Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:43])([O:12][C:13]1[C:14]([CH3:42])=[C:15]2[C:20](=[C:21]([CH3:24])[C:22]=1[CH3:23])[O:19][C:18]([CH3:41])([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:17][CH2:16]2)[O:2][CH2:3][CH2:4][CH:5]1[CH2:9][O:8]C(C)(C)[O:6]1.O1CCCC1.CO.Cl>CCOCC>[C:1](=[O:43])([O:12][C:13]1[C:14]([CH3:42])=[C:15]2[C:20](=[C:21]([CH3:24])[C:22]=1[CH3:23])[O:19][C:18]([CH3:41])([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[CH2:17][CH2:16]2)[O:2][CH2:3][CH2:4][CH:5]([OH:6])[CH2:9][OH:8]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCCC1COC(C)(C)O1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(O)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 90 %

Procedure:
A mixture comprising 5.0 g of 2,2-dimethyl-1,3-dioxolan-4-yiethyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 20 ml of tetrahydrofuran, 10 ml of methanol and 8 ml of 2N hydrochloric acid was heated under reflux for 3 hours with stirring. Then the reaction mixture was dissolved in ether, successively washed with water, an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=3.5:1.5) to thereby give 4.2 g of the title compound as a pale yellow, viscous liquid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:32]3[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:48].[BrH:48].[CH2:25]([O:24][C:22]([C@@H:21]([NH:27][C@@H:28]1[C:34](=[O:35])[N:33]([CH2:36][C:37]([OH:39])=[O:38])[C:32]2[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=2[S:30][CH2:29]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 1 ml of acetic acid is dissolved 0.75 g of tertbutyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.6 g of 3(R)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:24][CH2:23]2)=[N:19][C:18]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(N2CCN(C(=O)Nc3cccnc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (229 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 68.4 mg (23.4%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:40]=[CH:39][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([OH:29])=[O:28])=[CH:39][CH:40]=2)=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (1.12 g, 2.20 mmol) in THF (20 ml) and methanol (10 ml) was added 1N aqueous potassium hydroxide (6.6 ml, 6.6 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N aqueous hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound as an oily substance. 1.00 g, (yield 94%)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:22](OC(OCC)(OCC)C)[CH3:23].C(O)(=O)C>CO>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]([CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[C:22]([CH3:23])=[N:21][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cc(Cn2ccnc2)ccc1NCc1cccnc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2cc(Cn3ccnc3)ccc2n1Cc1cccnc1
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of 5.6 parts of 4-(1H-imidazol-1-ylmethyl)-N1 -(3-pyridinylmethyl)-1,2-benzenediamine, 20 parts of triethoxyethane, 2 parts of acetic acid and 200 parts of methanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated. Methanol and methanol, saturated with ammonia, were added. The mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (88:10:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 40 parts of 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.5 parts (41%) of 5-(1H-imidazol-1-yl-methyl)-2-methyl-1-(3-pyridinylmethyl)-1H-benzimidazole; mp. 174.0° C. (compound 116).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].C([NH:35][CH2:36][CH2:37][CH2:38]Br)(OC(C)(C)C)=O>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:38][CH2:37][CH2:36][NH2:35])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OCCCN
Yield: 38.4 %

Procedure:
The title compound (309 mg) is prepared in analogy to Example 201 starting from 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (700 mg, 1.82 mmol) and 3-(Boc-amino)-propylbromide (900 mg, 3.63 mmol); LC-MS: tR=0.46 min; [M+1]+=443.10.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:10][C@H:11]1[C:20]([CH3:22])([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]([CH3:25])([CH3:24])[CH2:12]1)(O)=[O:8].Cl>O1CCCC1>[OH:8][CH2:7][CH2:10][C@H:11]1[C:20]([CH3:21])([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]([CH3:25])([CH3:24])[CH2:12]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@H](CC(=O)O)CC2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C)(C)[C@H](CCO)CC2(C)C
Temperature: 60 °C
Yield: 95.2 %

Procedure:
A suspension of lithium aluminum hydride (16.8 g; 0.442 mol) in tetrahydrofuran (200 ml) was heated up to 60° C., a solution of (S)-3-carboxymethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronapthalene ([α]546 +25.3° (C=1 in benzene)) (76.4 g; 0.294 mol) in tetrahydrofuran was added dropwise thereto. The resultant mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled, treated with dilute hydrochloric acid and extracted with toluene (200 ml). The extract was washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated to give (S)-3-(2-hydroxyethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (70.5 g; 0.28 mol; 97.5%). [α]546 -8.1° (C=0.62 in ethanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].N[CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:47][CH2:46]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:47][CH2:46]2)=[N:3][CH:4]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(c2ccc(C)cn2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
2-Bromo-5-methylpyridine (8.56 g), 1,3-bis(diphenylphosphino)propane (4.10 g) and sodium tert-butoxide (6.69 g) were suspended in toluene (500 mL), to which was added ethyl 4-amino-1-piperidinecarboxylate (10.28 g). Tris(dibenzylideneacetone)dipalladium (3.19 g) was added to the suspension, and it was stirred at 70° C. for 4 hours. Ethyl acetate was added to the reaction solution, and then, it was washed with saturated aqueous sodium chloride solution, and dried (MgSO4). The solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, ethyl acetate), and then crystallized (ethyl acetate/hexane) to give the title compound (10.13 g).
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([O:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20]>>[CH2:1]([S:17][CH2:20][CH2:19][CH2:18][O:21][CH2:22][CH2:23][CH2:24][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: C=CCOCC=C
Product: CCCCCCCCCCCCCCCCSCCCOCCCSCCCCCCCCCCCCCCCC

Procedure:
The procedure that is used for this example is similar to that set forth in Example 3, except that n-hexadecyl mercaptan (129.26g., 0.5 mole) is reacted with diallyl ether (24.54g., 0.25 mole).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([NH:17][NH2:18])=[O:16])=[C:12]([CH3:14])[N:13]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C>[OH:19][C:20]1[CH:21]=[C:22]([CH:23]=[N:18][NH:17][C:15]([C:11]2[S:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:13][C:12]=2[CH3:14])=[O:16])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)sc1C(=O)NN
Reactant: COc1ccc(C=O)cc1O
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2sc(-c3ccc(Cl)cc3Cl)nc2C)cc1O
Yield: 85.6 %

Procedure:
In ethanol (5 ml), 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazide (34 mg) and 3-hydroxy-4-methoxybenzaldehyde (19 mg) was heated under reflux for 25 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration to give the title compound (42 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([NH:20]C(=O)C4C=CC=CC=4)=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Nc3cnc(NC(=O)c4ccccc4)nc3)ccnc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(Nc3cnc(N)nc3)ccnc2c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In 25 mL sealed tube, N-(5-(7-methoxyquinolin-4-ylamino)pyrimidin-2-yl)benzamide (400 mg, 1077 μmol) was added into 6 ml of MeOH followed by addition of 2 mL of HCl (conc.). The reaction was heated at 80° C. After 1.5 h the reaction mixture based on LCMS showed full conversion to desired product [M+H]++1=269 @ 0.8 min—protonated form. The reaction was cooled to 0° C., 50 mL of CH2Cl2 was added, and the mixture was neutralized with 6N NaOH. Solid precipitated out of the solution in the aqueous layer. The whole mixture was concentrated under reduced pressure. The solid was filtered off with an aid of water to yield a sticky solid. The solid was transferred into a flask with an aid of MeOH. The solvent was evaporated under reduced pressure to afford N5-(7-methoxyquinolin-4-yl)pyrimidine-2,5-diamine as a gray solid.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:18]=1>>[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[N:18]=1
Reactant: O=C1c2ccccc2CC1Br
Reactant: Cc1nc(CC(N)=S)c[nH]1
Agent: Cl
Product: Cc1nc(Cc2nc3c(s2)Cc2ccccc2-3)c[nH]1

Procedure:
Starting compounds: 2-bromo-1-indanone, (2-methyl-4-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=2)[S:3][N:2]=1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[S:3][N:2]=1
Reactant: O=C(O)c1cnc2snnc2c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cnc2snnc2c1
Yield: 15.9 %

Procedure:
The carboxylic acid (iii) (0.82 g) was reacted with isobutylchloroformate and sodium borohydride to afford a semi-solid (0.12 g), after chromatography on silica gel (chloroform).
Reaction SMILES: [CH2:1]([N:7]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:8](=[O:21])[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH2:1]([N:7]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]=2[CH:23]=1)[C:8](=[O:21])[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Yield: 82.7 %

Procedure:
A solution of ethyl 4-[3-hexyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (19) (296 mg, 0.62 mmole) in 8 mL ethanol was treated with 694 mg of potassium hydroxide in 3 mL water. THF (2 mL) was added and the mixture was heated to 45° C. for two hours. The reaction mixture was diluted with 10 mL water and the pH adjusted to 2 with concentrated HCl and then extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide a pale yellow solid. The product was purified by trituration in pentane and 231 mg (83%) of 4-[3-hexyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (13) were obtained as a pale yellow solid. M.P.: 176.6-177.1° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].ON1C(=O)N(O)C(=O)N(O)[C:14]1=[O:23].N(C(C)(C)C#N)=NC(C)(C)C#N.[O:36]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:14]([OH:23])=[O:36])(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: CC(=O)Oc1cccc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)O)c1

Procedure:
A mixture of 0.300 g of m-tolyl acetate, 0.018 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to m-tolyl acetate), 5 g of acetic acid, 0.003 g of cobalt(II) acetate.4 H2O and 0.003 g of 2,2′-azobisisobutyronitrile was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 3-acetoxybenzoic acid in 75% yield at 78% conversion of m-tolyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:13]([C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]=1)#[N:14]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.1 %

Procedure:
4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%).
Reaction SMILES: Cl.[C:2](O)(=O)[CH3:3].[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25]C)[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH2:2][CH3:3])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: CCNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 2.5 h

Procedure:
To 3 ml of a mixed solution (1:1, v/v) of 4 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 510 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylamino-pyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 454 mg of the title compound as a gray powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28]O)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10].S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28][Cl:32])=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCCN(Cc1nc2cc(CO)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Product: CCCN(Cc1nc2cc(CCl)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 93 %

Procedure:
(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide 0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 min a room temperature. The resulting mixture is concentrated in vacuo and partitioned between 100 mL sat NaHCO3 and 100 mL of ethyl acetate. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanes to afford 0.9 g (93%) of (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15]([O:17][CH3:18])=[O:16].C[O-].[Na+].[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].Cl>CC(OC)(C)C.CO.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])=[CH:8][C:7]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(C)=O)ccc1-c1ccco1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COC(=O)c1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reaction time: 2 h

Procedure:
4-(2-furyl)-3-(methoxycarbonyl)phenyl-1-ethanone (1.36 g, 5.57 mmol) was dissolved in MTBE (30 ml) at room temperature under nitrogen. Ethyl trifluroroacetate (0.87 g, 6.1 mmol) was added followed by a suspension of sodium methoxide (0.36 g, 6.7 mmol) in methanol (5 ml). After 2 hours of stirring, ethyl trifluoroacetate (2.03 g, 14.3 mmol) was added, followed by sodium methoxide (0.87 g, 6.1mmol). After an additional 18 hours, the mixture was poured into stirring ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([C:27](=[O:32])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>C1COCC1>[CH2:9]([O:8][P:7]([CH2:6][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:32])([O:11][CH2:12][CH3:13])=[O:14])[CH3:10]
Reactant: CCOP(C)(=O)OCC
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(CC(=O)C1CCN(C(=O)OC(C)(C)C)C1)OCC
Yield: 46.5 %

Procedure:
Add butyl lithium (98.0 mL, 157 mmol) dropwise to a solution of diethyl methylphosphonate (23.6 g, 155 mmol) in THF (194 mL) under nitrogen at −78° C. over 15 minutes. Add (S)-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert butyl ester (5.0 g, 19.4 mmol) in THF and stir at −78° C. for about 3.5 hrs. Pour into water and extract with ethyl acetate (3×). Wash the combined organics with water and brine. Dry (MgSO4), filter, and concentrate. Subject the residue to silica gel chromatography, eluting with 0-50% acetone in chloroform followed by another silica gel chromatography eluting with 0-30% acetone in dichloromethane to afford 3.15 g (47%) of the desired compound. MS (m/z)=294.0 (M−55)