Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([O:7][C:8](=[O:13])[O:9]CCC)[CH2:5][CH3:6]>>[CH3:1][N:2]([C:8]([O:7][CH2:4][CH2:5][CH3:6])=[O:9])[NH2:3].[CH3:1][NH:2][NH:3][C:8]([O:7][CH2:4][CH2:5][CH3:6])=[O:13]
Reactant: CCCOC(=O)OCCC
Reactant: CNN
Product: CCCOC(=O)N(C)N
Product: CCCOC(=O)NNC

Procedure:
Methylhydrazine (7.2 g, 1.16 mole) and di-n-propylcarbonate (5 g, 0.034 mole) were stirred at room temperature for 96 hours to yield 1-methyl-1-propoxycarbonyl hydrazine and 2-methyl-1-propoxycarbonyl hydrazine in approximately equal amounts. The reaction was concentrated in vacuo and fractionated (F1, 2.0 g, 72°-76° a/0.8 mm Hg; F2, 1.1 g, 76°-88° a/0.8 mm Hg; F3, 1.1 g, 88°-90° a/0.8 mm Hg). F1 was a mixture of 1-methyl-1-propoxycarbonyl hydrazine and 2-methyl-1-propoxycarbonyl hydrazine in 4 to 1 ratio. F2 was an equal mixture of 1-methyl-1-propoxycarbony hydrazine and 2-methyl-1-propoxycarbonyl hydrazine. F3 was mostly 2-methyl-1-propoxycarbonyl hydrazine. Thus the yield of 1-methyl-1-propoxycarbonyl hydrazine was ca. 46%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[C:48]2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[N:45]([CH2:58][CH3:59])[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[CH2:58]([N:45]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[C:48]=2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Method D, 0.340 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.272 g of 4-bromomethyl-1-ethyl-3-(2-trimethylsilanylethoxymethyl)-1,3-dihydrobenzimidazol-2-one are reacted. The title compound is obtained as a dark yellow resin. Rf=0.50 (1:1 EtOAc-heptane); Rt=6.67.
Reaction SMILES: [CH2:1]([Li])CCC.C[C:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C:8]=1[CH3:13]>CCCCC.CCCCCC>[CH3:1][C:8]1([CH3:13])[CH2:7][CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:1][C:8]1([CH3:13])[CH:7]=[CH:12][CH2:11][CH:10]=[CH:9]1
Reactant: [Li]CCCC
Reactant: CC1=C(C)CCC=C1
Solvent: CCCCC
Solvent: CCCCCC
Product: CC1(C)C=CC=CC1
Product: CC1(C)C=CCC=C1
Reaction time: 8 h

Procedure:
To 14.0 g (0.111 mol) of potassium t-amylate (KOC(CH3)2C2H5) in 200 mL of pentane was added 44.4 mL of 2.5M (0.111 mol) butyl lithium in hexane with formation of a small amount of brownish insoluble material. To this was added 12.0 (0.111 mol) of the dimethylcyclohexadiene isomeric mixture. A bright orange product resulted. After stirring overnight, the color became brownish orange. The product was filtered, washed several times with pentane, then dried under reduced pressure. The yield of orange powder was 11.8 g, 72.7 percent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH2:32][OH:33].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:32]1[O:33][C:26]2([CH2:27][CH2:28][CH:29]=[C:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:30][CH2:31]1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC3(C2)OCCO3)c(OCc2ccccc2)c1

Procedure:
A solution of 500 mg. of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-2-en-1-one, 7.8 g. of ethylene glycol, 375 mg. of hydroquinone and 50 mg. of p-toluenesulfonic acid monohydrate in 50 ml. of benzene is heated at reflux for 12 hours using a Dean-Stark condenser filled with 3A molcular sieves. The reaction is cooled, added to 500 ml. saturated sodium bicarbonate and the quenched mixture extracted with three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid is purified via column chromatography on 50 g. of silica gel eluted with 50% ether-petroleum ether to yield the title product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][CH:28]4[CH2:29][CH2:30][C:25]([F:32])([F:24])[CH2:26][CH2:27]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(F)(F)CC1
Temperature: 110 °C
Yield: 82.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.433 g, 1.28 mmol), 4,4-difluorocyclohexyl amine hydrochloride (0.242 g, 1.41 mmol), diisopropylethylamine (0.491 ml, 2.82 mmol) in propan-2-ol (10 ml) was heated at 110° C. in a microwave reactor for 20 min. The mixture was then cooled to 25° C. and was partitioned between water (50 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the resulting yellow solid by column chromatography on silica gel (gradient: 0 to 60% EtOAc in heptanes) afforded (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,4-di fluoro-cyclohexyl)-amine (0.46 g, 82%) as a yellow solid. LCMS (Method G, ESI): RT=1.21 min, m+H=437; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 7.17 (d, J=4.3 Hz, 1H), 4.39-4.26 (m, 1H), 2.29-1.98 (m, 6H), 1.83-1.68 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:21]O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:21][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as an orange oil. MS: 357.3 and 359.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29](/[CH:32]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\C1CCN(Cc3ccccc3)CC1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 1-benzylpiperidine-4-carbaldehyde 21 (123.4 mg, 0.607 mmol). p-Toluene sulphonic acid (PTSA) (230.9 mg, 1.214 mmol) was added to the reaction mixture, and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude material, which was purified through flash chromatography using 100-200 mesh silica gel. Eluting at 30% ethyl acetate in hexane gave yellow coloured solid (E)-2-((1-benzylpiperidin-4-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 22.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.CCOCC>C(O)(C)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]([CH3:28])=[C:13]2[S:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1[nH]c2ccc(Br)cc2c1SC1CCNCC1
Reaction time: 4 h

Procedure:
4-Bromophenylhydrazine hydrochloride (11.5 g) is solubilized in a solution of 1,1-dimethylethyl 4-[(2-oxopropyl)thio]piperidine-1-carboxylate (prepared in Example 10) in isopropanol (100 ml) under nitrogen. The solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. The solid obtained is taken up in the minimum amount of ether and recrystallized from xylene to give 5-bromo-2-methyl-3-(piperidin-4-ylthio) -1H-indole (9.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:20][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: O=C1Nc2cc(Br)ccc2Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of Example 2A (6.0 g, 15.6 mmol) and SnCl2.2H2O (10.54 g, 46.8 mmol) in 37% HCl (200 mL) and methanol (300 mL) was heated to reflux for 20 hours, cooled to room temperature, and filtered. The filter cake was washed with 1:1H2O/methanol and dried in a vacuum oven at 65° C. to provide 4.6 g (91%) of the desired product. MS (DCI) m/e 324 (M+H)+, 341 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.18 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.12-7.16 (m, 2H), 7.05 (d, J=2 Hz, 1H), 6.95 (dd, J=8.4, 2 Hz, 1H), 6.91 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+:14].[OH2:15]>>[CH3:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:1]([O-:10])=[O:15])[CH:7]=1.[K+:14]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C)ncn1
Agent: [K+]
Product: Cc1cc(C(=O)[O-])ncn1

Procedure:
1.77 g (16.37 mmol) of 4,6-dimethylpyrimidine was dissolved in 20 ml of water and stirred. 5.69 g (36.01 mmol) of potassium permanganate solution in 60 ml of water was added thereto and heated at temperature of 70° C. to 75° C. After the color of potassium permanganate disappeared, the mixture was filtered with celite and extracted with dichloromethane to collect the remaining starting material. The aqueous layer was removed under reduced pressure to obtain potassium 6-methylpyrimidine-4-carboxylate (Intermediate compound 57). 3.45 g of the intermediate compound 57 was mixed with 250 ml of methanol and 1.7 ml of conc. sulfuric acid, and the mixture was refluxed under heating for 6 hours. The solvent in the mixture was then removed under reduced pressure. The residue was diluted with ethyl acetate and water, and neutralized by sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated product was purified by the column chromatography (ethylacetate:hexane=1:1) to obtain 6-methylpyrimidine-4-carboxylic acid methyl ester (Intermediate compound 58, 930 mg, Yield of the first and second steps: 37%). The intermediate compound 58 was then subjected to the fifth step in the reaction of Example 1 to obtain 6-methylpyrimine-4-carboxylic acid (Intermediate compound 59, Yield of the third step: 62%). Next, the intermediate compound 59 and (−)-thiodeacetyl colchicine were subjected to the sixth step in the reaction of Example 1 to obtain the title compound 21 (Yield of the fourth step: 37%).
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([O:12][CH3:13])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COc1c(F)ccc2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(F)ccc2ccc(Cl)nc12
Yield: 90.5 %

Procedure:
A mixture of 7-fluoro-8-methoxy-2-quinolinol (4a) (2.26 g, 11.7 mmol) and POCl3 (5.5 mL, 60 mmol) was refluxed for 1.5 hours. The contents were concentrated and neutralized with NaHCO3 and the mixture heated with water and AcOEt. The solution was filtered to remove undissolved impurities, followed by extraction. The organic layer was washed with saturated NaCl and dried with MgSO4. The product was recrystallized from ***CHCl3-hexanes, which yielded white crystals (2.24 g, 90% yield): mp 85-86° C.; 1H NMR (400 MHz, CDCl3) 8.06 (d, J=8.8 Hz, 1H) 7.48 (dd, J=8.8, 5.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.35 (dd, J=9.2, 2.4 Hz, 1H), 4.23 (d, J=2.4 Hz, 3H). 19F NMR (376 MHz, CHCl3) −127.35 (dd, J=10.9, 2.6 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([OH:24])[C:18]([CH3:26])([CH3:25])[CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:27]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH2:28]>O1CCCC1>[C:7]([O:15][CH:16]1[CH2:17][C:18]([CH3:26])([CH3:25])[N:19]([O:24][CH2:28][CH2:27][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:20]([CH3:22])([CH3:23])[CH2:21]1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: C=CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)OCC
Temperature: 25 °C

Procedure:
To a suspension of 0.12 gram of potassium tert-butoxide in 25 ml of dry tetrahydrofuran is added 3.0 grams of 4-benzoyloxy-1-hydroxy-2,2,6,6-tetramethylpiperidine. After stirring the solution under nitrogen at room temperature for ten minutes, 1.78 grams of diethyl vinylphosphonate are added. After stirring the reaction mixture at room temperature under nitrogen for 24 hours, the solvent is removed under reduced pressure. The residue is partitioned between water and methylene chloride. The organic phase is washed with water, then brine and finally dried over anhydrous magnesium sulfate followed by evaportion. Purification of the residue by liquid chromatography affords the title compound as a colorless liquid. Analysis by nmr, ir and ms gives data consistent with the structure of the title compound.
Reaction SMILES: C(C1[CH:7]=[C:6]([Cl:8])[O:5][N:4]=1)C.[OH-:9].[Li+].[O:11]1[CH2:16][CH2:15]OCC1>>[Cl:8][C:6]1[O:5][N:4]=[C:15]([C:16]([OH:11])=[O:9])[CH:7]=1
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: CCc1cc(Cl)on1
Agent: [Li+]
Product: O=C(O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl-5-chloroisoxazole (1.5 g; 8.54 mmol) was added to a mixture of lithium hydroxide (10 mL; 2M in water) and dioxane (10 mL). The reaction mixture was stirred vigorously at room temperature for 1 h and concentrated under reduced pressure. The crude material was reparted between ethyl acetate and HCl 1M; the phases were separated and the aqueous were extracted with ethyl acetate. The organic rejoined were dried, concentrated under reduced pressure and the crude material 1.2 g (95%) was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17]C3CCCCO3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[NH2:28].C(=O)([O-])O.[Na+]>C(O)(C)C>[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: Clc1ncnc2ccn(CCCOCCOC3CCCCO3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cl
Product: OCCOCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
4-Chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3,2-d]pyrimidine (380.2 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (419.2 mg) was added, and the mixture was stirred at 80° C. for 18 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=50:50→0:100), and the mixture was dissolved in ethyl acetate (4 mL). 4N Hydrochloric acid-ethyl acetate (0.3 mL) was added to this solution, and the precipitate was collected by filtration, and dried to give the title compound (398.2 mg) as a white solid.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([OH:29])=[O:28].[CH3:30][S-:31].[Na+].I[CH3:34]>CS(C)=O.CCOCC>[CH3:26][C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)=[N:10][C:11]2[C:6]([C:7]=1[C:27]([O:29][CH3:34])=[O:28])=[CH:5][C:4]([S:31][CH3:30])=[C:13]([O:14][CH3:15])[CH:12]=2
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Reactant: CI
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(SC)cc12
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
Sodium hydride (0.949 g, 23.73 mmol) was added portionwise to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (6.0 g, 15.82 mmol) in dimethyl sulfoxide (50 mL). After 20 min, sodium thiomethoxide (1.44 g, 17.40 mmol) was added. The reaction mixture was heated to 100° C. for 2 h. The mixture was cooled to room temperature and iodomethane (4.95 mL, 79 mmol) was added. The reaction mixture was stirred for 2 h, diluted with ether, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (ISCO, 330 g silica, 0-15% ethyl acetate/hexanes) to give methyl 3-methyl-7-(methyloxy)-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.48 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.94-8.01 (m, 2H), 7.87 (d, J=7.28 Hz, 1H), 7.77 (d, J=7.53 Hz, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 2.53 (s, 3H), 2.34 (s, 3H); MS (m/z) 422.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5OC)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[Cl:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:32])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ccccc1C[Zn+]
Reactant: COc1ccccc1Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2ccccc2Cl)nc1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorobenzyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxybenzyl)pyridin-3-yl)cyclopropanecarboxamide from (2-chlorobenzyl)zinc(II) chloride and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]1[C:15]([OH:17])=[O:16].O.[CH3:19]O>>[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]1[C:15]([O:17][CH3:19])=[O:16]
Reactant: CO
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])cn1C

Procedure:
A cold solution of H2SO4 (2.9 mL) in MeOH (28.96 mL) was added to 1-methyl-4-nitropyrrole-2-carboxylic acid (2.897 g, 2.35 mmol). The mixture was refluxed for 24 hr. Water was added and the mixture extracted CHCl3. The organic layer was dried (MgSO4), and the solvent evaporated under vacuum to afford the creamy white product. NMR as previously reported.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:17](=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH2:31])[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[C:17](=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=3)[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>O1CCOCC1>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])/[C:20](/[CH3:38])=[CH:19]/[CH:18]=[C:17](\[CH3:39])/[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 16.7 %

Procedure:
Using General Procedure B with 1.14 g (2.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester and with dioxane as solvent afforded 127 mg (16%) of the title compound as a white solid.