Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>CN(C=O)C>[C:1]1([C:7]2[N:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCn1ccnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A solution of 2-phenylimidazole (14.4 g) in dry DMF (25 ml) was added dropwise to a stirred suspension of sodium hydride (4.0 g, 60% dispersion in oil) in dry DMF (125 ml) at ambient temperature under nitrogen for 2 hours. A slurry of N-(3-bromopropyl)phthalimide (25.5 g) in dry DMF (40 ml) was added and the mixture heated at 100° C. for 16 hours. The solvent was evaporated off and the residue was extracted with hot toluene. The combined toluene extracts were evaporated to dryness and the residue triturated with ether and dried to give N-[3-(2-phenylimidazol-1-yl)propyl]phthalimide, m.p. 109°-110.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][CH:18]=[O:19].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: COc1cc(CCCC=O)c(OC)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCCCO)c(OC)c2ccccc12
Yield: 95.2 %

Procedure:
Following a procedure similar to that described in Preparation 1(c), but using 2.96 g of 4-(1,4-dimethoxy-2-naphthyl)butyraldehyde [prepared as described in step (b) above], 0.87 g of sodium borohydride and 80 ml of ethanol, 2.84 g of the title compound were obtained as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([C@@H:10]([CH3:30])[CH2:11]2)=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]2)[C@@H:10]([CH3:30])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 223 mg of 11β,21-dihydroxy-17α-methoxyacetoxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 32. To this solution were added 404 mg of triethylamine and 204 mg of acetic anhydride, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was then treated in the same manner as described in Example 7 whereby 186 mg (yield: 76.2%) of the title compound was obtained as colorless needle crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:17](F)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (CAS number 72537-17-8; 1.44 ml, 10.98 mmol), DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.[Cl-].[NH4+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12])[CH:7]=1.[Si:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([B:17]([OH:22])[OH:18])[CH:3]=[N:4][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cncc(B(O)O)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 143.4 %

Procedure:
3-Bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine was prepared according to the published procedure (Zhang, N. et al, J. Med. Chem., 45, 2832-2840 (2002)). Under a nitrogen atmosphere, a solution of 3-bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine (28.70 g, 94.94 mmol) and triisopropyl borate (26.3 mL, 114 mmol) in dry THF was cooled to −70° C. n-Butyllithium (45.6 mL, 114 mmol) was added dropwise over a period of 1.5 hours. The reaction was stirred for an additional 30 minutes and then allowed to warm to −20° C. Dilute aqueous ammonium chloride was added, and the mixture was allowed to warm to ambient temperature. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were concentrated under reduced pressure, and methanol was added to the resulting oil. A solid formed, which was stirred with water for two days, isolated by filtration, and dried under reduced pressure to provide 18.19 g of 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](Cl)=[O:18])[CH3:15]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:17](=[O:18])[N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CCN(CC)C(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
In 40 ml of methylene chloride was dissolved 4.0 g (0.02 mole) of 1-(4-chlorophenyl)piperazine at room temperature. Then, a solution of 3.0 g (0.022 mole) of diethylcarbamoyl chloride in 30 ml off methylene chloride was dropped to the above solution over a period of 30 minutes and the mixture was stirred for 4 hours at room temperature. The precipitate was removed and the filtrate was made alkaline by addition of 30 ml of a 35% aqueous solution of sodium hydroxide and extracted with 50 ml of methylene chloride. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain crude 1-(4-chlorophenyl)-4-diethylcarbamylpiperazine as the residue. The low-boiling-point component was removed by distillation under reduced pressure and the residue was recrystallized from n-hexane to obtain 1.8 g of a purified product having a melting point of 63° to 64° C. The yield was 29.9%. The elementary analysis values are as follows.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][N:6]([C:13](=[O:44])[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:19]=[C:18]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:17]=1)=[O:15])[CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+]>CO>[C:8]([CH2:7][N:6]([C:13](=[O:44])[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:19]=[C:18]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:17]=1)=[O:15])[CH2:5][C:4]([OH:45])=[O:3])([OH:10])=[O:9]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 87.5 %

Procedure:
A solution of 1.2 g (1.9 mmol) of N-[[3,5-bis(decyloxy)phenyl]-1,2-dioxoethyl]-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester in 75 ml of methanol and 1.6 ml (9.6 mmol) of 6.0 N NaOH was stirred at reflux under argon for 4 hours. The solvent was removed at reduced pressure, the residue was treated with water and 2.5 ml of 6N HCl and the product was extracted with ethyl acetate. The dried extract was concentrated to a foam which was crystallized from hexane to give 0.96 g (87% yield, mp 76°-78°) of N-(carboxymethyl)-N-[[3,5-bis(decyloxy)phenyl]-1,2-dioxoethyl]glycine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CCN(CC)CC>O1CCOCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: c1ccc2c(c1)CCN2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: ClCCCN1CCc2ccccc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 45.4 %

Procedure:
To a solution of 1-bromo-3-chloropropane (1.98 g, 12.6 mmol) and indoline (500 mg, 4.20 mmol) in 1,4-dioxane (6.0 mL) was added Et3N (2.12 g, 21.0 mmol) at 20° C. The reaction mixture was then stirred for 15 h at 70° C. The reaction mixture was cooled to 20° C. and quenched by addition of H2O. The product was extracted with Et2O. The organic solution was then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. 1-(3-Chloro-1-propyl)indoline (373 mg, 45%) was isolated by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a pale yellow oil. 1H NMR (CDCl3, 300 MHz) δ2.07 (qu, 2H, J=6.2 Hz), 2.97 (t, 2H, J=8.2 Hz), 3.24 (t, 2H, J=6.6 Hz), 3.35 (t, 2H, J=8.3 Hz), 3.68 (t, 2H, J=6.2 Hz), 6.50-6.56 (m, 1H), 6.66 (t, 1H, J=6.6 Hz), 7.04-7.10 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([NH:16][C@H:17]([C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([O:35]CC)=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([NH:16][C@H:17]([C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCCCC3C(=O)O)ccc2c1
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A solution of 2.8 g of ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N-NaOH solution was warmed to 60° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion ® SK 102 ion exchange resin (200 - 300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH3:13])[CH:7]=[N:8]2.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH3:13])[CH:7]=[N:8]2
Reactant: COc1cccc2ncc(C)cc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cnc2cccc(O)c2c1
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 60.8 %

Procedure:
To a stirred solution of N-pivaloyl-3-methoxyaniline (4.14 g, 20 mmol) in dry tetrahydrofuran (80 mL) at 0° C. under argon was added a solution of sec-butyllithium in cyclohexane (1.4 M, 35.7 mL, 50 mmol), dropwise over 0.2 h (T≦0° C.) and the resulting mixture was stirred at 0-5° C. for 2 h. The mixture was cooled to −5° C. then dry N,N-dimethylformamide (2.3 mL, 30 mmol) was added dropwise, and the resulting solution stirred at 0° C. for 1 h then at 20° C. for 20 h. The mixture was cooled to 0° C. and propionaldehyde (1.17 g, 20.2 mmol) was added dropwise followed by a solution of potassium hexamethyldisilazide in toluene (0.5 M, 80 mL, 40 mmol) dropwise over 0.2 h. The mixture was stirred at 0° C. for 0.25 h, then at 20° C. for 2 h and at 30° C. for 1 h. The resulting mixture was partitioned between saturated aqueous NH4Cl (200 mL) and ether (3×50 mL), and the combined organic extracts dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on silica with 20-100% ether in hexane gradient elution gave 5-methoxy-3-methylquinoline (0.16 g, 5%) as an oil. A mixture of 5-methoxy-3-methylquinoline (0.16 g, 0.92 mmol) and pyridine hydrochloride (0.064 g, 5.5 mmol) was heated under argon at 200° C. with stirring for 2.5 h, then cooled and partitioned between saturated aqueous NaHCO3 (30 mL) and dichloromethane (5×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica eluting with ethyl acetate to give the title compound (0.089 g, 60%) as a solid.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:6][NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1

Procedure:
A solution of trans-methyl[4-(1-oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]-carbamic acid tert-butyl ester (400 mg, 1.07 mmol) in dichloromethane (9 ml) and trifluoroacetic acid (1 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo then purified by ion exchange chromatography to give trans-6-(4-methylaminocyclohexyloxy)-2H-isoquinolin-1-one, EI-MS: m/z=273.4 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]#[C:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C.C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1C#CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCNC(=O)OC(C)(C)C
Yield: 51.9 %

Procedure:
10% Palladium on carbon (0.05 g) was added to a solution of methyl 6-(benzenesulphonylmethyl)-2-(3-t-butyoxycarbonylamino-prop-1-yn-1-yl)-3-(furan-3-yl)benzoate (Intermediate 132, 0.22 g) in ethanol (10 ml) and THF (10 ml) and the mixture was stirred at room temperature in an atmosphere of hydrogen (balloon) for 60 hours. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 25-60% to give methyl 6-(benzenesulphonylmethyl)-2-(3-t-butoxycarbonylaminopropyl)-3-(furan-3-yl)benzoate (0.115 g) as a colourless gum.
Reaction SMILES: S1C=CC(C2C=C(C=CC=2)OCCOCCN)=C1.CC(C)(C)C#C/C=C/CBr.[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=2)[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[CH:30]1.[CH3:47][O:48][C:49]([CH3:57])([CH3:56])[C:50]#[C:51]/[CH:52]=[CH:53]/[CH2:54]Br>>[CH3:47][O:48][C:49]([CH3:57])([CH3:56])[C:50]#[C:51]/[CH:52]=[CH:53]/[CH2:54][NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36]1[CH:44]=[CH:45][CH:46]=[C:34]([C:31]2[CH:32]=[CH:33][S:29][CH:30]=2)[CH:35]=1
Reactant: COC(C)(C)C#C/C=C/CBr
Reactant: NCCCCCOc1cccc(-c2ccsc2)c1
Agent: CC(C)(C)C#C/C=C/CBr
Agent: NCCOCCOc1cccc(-c2ccsc2)c1
Product: COC(C)(C)C#C/C=C/CNCCCCCOc1cccc(-c2ccsc2)c1

Procedure:
Compound of Example 53 was obtained by performing the same reaction as in Example 52 except that 2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and (E)-6,6-dimethyl-2-hepten-4-ynyl bromide were used instead of the starting compounds, 5-[3-(3-thienyl)phenoxy]pentylamine and (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide, which were used in the above-mentioned reaction.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=1)(=[O:8])[CH3:7].[C:33]([O-])(=[O:35])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:33]=[O:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCCCNCCCCc1ccc(C=O)c(OCc2ccccc2)c1
Yield: 74.7 %

Procedure:
To 10 ml of N,N-dimethylformamide was added dropwise 1.11 g (7.24 mmol) of phosphoryl chloride over 8 minutes with stirring under ice cooling. After the mixture was stirred for 1 hour, 2.67 g (7.23 mmol) of 4-[(3-benzyloxyphenyl) butylamino]butyl acetate dissolved in 4 ml of N,N-dimethylformamide was added dropwise thereto. After stirred for 1 hour, the mixture was gradually heated and stirred at 50° C. for 3 hours and further at 70° C. for 0.5 hours. To this mixture, 20 ml of a 20% sodium acetate solution was added dropwise under cooling in an ice bath. The mixture was stirred for 1 hour and subjected to extraction with ethyl acetate. Washing was performed with a saturated sodium bicarbonate solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 2.14 g of a yellow oily matter (yield: 74.7%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[N:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])C.[OH-].[Li+]>C1COCC1.O>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:19]1[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)=[CH:21][C:17]([C:15]([NH:14][C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][C:4]([OH:36])=[O:3])=[O:16])=[N:18]1
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(OCC2(C)COC2)n(-c2ccccc2F)n1)c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC2(C)COC2)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
100 mg (0.2 mmol) of (S)-3-{[1-(2-fluoro-phenyl)-5-(3-methyl-oxetan-3-ylmethoxy)-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid ethyl ester were dissolved in a mixture of THF, MOH and water (2 ml each), and 14.5 mg (0.61 mmol) of lithium hydroxide were added. The mixture was stirred overnight at room temperature and the solvent removed. The residue was subjected to column chromatography (silica gel, DCM/MOH 9:1) to give 75 mg (75%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)cc1

Procedure:
To a solution of 55 (0.817 g; 2.31 mmol) in methanol (4.5 mL) was added aqueous sodium hydroxide (9.2 mL; 1N). After the reaction was complete, the mixture was partitioned between diethyl ether and water; the organic layer was separated and set aside. The aqueous layer was acidified with excess aqueous hydrochloric acid (2N) and extracted with ethyl acetate (2×). The diethyl ether and ethyl acetate organic layers were combined, dried over sodium sulfate, decanted, and concentrated under reduced pressure. The resulting residue yielded the desired product a white solid from a mixture of hexanes and dichloromethane (0.54 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:23]1[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccncc1
Product: COc1ccc2c(-c3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-pyridinylboronic acid to give (6-methoxy-1-pyridin-4-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 318(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:19]/[C:20](/[CH3:27])=[CH:21]/C(OCC)=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4](/[C:14](/[CH3:15])=[CH:21]/[C:20](=[O:19])[CH3:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCCC2)c(Br)c1
Solvent: CO
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCC2)c(Br)c1
Yield: 69 %

Procedure:
(E)-4-(3-Bromo-4-cyclohexyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52, from 3'-bromo-4'-cyclohexylacetophenone (b.p. 135°-138°C at 0.15 mm Hg; nD20 = 1.5740) an ethyl (E)-3-ethoxy-crotonate with a yield of 69% of theory. B.p. 170°-175°C at 0.3 mm Hg; m.p. 52°-53°C (from methanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:15]
Reactant: CCNCC
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])n1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc(C)nc([N+](=O)[O-])c1

Procedure:
To a mixture of 1.0 g. of 6-methyl-2-nitroisonicotinic acid, 20 ml. of chloroform and 3 ml. of diethylamine was added 7.0 g. of phosphorus pentoxide with stirring. The resulting mixture was refluxed for 1 hour. After cooling, the chloroform layer was separated and poured into 20 ml. of water. The resulting mixture was neutralized with sodium hydrogencarbonate and the chloroform layer was separated, dried over anhydrous sodium sulfate and the chloroform was distilled off in vacuo. The residual oil was gradually crystallized and then recrystallized from ethyl acetate-n-hexane to give 0.6 g. of the desired product.