Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:30][C:25]3([OH:31])[CH2:26][CH:27]([CH2:29][C:23]([OH:32])([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:20])[CH3:19]>>[C:18]([C:21]12[CH2:22][C:23]3([O:32][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:29][CH:27]([CH2:26][C:25]([OH:31])([CH2:24]3)[CH2:30]1)[CH2:28]2)(=[O:20])[CH3:19]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(=O)C12CC3CC(O)(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(O)(C1)CC(C(C)=O)(C3)C2
Yield: 84 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1-acetyl-3,5-dihyroxyadamantane was used instead of the 1-acetyl-3-hydroxyadamantane, and, as a result, a 1-acetyl-3-hydroxy-5-acryloyloxyadamantane (yield: 84%, white solid) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][N:30]([CH3:41])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:9]1[C:10]([C:23]([O:25]CC)=O)=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].C1CCN2C(=NCCC2)CC1.OS([O-])(=O)=O.[Na+]>CCO.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:25])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:42])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][N:30]([CH3:41])[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[N:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)N(CCN(C)C(=O)OCc1ccccc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (1.32 g, 2.3 mmol) in EtOH (25 mL) under nitrogen was treated with DBU (0.54 mL, 3.55 mmol). After stirring at ambient temperature for 5 min., the reaction mixture was treated with 1N NaHSO4 (3.6 mL). The resulting slurry was diluted with water, filtered, the filtered solid was washed with 1:1 water:EtOH, and Et2O and thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (q, J=6.96 Hz, 3 H), 2.84 (d, J=15.02 Hz, 3 H), 3.42-3.50 (m, 1 H), 3.54 (t, J=4.94 Hz, 1 H), 4.03 (s, 1 H), 4.14 (s, 1 H), 4.19-4.27 (m, 2 H), 4.32-4.38 (m, 2 H), 4.72 (s, 1 H), 4.93 (s, 1 H), 7.00 (d, J=4.21 Hz, 1 H), 7.10 (t, J=8.79 Hz, 2 H), 7.19-7.30 (m, 4 H), 7.30-7.39 (m, 2 H), 8.04 (s, 1 H), 8.41 (s, 1 H), 8.49 (s, 1 H); ES+ MS: 534 (M+H+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(C(F)(F)F)CC1
Temperature: 40 °C
Yield: 65.9 %

Procedure:
To a solution of compound 1-trifluoromethyl-cyclopropanecarboxylic acid (2 g, 13 mmol) in dry THF (80 mL) was added LAH (592 mg, 16 mmol) in portions at 0° C. and the resulting mixture was heated at 40° C. overnight. H2O (592 mg, 16 mmol) was added to quench the reaction at 0° C. and followed by 2N NaOH (0.6 mL). After filtration, the filtrate was distilled to remove the most solvent to give crude (1-trifluoromethyl-cyclopropyl)-methanol (1.2 g crude), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].[CH2:43]([Zn]CC)[CH3:44].C1(C)C=CC=CC=1.O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH2:43][CH3:44])=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (93.5 mg, 0.149 mmol) was dissolved in dimethoxyethane (4.7 mL), and the solution was added with 1.1 mmol/L diethyl zinc-toluene solution (0.68 mL, 0.744 mmol) and [bis(diphenylphosphino)ferrocene]dichloropalladium (34.4 mg, 0.030 mmol), followed by stirring at 90° C. for 12 hours under argon atmosphere. The reaction mixture was added with water and filtered using Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-ethyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (39.0 mg, yield 52%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)[CH2:4][C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)[CH2:4][CH2:5][OH:6]
Reactant: NC(CC(=O)O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(CCO)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To a stirred suspension of 3-amino-3-(3,4-difluorophenyl)propanoic acid hydrochloride (17 g, 72 mmol, <30% pure) in THF (100 mL) under N2 cooled to 0° C. was added a 1M solution LiAlH4 in THF (215 mL, 215 mmol) in THF dropwise. The reaction was stirred at 0° C. in an ice bath for 1.5 h. To the ice-cold solution was added carefully a ice-cold satd. aq. solution of Rochelle's salt (300 mL). The resulting mixture was stirred for 18 h warming to RT slowly as the ice bath melted. The mixture was diluted with EtOAc (500 mL), and filtered through CELITE to remove solids which were rinsed several times with EtOAc. The phases were separated and the aqueous phase re-extracted with EtOAc (200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (Biotage Flash 65) eluting with 5% MeOH (containing 7N NH3)/DCM (1 L to pre-wash column, followed by 1 L of elution), then 10% MeOH (containing 7N NH3) in DCM (1 L) to afford 0.92 g (6%) of 3-amino-3-(3,4-difluorophenyl)propan-1-ol (304).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][OH:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:17][CH:18]=1)(=[O:21])[CH2:19][OH:22]
Reactant: O=C(Cl)CO
Reactant: O=C1Nc2ncccc2C1=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: O=C(CO)Oc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 3-(4-hydroxybenzylidene)-7-azaoxindole (2,383 g. 10 mmol) in pyridine (10 ml) was added gradually glycoloyl chloride (0.945 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 4 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Li+].[CH3:14]C([N-]C(C)C)C.CI.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1F
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 2-fluorophenylacetate (24.2 g, 0.144 mol) in THF (75 ml) was added dropwise over 20 min to a -78° C. solution of LDA (diisopropylamine (16.0 g, 0.158 mol) and n-butyl lithium (2.5 M, 61 ml)) in THF (300 ml) and stirring was continued for 1 h. Methyl iodide (22.5 g, 0.158 mol) was added dropwise over 15 min and the reaction mixture allowed to warm to room temperature over 1 h. The solution was poured into saturated ammonium chloride solution and extracted with diethyl ether. The extract was washed with brine, dried and evaporated to yield methyl 2-(2-fluorophenyl)propanoate (26.2 g, 100%) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1.CI>O>[Br:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][O:16][CH3:3])[CH:10]=1
Reactant: CN(C)C=O
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1cncc(Br)c1
Reaction time: 1 h

Procedure:
Sodium hydride (61% in oil) (11 mg) was added to a DMF (0.9 ml) solution containing (5-bromopyridin-3-yl)methanol (34 mg) under ice cooling, followed by stirring for 1 hour. Then, methyl iodide (17 μl) was added, followed by stirring at room temperature for 13 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a light yellow solid of 3-bromo-5-(methoxymethyl)pyridine (26.5 mg) was thus obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(Cl)(Cl)Cl>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1c(Cl)c2ccccc2n(-c2ccccc2)c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(Nc2ccccc2C)c2ccccc2n(-c2ccccc2)c1=O
Yield: 69.4 %

Procedure:
A mixture consisting of 1.0 g (3.05 mmol) of ethyl 4-chloro-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate and 6.5 g (60.7 mmol) of o-toluidine was reacted at 100° C. for 5 hours. After the reaction, chloroform was added, and the resultant mixture was washed with a 5% aqueous solution of potassium hydrogensulfate and was then dried. The solvent was distilled off under reduced pressure, and the residue so obtained was purified by chromatography on a silica gel and was then recrystallized from ethanol/water, whereby 0.844 g of ethyl 4-(2-methylphenylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate (Compound No. 33) was obtained (yield: 69.5%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[CH:37]1([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[NH2:45])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:45][C:44]([CH3:46])([C:43]([O:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:48])[CH3:47])[CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)c1cc(C(=O)N2CCC(CCNC(C)(C)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and α,α-dimethylglycine cyclopentyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.34 (1H, s), 5.26-5.39 (1H, m), 4.29 (2H, br. s.), 3.28 (1H, br. s.), 3.18 (1H, dt, J=13.6, 6.8 Hz), 3.03-3.12 (2H, m), 2.98 (2H, t, J=12.4 Hz), 1.64-2.01 (11H, m), 1.59 (6H, s), 1.24-1.38 (3H, m), 1.19 (6H, d, J=7.0 Hz) LC/MS: purity 97%, m/z 461 [M+H]+
Reaction SMILES: [CH2:1]([CH:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:6](=[O:20])[C:5]([CH3:22])([CH3:21])[C:4]1=[O:23])[CH3:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[CH2:1]([C@H:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:9]=2)[C:6](=[O:20])[C:5]([CH3:22])([CH3:21])[C@H:4]1[OH:23])[CH3:2]
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (120 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.555 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 76 mg, 63%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1([CH:13]=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(CO)CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)C1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentyl]-methanol (1.1 g, 4.51 mmol) was dissolved in DCM (30 ml) and Dess-Martin reagent (3.82 g, 9.0 mmol) was added in portions. The reaction mixture was stirred at room temperature for 4 hr and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluted with hexanes:EtOAc, 10:1) to afford the title compound (0.75 g, 64%): 1H NMR (400 MHz, DMSO) delta 0.00 (s, 6H), 0.84 (s, 9H), 1.28-1.31 (m, 4H), 1.46-1.50 (m, 4H), 3.76 (s, 2H), 9.54 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][C:17]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:12][NH:8]1)=[O:19])[CH3:21]
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: CCON=C1CN[C@H](C(=O)NCCN(CC)CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=271.0.
Reaction SMILES: CCN(/C=C(/C(OCC)=O)\[C:8](C)=[O:9])CC.OCCNN.[C:21]([N:25]1[C:29]([CH3:30])=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=[N:26]1)(C)(C)[CH3:22].[H-].[Na+].[OH:38][CH2:39][CH2:40][N:41]1[C:45]([CH3:46])=[C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH:43]=[N:42]1.CI>C1COCC1>[OH:38][CH2:39][CH2:40][N:41]1[C:45]([CH3:46])=[C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH:43]=[N:42]1.[CH3:8][O:9][CH2:22][CH2:21][N:25]1[C:29]([CH3:30])=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=[N:26]1
Reactant: CCOC(=O)/C(=C/N(CC)CC)C(C)=O
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C
Agent: CCOC(=O)c1cnn(CCO)c1C
Agent: NNCCO
Agent: [H-]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(CCOC)c1C
Reaction time: 15 h
Yield: 62 %

Procedure:
Ethyl 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-4-carboxylate (376 mg, 67%) was synthesized from diethylaminomethylene ethyl acetoacetate (509 mg, 2.8 mmol) and 2-hydroxyethyl hydrazine (0.30 mL, 4.1 mmol) following the general procedure for ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate as described (see R. A. Fecik, P. Devasthale, S. Pillai, A. Keschavarz-Shokri, L. Sehn, and L. A. Mitscher; J. Med. Chem. 2005, 48, 122). To a stirred solution of NaH (91 mg, 2.3 mmol) in THF (5 mL) was added ethyl 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-4-carboxylate (376 mg, 1.9 mmol) in THF (1 mL) at 0° C. followed by MeI (0.18 mL, 2.9 mmol). The resulting mixture was stirred for 15 h and quenched with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduce pressure. The residue was purified by column chromatography to provide ethyl 1-(2-methoxyethyl)-5-methyl-1H-pyrazole-4-carboxylate (249 mg, 62%) as a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:19])[CH2:16][NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[OH:20])=[O:5]>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]([OH:19])[CH2:16][NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[OH:20])=[O:5]
Reactant: CNCC(=O)c1ccc(O)c2[nH]c(C(=O)OC)cc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCC(O)c1ccc(O)c2[nH]c(C(=O)OC)cc12
Yield: 25.7 %

Procedure:
A solution of 896 mg of 4-methylaminoacetyl-7-hydroxyindole-2-carboxylic acid methyl ester hydrochloride in 30 ml of methanol is combined with 150 mg of 10% palladium-animal charcoal catalyst and hydrogenated under shaking at normal pressure. The reaction mixture is then filtered and the filtrate evaporated to dryness under vacuum. The residue is extracted by boiling with 20 ml of acetonitrile and the insoluble proportion is vacuum-filtered and recrystallized from ethanol, thus producing 232 mg of 4-(1-hydroxy-2-methylaminoethyl)- 7-hydroxyindole-2-carboxylic acid methyl ester hydrochloride, decomposition point 177°-180° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[CH2:17]N2CCN(C)CC2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN1CCNCC1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][O:25]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)CN2CCN(C)CC2)cc1
Agent: CN1CCNCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CO2)cc1
Yield: 118.3 %

Procedure:
35 mg of tert-butyl((1S)-1-{4-[1-hydroxy-2-(4-methylpiperazin-1-yl) ethyl]phenyl}ethyl)carbamate [8-1] (hereinafter, referred to as the compound [8-1]) was obtained as a colorless oily product from 30 mg of the compound [7-2] and 2 mL of N-methylpiperizine according to the method of Example 7-(3).
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17](C(O)=O)[C:16]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:3]1([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: O=C(O)c1cc2ccccc2c(-c2c(O)c(C(=O)O)cc3ccccc23)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 50 g (60 mmol) of Merrifield resin (polCH2Cl where pol=1-2% crosslinked polystyrene, 200-400 mesh beads), 2,2′-dihydroxy-1,1′-binaphthalene-3,3′-dicarboxylic acid (33.7 g), potassium carbonate (12.4 g) and DMF (dimethlyformamide) (350 ml) was heated at 90° C. with stirring for 8 hrs. The color of the resin changed from white to green-yellow. The mixture was diluted with water, filtered, washed with H2O, DMF, and acetone, and then thoroughly dried in the air to give the desired product. IR (KBr, cm−1): 1712 (vs), 1676 (vs).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1.CCOCC>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiAlH4 (2.51 g, 66.3 mmol) was suspended in THF (60 mL) and then cooled in an ice-bath. To the suspension was added Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (11.357 g, 53.0 mmol) dissolved in THF (40 mL) dropwise and the reaction mixture was gradually warmed to room temperature over 1 h upon which LCMS indicated complete reduction of SM. The reaction mixture was diluted with ether (200 mL) and quenched with 2.5 mL water and then 5 mL (10% NaOH) and then 7.5 mL water. To this, anhydrous MgSO4 was added, which was then agitated for 30 min and filtered over Celite. The filtrate was concentrated in vacuo to afford the desired product in quantitative yield. LCMS (m/z): 173.1 (MH+), 0.41 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)C.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.[Cu]I>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and CuI (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:7][C:8]1[N:13]=[C:12]2[C:14](=[O:27])[CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:18][C:11]2=[CH:10][CH:9]=1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([NH:7][C:8]1[N:13]=[C:12]2[C@H:14]([OH:27])[CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:18][C:11]2=[CH:10][CH:9]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)Nc1ccc2c(n1)C(=O)CC[C@@H](c1cccc(F)c1F)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)Nc1ccc2c(n1)[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SODIUM BOROHYDRIDE (0.072 g, 1.893 mmol) was added to the MeOH (10 mL) solution of (R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridin-9(6H)-one (0.2173 g, 0.631 mmol) at rt. The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was finished. The solvent was removed via vacuum. The crude was separated via flash column eluted with ethyl acetate in hexane from 0 to 35% to 65% to give two compounds. This is the less polar compound (134.9 mg, 61%). HPLC tR=2.43 min; MS(ESI)[M+H+]=347.33; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (d, J=8.06 Hz, 1H) 6.99-7.11 (m, 3H) 6.28 (d, J=8.06 Hz, 1H) 4.76 (dd, J=11.33, 2.01 Hz, 1H) 4.53 (br.s., 1H) 3.03 (d, J=13.85 Hz, 1H) 2.89 (d, J=4.28 Hz, 1H) 2.64 (d, J=14.10 Hz, 1H) 2.28 (dd, J=12.59, 2.01 Hz, 1H) 2.13 (dd, J=9.82, 3.78 Hz, 2H) 1.58-1.71 (m, 1H) 1.42-1.55 (m, 9H).