Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1>C(N)C(C)C>[CH3:14][N:13]([CH3:15])[C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][CH:16]([CH3:17])[CH3:21])[N:7]=2)=[C:9]([C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 35 °C
Yield: 66 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35° C. overnight. The solvent was removed under reduce pressure and the residue taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated to afforded the title compound (36 mg, 0.066 mmol, 33.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 7.74 (d, J=5.3 Hz, 1H), 7.67 (ddd, J=14.6, 8.4, 6.1 Hz, 1H), 7.28-7.35 (m, 1H), 7.18-7.28 (m, 4H), 7.12 (d, J=7.7 Hz, 1H), 7.07 (t, J=5.5 Hz, 1H), 5.68 (s, 1H), 3.06 (s, 6H), 3.02 (t, J=6.3 Hz, 2H), 1.82 (dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.8 Hz, 6H). MS (ESI): 545 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[C:9]([CH3:14])([C:11](O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:12][CH2:11][C:9]([N:8]([CH3:15])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:10])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(C)(C)CO
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-N,2-dimethylalanine in THF (0.17 M) was treated at RT with BH3-DMS complex in THF (10 eq., 2M) and the mixture was stirred at 45° C. for 8 h. The reaction was carefully quenched with H2O and the pH adjusted to 9 with 2M aq. Na2CO3. The mixture was then extracted with EtOAc and washed with brine. After drying over Na2SO4, the crude material was purified by FC (10-50% EtOAc in PE) to afford the product. (ES+) m/z 204 (M+H)+.
Reaction SMILES: Cl.C([O:4][C:5]([CH:7]([NH:20][C@H:21]([C:23]([N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[CH3:22])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:6])C.[OH-].[Na+]>CO>[C:5]([CH:7]([NH:20][C@H:21]([C:23]([N:25]([CH:30]1[CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38]1)[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[CH3:22])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)C(CCc1ccc(OC)c(OC)c1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(N[C@@H](C)C(=O)N(CC(=O)O)C2Cc3ccccc3C2)C(=O)O)cc1OC
Reaction time: 4 h
Yield: 6.2 %

Procedure:
N-[1-Ethoxycarbonyl-3-(3,4-dimethoxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride (1.1 g) is dissolved in 30 ml of methanol. To the solution is added 5 ml of 2N aqueous sodium hydroxide. After stirring for 4 hours, the reaction mixture is concentrated, and 30 ml of water is added. On adjusting the pH to about 5 with diluted hydrochloric acid, an oily substance separates, which is extracted with ethyl acetate. The extract is washed with water, dried and concentrated. Methanol (4 ml) is added to the residue, and the mixture is allowed to stand. There is obtained 60 mg of N-[1-carboxy-3-(3,4-dimethoxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine as crystals melting at 160°-165° C. with decomposition.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)cn1
Temperature: 85 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg) and potassium carbonate (4.94 mg) in DMF (15 mL) was added (3R)-1-benzyl-3-piperidinamine dihydrochloride (668 mg) under nitrogen at ambient temperature and the mixture was stirred at 85° C. for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=97-3) to give ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-piperidinyl]amino}2-pyrazinyl)acrylate (125 mg) as an oil.
Reaction SMILES: [C:1]([CH:3]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)C(OC(C)(C)C)=O)#[N:2].C1(C)C=CC=CC=1.CS(O)(=O)=O.O>C(OCC)(=O)C>[C:1]([CH2:3][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=1)#[N:2]
Reactant: COc1cc(OC)nc(C(C#N)C(=O)OC(C)(C)C)n1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(CC#N)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a 50-ml eggplant-shaped flask provided with a magnetic stirrer and a reflux condenser were added 2.79 g (10 mmol) of tert-butyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate, 10 ml of toluene and then 0.38 g (4 mmol) of methanesulfonic acid. The system inside was purged with nitrogen and stirred for 2 hours at 100° C. After the completion of a reaction, the system was cooled to room temperature; 30 ml water and 30 ml of ethyl acetate were added for phase separation; and re-extraction was conducted using 20 ml of ethyl acetate. Two ethyl acetate phases were combined, washed with saturated sodium chloride water, and dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure to obtain 2-cyanomethyl-4,6-dimethoxypyrimidine as white crystal of 1.45 g. HPLC purity: 95.7% Yield: 81%
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2]>C(OCC)(=O)C>[C:1]([CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Solvent: CCOC(C)=O
Product: N#CC(Cc1ccc(O)cc1)C(=O)O
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a 250 mL par shaker flask was charged 2-cyano-3-(4-hydroxy-phenyl)-acrylic acid (0.5 g, 2.6 mmol) in ethyl acetate (10 mL) and the solution was purged with nitrogen for 10 minutes. Then 10% palladium on carbon (0.07 g) was added under nitrogen atmosphere. After addition, the mixture was hydrogenated at 30 psi for 3 days. After completion of the reaction (monitored by TLC), the RM was filtered through celite bed and the residue was washed thoroughly with methanol (15 mL). After filtration, the filtrate was concentrated to distill off the solvent and dried under vacuum. The product was obtained as yellow liquid 0.5 g, yield: 98.9%): MS (ESI, 120 eV): m/z=192.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 7.07-7.10 (d, 2H), 6.70-6.72 (d, 2H), 4.17-4.21 (t, 1H), 2.92-3.09 (m, 2H).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (879 mg) was dissolved in DMF (3 mL), tert-butyl bromoacetate (421 mg) was added, and potassium carbonate (299 mg) was further added. The reaction solution was stirred at room temperature overnight. After water was carefully added, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further, recrystallization from methanol afforded 846 mg of white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Reactant: C1COCCN1
Product: c1ccc(-c2cc(OCCN3CCOCC3)no2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Morpholine (871 mg) was added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg), and the mixture was stirred at 100° C. for one hour. After ice-cold water (20 ml) was added to the reaction mixture and the resulting mixture was extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (250 mg, 91%) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].[NH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1>CC#N>[C:4]([CH2:3][CH2:2][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][CH2:11]1)#[N:5]
Reactant: N#CCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Temperature: 60 °C
Yield: 31.6 %

Procedure:
3-Bromopropionitril (0.74 g, 5.49 mmol) was added to a solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 4.99 mmol) and TEA (0.56 g, 5.49 mmol) in MeCN (15 mL), and the mixture was heated at 60° C. for 5 h and then evaporated. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 40:60 and then 15:85-10:90 mixture of heptane and EtOAc as eluant, to give the title compound (0.40 g, 32%). 1H NMR (500 MHz, CDCl3): δ 4.44 (br s, 1H), 3.54-3.42 (br m, 1H), 2.88-2.79 (m 2H), 2.69 (t, 2H), 2.51 (t 2H), 2.24-2.16 (m, 2H), 1.99-1.92 (m 2H), 1.47 (s 9H), 1.49-1.41 (m 2H); 13C NMR (125 MHz, CDCl3): δ 155.4, 119.0, 53.6, 52.2, 47.7, 32.7, 28.6, 16.4.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12

Procedure:
0.204 g (4.9 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.6 g (1.62 mmol) of 3-methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.3 g of 3-carboxy-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 356 (M+•), m/e 311.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][N:25]([CH:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)[CH2:30][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)nn1C(C)(C)C

Procedure:
107 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (65 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(OCc2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(OCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 64 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide was prepared, as described in Example 10, by reacting 3-chlorosulfonyl-2-[(4-methylphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, resulting in a 64% yield, m.p. 128-130° C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10][C:11](=S)[S:12]C>C(#N)C.C(OCC)C>[CH3:9][S:10][C:11]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:8])=[S:12]
Reactant: NNc1ccccc1
Reactant: CSC(=S)SC
Solvent: CC#N
Solvent: CCOCC
Product: CSC(=S)N(N)c1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of phenylhydrazine (30 mmol, 1 equiv) in dry acetonitrile (20 mL) was added trithiocarbonic acid dimethyl ester (30 mmol, 1 equiv) slowly at ice bath temperature. The mixture was stirred for 18 hours and diluted with diethylether (30 mL). The resulting white solid was filtered and was washed with ether and dried under nitrogen to afford title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].N1C=CC=CC=1.C1(C)C=CC=CC=1.[F:27][C:28]1[CH:36]=[C:35]([CH2:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[F:27][C:28]1[CH:36]=[C:35]([CH2:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:29]=1[C:30]([O:13][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([F:10])([F:11])[F:9])=[C:6]([F:12])[CH:5]=1)=[O:31]
Reactant: CCCc1ccc(C(=O)Cl)c(F)c1
Reactant: Oc1cc(F)c(C(F)(F)F)c(F)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCc1ccc(C(=O)Oc2cc(F)c(C(F)(F)F)c(F)c2)c(F)c1
Yield: 90.5 %

Procedure:
Then, 1.2 g (6.1 mmol) of 3,5-difluoro-4-trifluoromethyl-phenol, 0.7 ml of pyridine, and 2 ml of toluene were mixed. To this mixture was added dropwise 3 ml of toluene solution containing 6.1 mmol 2-fluoro-4-propylbenzoyl chloride at room temperature in 10 minutes. After the dropping was finished, they were reacted at 50° C. for 2 hours. After finishing of the reaction, 10 ml of water was added to the reaction product and then extracted with 30 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.0 g of a crude 3,5-difluoro-4-trifluormethylphenyl 2-fluoro-4-propylbenzoate. This product was recrystallized from a mixed solvent of heptane/ether (1/1) to obtain 1.1 g (yield: 50.2%) of the subject compound.
Reaction SMILES: [CH:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])=[CH:2][CH2:3][CH3:4]>CO.[Pt]>[CH2:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCC=CC(CC(=O)O)C(=O)O
Agent: [Pt]
Solvent: CO
Product: CCCCC(CC(=O)O)C(=O)O

Procedure:
40 g. of the butenylsuccinic acid is hydrogenated in methanol over a platinum catalyst to yield n-butylsuccinic acid, m.p. 82°-83° C. Ring closure to n-butyl-succinic anhydride is achieved by mixing it with 100 g. of acetic anhydride and distilling acetic acid as it is formed. The resulting crude product is directly sulfonated by the procedure of 7)b) using corresponding molar amounts of the n-butyl-succinic anhydride and SO3.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[CH2:41]([Li])CCC.CI>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH:25]([C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)[CH3:41])[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(C(=O)OC)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.200 g, 0.346 mmol) and tetrahydrofuran (2 mL). The solution was cooled to −78° C. and a 1.83 M solution of n-butyl lithium in hexanes (0.23 g, 0.41 mmol) was added. The reaction was stirred at −78° C. for 45 min, then methyl iodide (0.026 mL, 0.41 mmol) was added and the reaction was warmed to 0° C. and stirred for 90 min. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give crude product. Purification by silica gel chromatography using 20% ethyl acetate/hexanes, followed by 70% ether/hexanes as eluent afforded the desired methylated product. MS m/z 593 (M++H); 1H NMR (CDCl3) δ7.85 (bs, 1H), 7.8 (bs, 2H), 7.05 (bs, 1H), 6.5 (bs, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 1.65 (d, 1.5H, J=7Hz), 1.05 (d, 1.5H, J=7.0Hz).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][Cl:23])[CH:8]=[CH:9][C:2]1=2
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)CCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (2,3-dihydrobenzo[b]furan-5-yl)methanol (1.5 g, 10 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.85 mL, 10 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.6 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[C:1]([O:5][C:6](=[O:36])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:43]([C:42]2[S:41][C:40]3[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=3[C:38]=2[Cl:37])=[O:44])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[CH:28][CH:29]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1

Procedure:
The title compound was prepared from amine (264) (220 mg, 0.43 mmol) and 3-chlorobenzo[b]thiophene-2-carbonyl chloride (110 mg, 0.48 mmol) following Method D.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]1[CH:7]=[CH:6][S:5][N:4]=1.C([Li])CCC.[CH2:14]([Sn:18]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])Cl)[CH2:15][CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][CH:2]([F:8])[C:3]1[CH:7]=[C:6]([Sn:18]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH3:17])[S:5][N:4]=1
Reactant: FC(F)c1ccsn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)F)ns1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 3-(difluoromethyl)isothiazole (93 mg, 0.688 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.473 mL, 0.757 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.223 mL, 0.826 mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was subsequently allowed to warm to room temperature over a period of about one hour. Saturated aq NaHCO3 was added, and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, passed through a short pad of silica gel (eluting with EtOAc) and evaporated in vacuo to give the title compound, which was used without further purification.