Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1.C(OCC)C>[C:21]([N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the solution of 1.9 g of 2-methyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 50 ml of benzene, 2.14 g of ethyl chloroformate are added and the mixture is refluxed for 3 days. It is diluted with diethyl ether, washed with N hydrochloric acid and with both saturated aqueous sodium chloride and sodium bicarbonate, dried and evaporated, to yield the 2-carbethoxy-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine showing in the NMR-spectrum peaks at 8.55(t), 6.60(m), 5.65(q) and 3.90(d) ppm, and in the mass-spectrum a molecular ion of 311.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([O-])=O.[S]>O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [S]
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 1,3-dinitro-4-tert-butylbenzene (10.0 g) in H2O (56 mL) was heated to reflux. A mixture of Na2S (21.42 g) and sulfur (2.85 g) in H2O (34 mL) was added over 1 h via an addition funnel. The reaction maintained at reflux for 1.5 h then cooled to RT and extracted with EtOAc. The organic extracts were combined and washed with H2O, brine, dried over MgSO4 and concentrated in vacuo to afford 4-tert-butyl-3-nitro-phenylamine which was used as is without further purification.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[F:12][C:13]([F:17])([F:16])[CH:14]=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:17])([F:16])[CH:14]([OH:15])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: O=CC(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC#CC(O)C(F)(F)F
Yield: 72 %

Procedure:
1-hexene (6.2 g, 76 mmol) and n-butyllithium (52 ml, 1.5 M in hexane) and trifluoroacetaldehyde (7 g, 71 mmol) were reacted 3 hours under the action of ultrasonic irradiation (as generated by a commercially available ultrasonic cleaner 220H manufactured by Branson Cleaning Equipment Company). The reaction mixture was poured into aqueous 2% HCl solution and diethyl ether was used for extraction of the oily layer. The extracts were then distilled to give 1,1,1-trifluoro-3-octyne-2-ol (b.p.: 83-85° C./21 mmHg) in a yield of 72%. This hydroxyalkyne gave the following analytical data:
Reaction SMILES: CO[CH:3]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([OH:17])[C:14]=2[CH3:16])[O:9][C:5]2([CH2:8][CH2:7][CH2:6]2)[CH:4]1[CH3:20]>CO.Cl>[CH3:20][C:4]1[C:5]2([CH2:8][CH2:7][CH2:6]2)[O:9][C:10]2[C:15](=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH:3]=1
Reactant: COC1c2c(C)c(O)c(C)c(C)c2OC2(CCC2)C1C
Agent: Cl
Solvent: CO
Product: CC1=Cc2c(C)c(O)c(C)c(C)c2OC12CCC2

Procedure:
To a stirred solution of 4-methoxy-3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol. (50 mg) in 10 mL of MeOH was added 5 drops of conc. HCl. The reaction mixture was concentrated, and the residue was purified by flash chromatography eluted with 40% ethyl acetate in hexane to give 7.6 mg of the desired product 3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:16]([C:27]([CH3:29])=[CH2:28])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.CO>[Pd].C(O)C>[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]([CH:27]([CH3:29])[CH3:28])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=C(C)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
10% Palladium on carbon (350 mg) was added to a suspension of methyl 2,4-bis-benzyloxy-5-isopropenylbenzoate [prepared as per WO 2006/109085 A1] (3.88 g, 10.0 mmol) in ethanol (30 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Methanol (20 ml) was added to aid dissolution and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the catalyst was rinsed with methanol (3×20 ml) and the combined filtrates were evaporated in vacuo to afford methyl 2,4-dihydroxy-5-isopropylbenzoate (2.10 g, 100%) as a colourless solid. 1H NMR (DMSO-d6) 10.54 (1H, s), 10.44 (1H, br s), 7.52 (1H, s), 6.37 (1H, s), 3.85 (3H, s), 3.08 (1H, m), 1.13 (6H, d). MS: [M+H]+ 211.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (29 mg, 0.055 mmol), β-alanine (487 mg, 5.5 mmol) and NaOMe solution (8.8 mL, 4.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 589.24 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:29]([O:31]CC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:29]([OH:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxide monohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid (0.05 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94 (m, 2H); 1.78 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:39])[CH:9]([NH:23][C:24]([C:26]1([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:13][CH:12]=1)[CH3:6].CCN(CC)CC>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:39])[CH:9]([NH:23][C:24]([C:26]1([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:25])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:1](=[O:3])[CH3:2])[CH2:18]2)=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)C(Cc1ccc(C2CCCNC2)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(C2CCCN(C(C)=O)C2)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (50 mL, 0.70 mmol) is added slowly to a solution of 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-[4-(piperidin-3-yl)-phenyl]-propionic acid ethyl ester (277 mg, 0.57 mmol) and 11 mL (0.79 mmol) of Et3N in 2 mL of CH2Cl2. The reaction mixture is stirred at 0° C. for 2 h, and then partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The organic phase is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (EtOAc) to furnish 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-[4-(1-acetyl-piperidin-3-yl)-phenyl]-propionic acid ethyl ester; 1H NMR (300 MHz, CDCl3) δ7.00-7.15 (m, 4 H), 4.80-4.90 (m, 1 H), 4.70 (br t, 2 H), 4.15 (q, 2 H), 3.00-3.15 (m, 3 H), 2.45-2.70 (m, 2 H), 2.12, 2.08 (s each, 3 H) 1.95-2.40 (m, 6 H), 1.50-1.95 (m, 8 H), 1.40 (s, 9 H), 1.20 (t, 3 H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:20]2[CH2:19][CH:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.C(Cl)Cl>[NH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH2:19][CH:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:16]2
Reactant: CS(=O)(=O)NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCc2cccc(N)c2C1
Yield: 71.8 %

Procedure:
The title compound was prepared using the procedure as described in Example 20E substituting the product of Example 23A (280 mg, 0.748 mmol) for the product Example 20D. Flash chromatography (5% to 10% CH3OH/CH2Cl2) gave 129 mg (72%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.20 (d, J=7.5 Hz, 1H), 6.79 (t, J=7.8 Hz, 1H), 6.43 (m, 1H), 6.30 (m, 1H), 4.74 (s, 2H), 3.55 (m, 1H), 2.99 (s, 3H), 2.75 (m, 3H), 2.22 (m, 1H), 1.95 (m, 1H), 1.58 (m, 1H); MS (DCI+) m/z 241 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH3:22])[C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])C.[OH-].[K+]>CO.O>[CH3:22][N:6]([C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)CN(C)C(=O)c1ccccc1-c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1ccccc1C(=O)N(C)CC(=O)O
Yield: 48.9 %

Procedure:
N-methyl-N-[2-(methylphenyl)benzoyl]glycine ethyl ester (4.5 g, 14.45 mmol) and KOH (2.43 g, 43.4 mmol) in MeOH/H2O (200 mL/50 mL) were heated at reflux for 45 minutes. The solvent was removed and the residue dissolved in H2O. The aqueous solution was washed with Et2O and acidified with HCl (10%). The acidified aqueous layer was extracted with EtOAc, the EtOAc extract was washed with brine (2×), dried over (MgSO4) and evaporated. There was obtained N-methyl-N-[2-(methylphenyl)benzoyl]glycine (2.0 g); LRMS (M+H)+=284.1, (M+NH4)+=301.1
Reaction SMILES: [NH:1](/[CH:8]=[C:9](/[C:15]1C=CC=CC=1)\C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1([O:39]C2C=CC=CC=2)C=CC=CC=1>>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:9][C:8]1=[O:39]
Reactant: CCOC(=O)/C(=C\Nc1ccccc1)c1ccccc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1ccc2ccccc2[nH]1
Temperature: 250 °C
Reaction time: 0.17 h
Yield: 144 %

Procedure:
Compound 1 (1.10 g, 4.11 mmol) is added portionwise and rapidly with stirring, to a solution of biphenyl (1.70 g) and diphenyl ether (13.10 g) heated to 250° C. After 10 minutes, the heating is stopped. During the cooling, the quinolone 2 precipitates out in the reaction medium. This product is collected by filtration and then rinsed with petroleum ether. After drying, 859 mg (94%) of compound 2 are obtained in the form of white crystals.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][C:33]1[S:37][C:36]([CH:38]=[O:39])=[N:35][CH:34]=1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:38]([C:36]3[S:37][C:33]([CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[CH:34][N:35]=3)=[O:39])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(COC2CCCCO2)s1
Yield: 79.9 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.84 g), 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (1.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (0.14 g), triethylamine (0.32 mL), tetrahydrofuran (5 mL) and ethanol (10 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (2.43 g, yield 80%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 576 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Li+]>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1coc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 24 using {6-[2-(4-trifluoromethyl-benzyloxy)-benzyloxy]-benzofuran-3-yl}-acetic acid methyl ester and lithium hydroxide. mp 126–127° C.; IR (thin film) cm−1: 1716, 1624, 1494, 1320, 1231, 1109; 400 MHz 1H NMR (DMSO-d6) 12.39 (br s, 1H), 7.71 (s, 1H), 7.61–7.67 (m, 4H), 7.39–7.42 (m, 2H), 7.24–7.29 (m, 1H), 7.20 (d, 1H, J=2.0 Hz), 7.06 (d, 1H, J=7.6 Hz), 6.90–6.95 (m, 2H), 5.27 (s, 2H), 5.15 (s, 2H), 3.59 (s, 2H); MS m/z 455 (M−1). Anal. Calc'd for C25H19F3O5: C, 65.79; H, 4.20; found: C, 65.75; H, 4.02.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([CH3:23])([N:6]([CH2:20][CH2:21][CH3:22])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:23][C:4]([N:6]([CH2:20][CH2:21][CH3:22])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])([CH3:5])[C:3]([OH:24])=[O:2]
Reactant: CCCN(C(C)(C)C(=O)OC)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C(C)(C)C(=O)O)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
Methyl-2-methyl-2-(N-propyl-2-(trifluoromethyl)phenylsulfonamido)propanoate (340 mg, 0.93 mmol) was charged, and dissolved through addition of THF (4 ml), and methanol (4 ml). LiOH.H2O dissolved in H2O (4 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-methyl-2-(N-propyl-2-(trifluoromethyl)phenylsulfonamido)propionic acid (320 mg, 0.91 mmol, 98%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[C:50]1([CH3:53])[CH:51]=[CH:52][C:47]([CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:48][CH:49]=1
Reactant: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 43.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[3-(4-methylphenyl)propyl]-1-piperidine-carboxamide (0.185 g, 0.23 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.058 g, 0.1 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH2:21][CH2:22][NH2:23])[CH3:20].C(O)(=O)C.Cl>O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: CN(C)CCN
Reactant: O=C(CC1CSCCC1=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCn1c(-c2ccc(Cl)cc2)cc2c1CCSC2

Procedure:
A solution of 5.0 g (0.019 mole) of 3-(4-chlorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 7.14 g of dimethylaminoethylamine and 15 ml. of acetic acid is heated under reflux under nitrogen for 24 hours, diluted with water, acidified with hydrochloric acid, extracted with ether, neutralized with sodium hydroxide, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated. The residue is recrystallized from ethanol to give off-white crystals of 1-(2-dimethylaminoethyl)-2(4-chlorophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole, m.p. 91.5° to 92.5°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].[C:13](Cl)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:13])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)c(OC)c1
Reaction time: 36 h
Yield: 98 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (6.0 g.) in methanol (120 ml.) was treated with acetyl chloride (6 ml.) and stirred for 36 hours. The solution was evaporated. The residue was dissolved in methanol (100 ml.) and the solution evaporated. This procedure was repeated to give methyl 3-methoxy-4-methylbenzoate (6.34 g., 98%) as a colorless oil; NMR: 2.2(s,3H, CH3), 3.9(2s,6H, 2×OCH3), 7.1(d,1H), 7.5 (m,2H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.ClCCl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:28])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24]>O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH2:10][O:11][CH3:12])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: COCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(F)cc1C(=O)OC

Procedure:
N,N-diisopropylethylamine (15.4 ml) and chloromethyl methyl ether (4.91 ml) were added to a dichloromethane (100 ml) solution of methyl 5-fluoro-2-hydroxybenzoate (10 g), while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain the title compound (12.4 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,3,3-trimethyl-butanamide, (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 96%, 360.2272 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[CH:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCNCC
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=CN(CC)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 14.6 g of diethylamine (0.2 m) in 100 ml of ethyl alcohol was added dropwise to a stirred solution of 19.6 g of ethyl propiolate (0.2 m) in 150 ml ethyl alcohol at room temperature. The exothermic reaction mixture was stirred at room temperature for 31/2 hours. The solvent was removed and the residue distilled through a short Vigreux column (boiling point 88° C./6 mm) to give 29.38 g (87 percent) of ethyl 3-(diethylamino)acrylate.
Reaction SMILES: C([N:4]([CH:23]1[CH2:25][CH2:24]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([F:22])=[CH:7][CH:6]=1)(=O)C.Cl>CO>[CH:23]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A solution of 21.9 g (63 mmole) of 4-[6-(acetylcyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 170 ml of 15% hydrochloric acid and 235 ml of methanol was refluxed for one hour and allowed to stir at room temperature for 18 hours. The methanol was removed in vacuo and the aqueous acid was made basic with 1.0 N sodium hydroxide to pH 10.5. The mixture was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 17.6 g of the title compound, mp 68°-70° C.