glass rod. At first, the mixture became nearly homogeneous and then it began to solidify. Small amounts of anhydrous ethanol were added to keep the mixture in a stirrable slurry. The mixture was then cooled, the solid was collected and washed with ether and was recrystallyzed twice from methanol-acetone to give 11.7 g of the title compound, m.p. 238°-240°C. The identity of the compound was confirmed by micro-analysis, infrared and ultraviolet spectra.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9](OC)=[O:10])=[CH:6][C:5](=[O:13])[NH:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>C1COCC1>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][NH:4][C:5](=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cc(=O)[nH][nH]c1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=c1cc(CCO)c(=O)[nH][nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of methyl (3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)acetate (11.1 g, 60.3 mmol) in THF (2 litres) was sonicated to give a fine dispersion. The mixture was called to −15° C. and treated dropwise with a solution of lithium aluminium hydride in THF (1M; 90 ml, 90 mmol). The mixture was stirred at 0° C. for 2 hours. Sodium hydroxide (2M; 15 ml, 30 mmol) was added, then the mixture was acidified with 5M hydrochloric acid to around pH4-5. The supernatant was decanted off and discarded. The oily residue was extracted with water/methanol (500 ml/1 litre). This extract was decanted from the remaining residue, treated with silica and evaporated. The silica residue was added to the top of a column, eluting with 10-30% methanol in DCM affording a pale yellow oil (2.7 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@:10]1([O:24][CH3:25])[CH2:21][CH:22]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:26]=[O+][O-]>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:11][C@@:10]1([CH2:21][CH2:22][OH:26])[O:24][CH3:25])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C=CC[C@@]1(OC)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CO[C@]1(CCO)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-methoxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate (230 mg) in CH2Cl2 (10 mL) was cooled to −78° C. and treated with a stream of ozone until a blue color persisted. A stream of nitrogen was passed through the solution for 15 minutes to remove excess ozone from solution. The solution was then treated with dimethylsulfide (0.2 mL) and allowed to warm to 23° C. over 30 min. Volatile components of the reaction mixture were removed in vacuo. The residue was dissolved in methanol (10 mL). To the solution was added NaBH4 (50 mg) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=99/1˜1/99) to give tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-(2-hydroxyethyl)-3-methoxypyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CC#N>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: COC(=O)CCc1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)propanoic acid (0.3 g) in MeCN (9 mL) was added K2CO3 (0.33 g) at ambient temperature followed by addition of iodomethane (0.15 mL). After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (n-hexane:EtOAc=3:1) to give methyl 3-(1H-indol-3-yl)propanoate (0.32 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18]([OH:20])=O)[N:16]=2)=[CH:8][CH:7]=1.ON1C2C=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=N1.Cl.CN(C)CCCN=C=NCC.N1CCCC1>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:20])[N:24]3[CH2:25][CH2:30][CH2:29][CH2:28]3)[N:16]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1coc(-c2ccc(OCCCCl)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetic acid ax63 (0.5 g, 1.69 mmol, 1 eq) in dichloromethane (50 ml) is added 1-hydroxybenzotriazole (0.025 g, 0.19 mmol, 0.11 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.357 g, 1.86 mmol, 1.1 eq). To that solution is added pyrrolidine (0.29 ml, 3.38 mmol, 2 eq) and the mixture is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum to afford 0.51 g of 2-[4-(3-chloropropoxy)phenyl]-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole ax64 as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([O:5][Si](C)(C)C)[CH3:4])#[N:2].Cl.C(=O)([O-])O.[K+]>O1CCCC1>[C:1]([C:3]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([OH:5])[CH3:4])#[N:2]
Reactant: CC(C#N)(O[Si](C)(C)C)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(O)(C#N)C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
The obtained 1-(1-cyano-1-trimethylsilyloxyethyl)adamantane was added to 45 ml of tetrahydrofuran and 17 ml of 2N-hydrochloric acid, and the resultant mixture was refluxed with stirring for 3 hours. After cooling the reaction mixture and adding an aqueous solution (water: 170 ml) of potassium hydrogencarbonate (11 g) thereto, the resultant mixture was extracted with ether, and the obtained organic layer was concentrated to give 24.1 g of 1-(1-cyano-1-hydroxyethyl)adamantane (white solid substance).