Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:21])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(C(=O)Cl)cc2)cc1

Procedure:
A solution of 2.0 g of 4-(4-methylphenoxy)benzoic acid in 30 ml of methylene chloride is added 1.67 g of oxalyl chloride and the mixture refluxed for 30 minutes with stirring under nitrogen. The reaction mixture is evaporated in vacuo to a residue which is evaporated with carbon tetrachloride(2×30 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C=CC(=O)OC(C)(C)C)c[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CCC(=O)OC(C)(C)C)c[nH]1
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of methyl 4-(3-tert-butoxy-3-oxoprop-1-enyl)-1H-pyrrole-2-carboxylate (2.0 g, 7.96 mmol) in EtOAc (20 mL) under nitrogen was added 10% Pd/C. The flask was evacuated and refilled with hydrogen three times. The reaction mixture was stirred for 2 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to give methyl 4-(3-tert-butoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate as a white solid (2.02 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H), 2.48 (t, J=7.59 Hz, 2H), 2.77 (t, J=7.54 Hz, 2H), 3.84 (s, 3H), 6.77 (dd, J=2.37, 1.93 Hz, 2H), 930 (br s, 1H); LCMS-MS (ESI+) 198.2 (M-isobutylene).
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[C:5]1=[O:29])=C.Cl>C(O)C>[C:23]1([CH2:22][N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:4][C:5]3=[O:29])[CH2:17][CH2:18]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 70 parts of 1,3-dihydro-1-(1-methylethenyl)-3-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one in 240 parts of ethanol are added 55 parts of a hydrochloric acid solution 6 N. The whole is stirred for 2 hours at 40°-50° C. The reaction mixture is evaporated and the residue is taken up in a diluted ammonium hydroxide solution. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.28 mmol) and isobutyraldehyde (0.14 g, 1.92 mmol) in dichloroethane was added sodium triacetoxy borohydride (0.81 g, 3.85 mmol) and catalytic acetic acid. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 0.80 (6H, 2×d), 1.45 (9H, s), 1.60–1.90 (2H, m), 2.20 (2H, d), 3.00–3.70 (7H, m), 7.20 (4H,s). ESI-MS m/z: 367 (M+1), UV retention time: 1.89 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2[N:19]=[CH:20][CH:21]=[C:22]([C:23]#[N:24])[C:17]=2[CH:16]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:25][C:18]2[N:19]=[CH:20][CH:21]=[C:22]([C:23]#[N:24])[C:17]=2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(C#N)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(-c3cc4c(C#N)ccnc4[nH]3)cn(C)c2cc1OC
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A suspension of 0.14 g of 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile in 1.3 ml of a 5 N aqueous potassium hydroxide solution and 5 ml of methanol is brought to a temperature in the region of 60° C. for approximately 30 minutes. After returning to around 20° C., the insoluble material is filter-dried, and washed with water until a neutral pH is obtained. The insoluble material is purified by flash chromatography on a silica column [eluent: dichloromethane/methanol (98/2 by volume)]. 0.05 g of 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:13])[C:7](=[O:21])[CH:6]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (154 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (424 mg, 0.96 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 41%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75-1.32 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.51-1.84 (m, 7H) 3.89 (s, 2H) 4.24 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.91 (dd, J=10.7, 5.0 Hz, 1H) 4.96 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.36-7.53 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.81 (s, 1H). HR-ES-MS m/z calculated for C26H32ClFN4O4 [M+H]+ 519.2169, observed 519.2169.
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClCC1C=CC(CCl)=CC=1.[OH-].[Na+].O>C1(C)C=CC=CC=1>[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: COC(=O)c1ccccc1O
Agent: ClCc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a reactor equipped with a thermometer and a stirrer, 913 parts of methyl salicylate were charged, followed by heating to 100°-110° C. At the same temperature, 525 parts of α,α'-dichloro-p-xylene were charged in portions over 5 hours. The resulting mixture was subjected to aging at 150° C. for 2 hours. The pressure of the reactor was reduced to 10 mmHg by a pump and unreacted methyl salicylate was separated for reuse at 150°-180° C. After allowed to cool down to 100° C., 350 ml of toluene were added to the residue, whereby a toluene solution of a salicylic acid ester resin was obtained. In a reactor equipped with a thermometer and a stirrer, 160 parts of caustic soda and 907 parts of water were charged, followed by the dropwise addition of the above-obtained toluene solution at 85°-90° C. over 4 hours. The temperature was raised to 100° C. so that the toluene was distilled off. After removal of insoluble matter, the residue was neutralized with 2,250 parts of an 8% aqueous solution of hydrochloric acid. The solid so precipitated was collected by filtration, washed with water and dried, whereby a salicylic acid resin was obtained in a yield of 705 parts. In a reactor equipped with a thermometer and a stirrer, 100 parts of the salicylic acid resin obtained above [composition (area %) according to a GPC analysis: 51.1% l=0, 22.3% l=1, 20.3% l=2, 4.3% l≥3, 1.0% others; number-average molecular weight: 543], 33.5 parts of benzyl chloride, 400 parts of 1,1,2-trichloroethane and 0.4 part of zinc chloride were charged, followed by reaction at 110° C. for 3 hours. After completion of the reaction, 1,000 parts of water were added and the 1,1,2-trichloroethane was azeotropically distilled off. The solid so precipitated was collected by filtration and dried, whereby 121 parts of an aralkylated salicylic acid resin were obtained. The resin was found to have a number-average molecular weight of 641 and a carboxylic acid equivalent of 251 g/eq.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH:17]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:3]2[CH:4]=[CH:5][N:1]=[C:2]2[CH:6]([CH2:15][C:16]2[CH:24]=[C:23]([CH3:25])[C:22]3[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[N:21]=3)[CH:17]=2)[CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(CC(CC(=O)OC(C)(C)C)c2nccn2Cc2ccc(C(C)(C)C)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-(1H-imidazol-2-yl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoate (0.16 mmol), 4-tert-butylbenzyl bromide (1.0 equiv), and potassium carbonate (1.0 equiv) in dimethylformamide (2 mL) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3×5 mL). The ethyl acetate layer was dried, filtered and concentrated in vacuo. The product was obtained by flash chromatography using 0% to 50% ethyl acetate/hexane (65%). 1H-NMR (400 MHz, CDCl3) δ 7.93 (1H, s), 7.23 (2H, m), 7.03 (2H, m), 6.82 (2H, m), 6.63 (1H, s), 6.49 (1H,s), 5.68 (2H, s), 4.82 (2H, d, J=4.0 Hz), 3.60 (2H, t, 8.0 Hz), 3.41 (1H, m), 2.86 (2H, d, J=8.0 Hz), 2.79 (1H, dd, J1=8.0 Hz, J2=16 Hz), 2.61 (1H, dd, J1=8.0 Hz, J2=16 Hz), 2.49 (3H, s), 1.31 (9H, s), 1.25 (9H, s), 0.91 (2H, t, J=8.0 Hz), −0.06 (9H,s). MS(ESI)[M+H]+=617.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([CH3:25])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccnc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C)cc(C)c2)cnc1-c1cccnc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[O:6]>C1COCC1>[CH3:1][N:2]([CH3:3])[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 30 ml of a 40% dimethylamine solution in 200 ml of THF are initially introduced. 20 g of methyl 4-chlorocarbonylbenzoate are dissolved in 300 ml of THF and added dropwise, and the mixture is stirred at room temperature for a further 2 hours. The solvent is removed, and the mixture is subjected to conventional work-up, giving 19.2 g of methyl 4-(N,N-dimethylaminocarbonyl)benzoate (“BB”), m.p. 107°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCN(C(C)C)C(C)C.[Cl-].[CH:28]1([O:34][C:35]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([O:34][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:36])[N:38]=3)[CH2:47][CH2:46]2)=[O:15])[N:4]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][CH3:22].[C:23](=[O:25])=[O:24]>C1COCC1.CCOCC>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]([F:20])[C:15]=1[O:21][CH3:22]
Reactant: O=C=O
Reactant: COc1c(F)cccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (17.0 mL, 42.5 mmol) was added dropwise to the solution of NH(i-Pr)2 (4.50 g, 44.5 mmol) in 70 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −70° C. again. The solution of 1-bromo-3-fluoro-2-methoxybenzene (8.30 g, 40.5 mmol, in 30 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 1 hour then poured into fresh dry ice and stirred overnight. The mixture was diluted with 1 L of ether and washed with water twice. The combined water layer was washed with ether then acidified to pH=2 with hydrochloric acid and extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-bromo-2-fluoro-3-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 45.6 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and piperidine (0.018 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (30 mg, 0.073 mmol, yield 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[O:13]1[CH2:16][C:15](=[O:17])[CH2:14]1>C1COCC1.[Li]CCCC.[NH4+].[Cl-]>[Br:12][C:4]1[CH:3]=[C:2]([C:15]2([OH:17])[CH2:16][O:13][CH2:14]2)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: O=C1COC1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)cc(C2(O)COC2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,3-dibromo-5-(tert-butyl)benzene (316 mg, 1.05 mmol) in dry THF (15 mL), n-BuLi (1 mL, 2.5M) was added dropwise under N2 at −78° C. The mixture was stirred at this temperature for 1 h. Then oxetan-3-one (91 mg, 1.27 mmol) was added and the mixture was stirred at rt overnight, diluted with aq. NH4Cl (20 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the product P29a (120 mg, 40%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:16]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH2:31]([O:30][C:17]1[CH:16]=[C:15]([S:14][C:10]2[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=2)[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:18]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)COc1cc(C)c(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)c(C)cc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2,5-dimethylphenoxy}-acetic acid ethyl ester (350 mg; 0.68 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 250 mg; 76%. HPLC-MS: m/z: 484.6 (M+H)+; Rt: 1.87 min.
Reaction SMILES: C1(C[O:8][C:9]2[CH:34]=[CH:33][C:12]3[CH:13]=[C:14]([CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]([C:23]45[CH2:32][CH:27]6[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]6)[CH2:24]4)[CH2:30]5)=[O:22])[O:15][C:11]=3[CH:10]=2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:34]=[CH:33][C:12]2[CH:13]=[C:14]([CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]([C:23]34[CH2:24][CH:25]5[CH2:31][CH:29]([CH2:28][CH:27]([CH2:26]5)[CH2:32]3)[CH2:30]4)=[O:22])[O:15][C:11]=2[CH:10]=1
Reactant: O=C(NCCNCc1cc2ccc(OCc3ccccc3)cc2o1)C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CCO
Product: O=C(NCCNCc1cc2ccc(O)cc2o1)C12CC3CC(CC(C3)C1)C2
Yield: 43.4 %

Procedure:
N-[2-[[(6-Phenylmethoxy-2-benzofuranyl)methyl]amino]ethyl]tricyclo[3.3.1.13,7 ]decane-1-carboxamide (4.74 g, 10 mmole) was dissolved in 100 ml of ethanol and 1.0 g of 10% palladium on carbon was added. The mixture was hydrogenated at 50 psi on a Parr apparatus overnight. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using 5% methanol/chloroform as eluant and the crude product thus obtained was crystallized from 15 ml of ethanol with the addition of 8 ml of 4N HCl/isopropanol and 100 ml of diethyl ether to give 1.6 g of the title compound as a white solid, monohydrochloride, quarter hydrate, m.p. 136°-139° C.