Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 100 %

Procedure:
First, about 1 mole of methyl 4-hydroxybenzoate and about 1 mole of 4-bromo-1,1,1-trifluorobutane were added to excess acetone which was mixed with potassium carbonate at a temperature of about 40° C. for about 90 minutes to obtain about 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate. About 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate was mixed with about 1 N (normality) of excess sodium hydroxide, and methyl 4-(4,4,4-trifluorobutoxy)benzoate and sodium hydroxide were mixed to perform reflux for about 30 minutes and then neutralized to hydrochloric acid to obtain about 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid. About 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid was mixed with carbon dichloride and carbonyl diimidazole (CDI). After 4-(4,4,4-trifluorobutoxy)benzoic acid, carbon dichloride, and CDI were reacted at a temperature of about 25° C. for about 2 hours. About 1 mole of 4-hydroxybenzaldehyde was mixed with the above mixture at a temperature of about 25° C. for about 12 hours and, carbon dichloride and water were added to extract about 1 mole of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([NH:12][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.07 g (30.6 mmol) of succinic anhydride was suspended in 30 ml of dichloromethane. 4.1 ml (34.5 mmol) of t-butylamine was dropped into the suspension, and the resultant mixture was stirred at room temperature for 1 hour. White crystals thus formed were washed with ethyl acetate and then dissolved in 40 ml of 1 N aqueous sodium hydroxide solution. The resultant solution was stirred at room temperature for 2 hours and then acidified with 1 N aqueous hydrochloric acid solution under cooling with ice. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13](I)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([O:34][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:30]4[CH:42]=[CH:41][C:33]([O:34][C:35]5[N:36]=[CH:37][CH:38]=[CH:39][N:40]=5)=[CH:32][CH:31]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(Oc3ncccn3)cc2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
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: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 75.7 %

Procedure:
A mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate N) (1.50 g, 0.00374 mol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-pyrimidine (intermediate BA) (1.23 g, 0.00412 mol), tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.00022 mol) and sodium carbonate (0.993 g, 0.00937 mol) in 40 mL 1,2-dimethoxyethane and 20 mL water was heated at 80° C. for eighteen hours, after which time additional 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.15 g, 0.00037 mol) was added. The mixture was stirred for an additional hour and then allowed to cool to ambient temperature. The precipitate was filtered and washed with 1,2-dimethoxyethane and dried in vacuo, to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.26 g, 0.00283 mol):1H NMR (DMSO-d6, 400 MHz) 8.68(d, 2H), 8.254(s, 1H), 7.73 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 4.78-4.84 (m, 1H), 3.91 (s, 4H), 2.22-2.30 (m, 2H), 1.73-1.92 (m, 6H).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:17][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8])[CH3:11]
Reactant: CC(C)CCN
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCO
Product: CCOC(=O)C1=C(NCCC(C)C)CCC1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (5.00 mL, 32.1 mmol) in ethanol (50 mL) was added isoamylamine (3.8 mL, 32.3 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-30% ethyl acetate in hexanes) to afford the desired product, 2-(3-methylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.84 g, 30.4 mmol, 95%), as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 0.92 (6H, d, J=6.1 Hz), 1.28 (3H, t, J=6.9 Hz), 1.44 (2H, q, J=7.2 Hz), 1.63-1.74 (1H, m), 1.80-1.87 (2H, m), 2.50-2.58 (4H, m), 3.19 (2H, q, J=6.7 Hz), 4.14 (2H, q, J=7.1 Hz), 7.34 (1H, bs).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(=O)OCC2C=CC=CC=2)[C@@H:4]([CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[NH:3]1>CCO.CO.[Pd]>[NH2:6][C@@H:5]1[C:2](=[O:1])[NH:3][C@@H:4]1[CH2:17][N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidin-3-yl)carbamate (96 mg, 0.30 mmol) and Pd/C 10% Degussa type 101 (10%, 64 mg) in EtOH:MeOH (4:1, 1.5 mL) for 1 h. The crude residue was used as such in following step. LCMS: Rt=0.11 min, m/z=186.0 (M+1) Method 2m_acidic.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3]1.O[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([CH2:32][CH3:33])[CH:30]=[CH:31][C:24]=2[S:23]1(=[O:35])=[O:34]>O>[O:34]=[S:23]1(=[O:35])[C:24]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][C:25]=2[C:26](=[O:27])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[O:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: CCc1ccc2c(c1)C(=O)N(CCCCO)S2(=O)=O
Reactant: O=c1oc2ccccc2n1C1CCNCC1
Solvent: O
Product: CCc1ccc2c(c1)C(=O)N(CCCCN1CCC(n3c(=O)oc4ccccc43)CC1)S2(=O)=O

Procedure:
From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)-1,1-dioxido-5-ethyl-1,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: mp 165°-168 ° C. 1H NMR (400 MHz, CDCl3) 7.9 (s, 1H), 7.8 (m, 1H), 7.66 (m, 1H), 7.3 (m, 1H), 7.2-7.05 (m, 3H), 4.2 (m, 1H), 3.8 (m, 2H), 3.1 (m, 2H), 2.82 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 2.0-1.8 (br m, 4H), 1.8-1.6 (br m, 4H), 1.3 (t, 3H) Analysis calculated for C25H30N3O6S·HCl·1.4 H2O C: 55.66, H: 6.06, N: 7.01 found C: 55.82, H: 5.81, N: 6.91.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:24](Br)([CH3:26])[CH3:25]>C(#N)C>[CH:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1)([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(c2cccc(C(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and isopropyl bromide (0.01 ml). MS m/z (relative intensity, 70 eV) 287 (M+, 13), 272 (bp), 253 (13), 252 (44), 166 (12).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](OC)(OC)OC>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Yield: 57.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) and tetramethoxymethane (151 mg, 1.11 mmol) were heated under reflux in tetrahydrofuran (3.7 mL) for 2 hr. The reaction solution was diluted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (58.4 mg, yield 58%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:20]=[CH:21][CH:22]=[N:23]5)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: O=Cc1ccc2nccnc2c1
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccc5nccnc5c4)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoxaline-6-carbaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 11.0 (brs, 1H), 8.81 (s, 2H), 8.13 (d, J=8.7, 1H), 8.01-7.92 (m, 3H), 5.01-4.94 (m, 1H), 4.01-3.88 (m, 2H), 3.37 (t, J=8.3, 1H), 3.05 (d, J=9.9, 1H), 2.86-2.85 (m, 1H), 2.70-2.68 (m, 1H), 2.49-2.44 (m, 1H), 2.07-2.01 (m, 1H). 1.48 (dd, J=15.3, 6.6 Hz, 6H), 1.20 (d, J=7.05 Hz, 3H). MS: (M+H m/z 404.1).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([N+:22]([O-])=O)=[CH:20][N:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:30](O)(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C.[Fe]>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([NH:22][C:30](=[O:32])[CH3:31])=[CH:20][N:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Reactant: CC(=O)O
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Iron powder (162 mg, 2.9 mmol) was added to a stirred solution of 3-cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E210a) (162 mg, 0.47 mmol) in acetic acid (1 ml) and acetic anhydride (1 ml). The reaction mixture was stirred at 80° C. for 16 hours then cooled and poured onto ice. The solution was basified to pH 8 (sodium bicarbonate) and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried (sodium sulfate). Concentration in vacuo and subsequent purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.3:2.7:97) afforded the title compound (E210). MS (ES+) m/e 358 [M+H]+.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:24]([OH:26])=O)[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>ClCCl>[C:1]([NH:18][C@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-L-Methionine (5.00 g, 13.46 mmol) (Bachem) was dissolved in dichloromethane (70 mL). Pyridine (1.09 mL, 13.46 mmol) (Aldrich) and cyanuric fluoride (1.82 g, 13.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-L-methionyl fluoride as a white powder. (Yield 3.7 g., 74%).
Reaction SMILES: [C:1]1([S:7][C:8]2([C:11]([CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1(C)C=CC=CC=1>[C:1]1([S:7][C:8]2([C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 50 °C
Yield: 89.6 %

Procedure:
460 mg (0.5 mmol) o& tris-triphenylphosphinyl rhodium chloride (=1 mol %, with respect to the reaction components) is added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 15.7 g (0.05 mol) of 4-chlorophenylethenyl 1-phenylmercapto-cyclopropyl ketone in 40 ml of toluene is added and heated at 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is kept between 40 and 50 bar until the absorption of gas is complete. The mixture is subsequently reacted for 1 hour. For working up, the solvent is removed under reduced pressure and the residue which remains is purified on silica gel using dichloromethane as the eluant. 14.2 g (90% of theory) of 4-chlorophenylethyl 1-phenylmercaptocyclopropyl ketone are obtained in the form of an oily product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[H][H]>CO.[C].[Pd]>[CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
1.77 g of N-methyl-1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 30 ml of methanol. Then, 200 mg of 10% palladium carbon was added to the obtained solution. The reaction atmosphere was replaced by hydrogen, and it was then stirred at room temperature. After completion of the reaction, 10% palladium carbon was filtered off from the reaction solution, and the reaction solution was then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), followed by solidification from a mixed solution consisting of ethyl acetate, t-butylmethyl ether, and methanol, so as to obtain 973 mg of the subject compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to 0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was added drop-wise, catalytic amount (2, drop) of dimethyl formamide was added to the reaction mixture. After the addition, reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. To this residue, solution of Piperidine (0.68 mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added under nitrogen at room temperature and reaction mass was stirred for 0.5 h at room temperature. The reaction mixture was quenched by ice water and extracted with Dichloromethane and purified by column chromatography to gives 0.8 g of desired compound as free base. The free base was converted into HCl salt by treatment with ethanolic HCl. Sodium hydride (0.8 g, 20 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol) in THF was added drop wise in reaction mixture. Then reaction mixture stirred at RT for 2 h. Reaction monitored by TLC. After completion of reaction, reaction mixture quench with ice-water. THE was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to give 1 g of desired compound then it was stirred with ethanolic HCl to give HCl salt of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][NH:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.57 g of methylamine is condensed in a solution of 1.8 ml of (3-bromo-propoxymethyl)-benzene in 15 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium chloride solution, extracted with ether, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 1.91 g of (3-benzyloxy-propyl)-methyl-amine is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1Cc2ccccc2C1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1Cc2ccccc2C1)c1cnc2ccccc2n1
Yield: 53 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.32 g, 1.7 mmol), 2-aminoindan (0.20 g, 1.5 mmol), pyridine (3 mL), and water (30 mL) yielding 0.23 g (53%) of (221):
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:18]=1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7])#[N:2].CO>[Pd].C1COCC1>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:17][CH:18]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
A mixture of Example 108C (140 mg, 0.34 mmol), 10% Pd/C (73 mg, 0.03 mmol), methanol (4 mL), and THF (8 mL) was stirred under a hydrogen atmosphere for 45 minutes and filtered. The filtrate was concentrated to an oil which was triturated with diethyl ether to provide the desired product. MS (ESI(−)) m/e 315 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (m, 2H), 7.56 (m, 4H), 7.22 (d, 1H), 3.32 (br s, 2H), 2.56 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:13][CH:14]=1)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:22])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(-c2ccccc2F)nc1
Reaction time: 1.5 h

Procedure:
300 mg (0.99 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 1.5 h. The mixture was concentrated and lyophilized. Yield: 286 mg.