Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13](S(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:24][CH:23]=2)[C:3]1=[O:40].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:26][CH:27]=2)[C:3]1=[O:40]
Reactant: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(c2ccc(NS(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a stirred solution of N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (40 mg, 0.06 mmol) in THF: H2O (6 mL) was added 2N NaOH (1.0 mL) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. Upon complete consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl) phenyl)methane sulfonamide (20 mg, 26%), as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1H), 8.12 (t, J=7.9 Hz, 1H), 7.78 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.64 (t, J=8.2 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 6.98 (d, J=8.2 Hz, 2H), 5.42 (s, 2H), 2.85 (s, 3H), 1.44 (s, 6H). MS: [M+Na]: m/z=537.3, [M+H]: m/z=515.2 HPLC: 95.7% (RT-2.37 min),
Reaction SMILES: CC(C)[N:3]=C=NC(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH:43](C(OC(C)(C)C)=O)[C@H:44]([C:49]([OH:51])=O)[CH2:45][CH:46]([CH3:48])[CH3:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH2:43][C@H:44]([C:49]([NH2:3])=[O:51])[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)N=C=NC(C)C
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIC (302 mg, 2.4 mmol) was added with stirring to a DMF (4 mL) solution of dasatinib (196 mg, 0.4 mmol), Boc-Leu-OH (111 mg, 0.48 mmol), and DPTS (124 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours. After this period, DCM (100 mL) was added to the reaction mixture which was allowed to stir for an additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 5% NaCl (100 mL×3). The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 25 CV). The obtained solid was dissolved in 5.0 mL of TFA/DCM (2:3) and the solution was stirred at room temperature for one hour. TFA and DCM were removed under reduced pressure. The residue was dissolved in 150 mL of DCM and the resulting solution was washed with 5% Na2CO3 and 5% NaCl. The desired product was obtained (146 mg, yield: 61%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.98 (m, 6H), 1.46 (m, 1H), 1.60 (m, 1H), 1.80 (m, 1H), 2.33 (s, 3H), 2.48 (s, 3H), 2.62 (t, 4H), 2.74 (t, 2H), 3.50 (m, 1H), 3.65 (t, 4H), 4.33 (m, 2H), 6.02 (s, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 8.15 (s, 1H); LC-MS (m/z) calcd., 600.2, found 601.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32].N1C=CC=CC=1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=S)NCC3)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A suspension of 7-(3-t-butyl-5-amino-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-thione (0.150 g, 0.499 mmol) in THF (3 mL) was added to a solution of 2,3-dichlorophenyl isocyanate (0.141 g, 0.749 mmol), pyridine (0.061 mL, 0.059 g, 0.749 mmol) and THF (3 mL). The flask which contained the starting material was again rinsed with THF (4 mL) and the solution was added to the reaction flask. The resulting yellow suspension was briefly heated with a heat gun, causing the reaction mixture to become clear. After 18 h, the solution was concentrated and the residue was purified by column chromatography to yield 1-[3-t-butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea as a yellow solid (203 mg, 83% yield). 1H NMR (400 MHz, acetone-d6): δ 9.60 (brs, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.61 (brs, 1H), 8.26 (dd, J=8.4, and 2.0 Hz, 1H), 8.17 (brs, 1H), 7.68 (dd, J=8.0, and 2.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.23 (dd, J=7.6, and 1.2 Hz, 1H), 6.48 (s, 1H), 3.62-3.58 (m, 2H), 3.07 (t, J=6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 488.0 (M+H+).
Reaction SMILES: [CH2:1]1COCC1.[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Mg]Cl.O>C(OCC)(=O)C>[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14]([OH:16])([CH3:1])[CH3:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)=O)ccc1-n1cnc(C)c1
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)(C)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (1.0 mL) solution of (E)-N-(1-benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (12.0 mg), methyl magnesium chloride (3MTHF solution, 198 μL) was added at −78° C., the reaction solution was allowed to be warmed to room temperature and agitated for further 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate ethanol=10:1), and 6.8 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12.O.C(=O)(O)[O-].[Na+].[OH:27][C:28]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]>CO>[OH:27][C:28]1[C:35]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:34][C:31]([CH:32]=[N:2][C@@H:3]2[C:19](=[O:20])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:18])[Cl:17])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]23)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1
Reaction time: 4 h

Procedure:
To 10 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-3-cephem-4-carboxylate hydrochloride was added about 70 ml. of water. About 2.5 g. of sodium bicarbonate was added thereto and, after stirring for a while, the resultant was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated at a temperature below 35° C. The so obtained free base was dissolved in 40 ml. of methanol and 5 g. of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde was added thereto and stirring was continued at room temperature for 4 hours. The insolubles were dissolved by heating briefly and the reaction mixture was concentrated into a half amount thereof, which was then cooled to separate out crystalline substances. The substances were recovered by filtration and washed with cold methanol to give 2,2,2-trichloroethyl 7β-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-methyl-3-cephem-4-carboxylate. Yield 7 g. The product was recrystallized from a small amount of methanol to give the pure product as slightly yellow colored crystals. m.p. 94° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:13][CH:12]=1.O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1ccc2ccn(-c3cc(N)ncn3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1-c1ccc2ccn(-c3cc(N)ncn3)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
6-(6-(2-Methyl-5-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (130 mg, 0.38 mmol) was dissolved in ethanol and, after adding SnCl2.2H2O (425 mg, 1.88 mmol), the mixture was stirred at 100° C. for 3 hours. The reaction mixture was added to sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, MC:MeOH=20:1) yielded 6-(6-(5-amino-2-methylphenyl)-1H-indol-1-yl)pyrimidin-4-amine (83 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[CH2:37]([NH2:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:44][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 2 h
Yield: 86 %

Procedure:
Part C, Method 1. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in N,N-dimethylformamide (25 mL) was added 1-hydroxybenzotriazole hydrate (0.93 g, 0.0069 mol) followed by a solution of heptylamine (1.10 mL, 0.86 g, 0.0074 mol) in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0° and dicyclohexylcarbodiimide (1.42 g, 0.0069 mol) was added portionwise as a solid. The reaction mixture was stirred for 2 hours at 0° and then stirred for 48 hours at ambient temperature. The solids were filtered and washed with N,N-dimethylformamide. The filtrate was concentrated and the residue was chromatographed with 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.21 g, 0.0049 mol) as a white solid, mp 104°-106°. 1H NMR (CDCl3) δ 11.6(s,1H) , 7.6-7.1(m,10H), 6.1-6.0(m,1H), 3.1-2.8(m,4H), 2.2(t,2H,J=7 Hz), 1.9-1.7(m,2H), 1.7-1.5(m,2H), 1.4-1.1(m,10H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C(O)C>C1(O)C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: CCO
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1

Procedure:
In a manner analogous to that of Example 6, 4-chloro-2-(4-chlorophenyl)quinoline was reacted with isonipecotamide in phenol at 170° C., yielding the named compound, mp. 245°-247° dec., from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([CH:15](C(C)=O)[C:16]([O:18]CC)=[O:17])[CH:8](C(C)=O)[C:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([CH2:15][C:16]([OH:18])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(C)=O)C(c1ccc(OC)cc1)C(C(C)=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Yield: 16.1 %

Procedure:
A mixture of ethyl 2,2'-(4-methoxybenzal)-bis-acetoacetate (30 g), ethanol (450 ml) and 50% sodium hydroxide (450 g) is refluxed vigorously for 1.0 hour. Water (150 ml) is added and most of the ethanol is removed by distillation in vacuo. The concentrate is acidified with concentrated hydrochloric acid and is extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, evaporated and the residue is crystallized from benzene-methanol to afford 3.3 g of 3-(4-methoxyphenyl)glutaric acid, melting point 147°-150° C.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[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].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[O:20][CH3:21])[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: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3.0 grams (0.009 mole) (±)-1-S-hexadecyl-2-O-methylthioglycerol in 200 milliliters of DCM and 1.0 milliliter (0.010 mole) of triethylamine was added 1.2 grams (0.012 mole) of methanesulfonyl chloride and the reaction stirred at room temperature for 24 hours. The reaction mixture was then extracted twice with 200 milliliter portions of water, twice with 200 milliliter portions of 5% HCl, once with 200 milliliters of saturated NaHCO3, and once with 200 milliliters of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 3.4 grams (89%) of a colorless oily residue. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.08(s, 3H, SO2 --CH3), 3.40-3.50(m, 4H, CH, CH3 --O), 4.35 (m, 2H, CH2 --OSO2).
Reaction SMILES: N1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:4][N:3]=N1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([C:11]1[O:16][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:4][N:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(C(C)(C)C)o1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of ethyl tetrazole-5-carboxylate (8.53 g, 60 mmol) and pivaloyl chloride (7.23 g, 60 mmol) in dry toluene (240 ml) is refluxed for 16 hours. After the solution has cooled to room temperature, it is washed two times with 1 N sodium hydroxide solution (20 ml) and then once with water (20 ml). The organic phase is dried over magnesium sulphate and the solvent is evaporated in vacuo to give ethyl 5-tert-butyl-[1,3,4]oxadiazole-2-carboxylate as a red oil (6.96 g, 59%), which is used in the following stage without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:19])([F:18])[F:17])[N:5]=1.C(C1C(C)=C([O:34][C:35]([CH:37]2[CH2:39][CH2:38]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([O:15][C:35]([CH:37]2[CH2:39][CH2:38]2)=[O:34])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:17])([F:19])[F:18])[N:5]=1
Reactant: Cc1nc2ccc(F)c(C(F)(F)F)c2c(O)c1C
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(F)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
In 3 ml dimethyl formamide was suspended 18.8 mg of 60% sodium hydride. The mixture of 2,3-dimethyl-4-hydroxy-5-trifluoromethyl-6-fluoroquinoline with 2,3-dimethyl-4-hydroxy-6-fluoro-7-trifluoromethylquinoline (starting material 1) (100 mg) was suspended in 3 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 40.8 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on a silica gel packed column (Varian) (20 g; elution solvent=n-hexane-ethyl acetate (40:1) to (20:1)) to give 27.9 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5-trifluoromethyl-6-fluoroquinoline (compound 61) and 51.3 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-trifluoro -methylquinoline (compound 63). 1H-NMR data are shown in Table 3.
Reaction SMILES: O[C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>P(Cl)(Cl)(Cl)=O>[Cl:12][C:2]1[C:3]([C:8]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1Cl
Yield: 14.9 %

Procedure:
To a solution of 3-hydroxypicolinamide (2.00 g, 14.5 mmol) in phosphorus oxychloride (10 mL) at room temperature was added phosphorus pentachloride (6.00 g, 28.8 mmol). The mixture was heated at reflux for 90 min, and the solvent was removed by distillation. The residue was poured into water, the aqueous solution was neutralized by addition of sodium bicarbonate, and was extracted with ethyl acetate. The organic phase was filtered through silica gel, the filtrate was concentrated, and the residue was subjected to flash chromatography on silica gel, affording 300 mg of 3-chloro-2-cyanopyridine. 1H NMR (CDCl3) δ7.50 (dd, 1, J=4.8, 8.4), 7.89 (dd, 1, J=1.6, 8.4), 8.63 (dd, 1, J=1.6, 4.8).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc(C(F)(F)F)cc1
Yield: 85.8 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 2.00 g (0.00869 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 3.62 g (0.01738 mol) of p-trifluoromethylbenzoyl chloride with the exception that removal of ethyl acetate provided a solid. This solid was recrystallized from ethyl acetate containing a small amount of methanol to provide 3.00 g of the desired titled compound (m.p. 207°-215° C.).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C([Cl:16])(=O)C>II>[Cl:16][CH2:2][CH2:1][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(=O)Cl
Agent: II
Product: CCOC(=O)COCCCl
Temperature: 50 °C
Yield: 97.3 %

Procedure:
40 mL (224 mmol) of ethyl diethoxyacetate, 38 mL (536 mmol) of acetyl chloride and 0.11 g (0.45 mmol) of iodine are placed in a round-bottomed flask and heated at 50° C. for 24 hours. The reaction progress is monitored by NMR. The excess acetyl chloride is removed by evaporation under vacuum. 36.3 g (100%) of ethyl chloroethoxyacetate are obtained in the form of a liquid colored brown by the residual iodine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:8]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2cnccn2)cc1
Yield: 28.2 %

Procedure:
To 3.5 g (25 mmol) of pyrazinoyl chloride dissolved in methylene chloride (20 mL) and pyridine (2 mL) cooled to 0° C. in a 50 mL round bottom flask was added 4-methyl-phenol (3.2 g, 30 mmol). Upon completion of the reaction and isolation as described above, recrystallization from hexanes yielded 1.51 g (24% yield) of the crystalline title compound; m.p.: 120°-123° C. Elemental Analysis: C12H10N2O2Calcd: C:67.28, H:4.71. Found: C:67.4, H:4.66.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O>C(OCC)(=O)C>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2ccccc2c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCOC(C)=O
Product: BrCc1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Under nitrogen gas flow, 600 g of 2-methylnaphthalene was dissolved into 6,000 ml of ethyl acetate, the mixture was then added with 422 g of 1,3-dibromo-5,5-dimethylhydantoin, and heated to 40° C. The mixture was added with 7.4 g of V-65 from Wako Pure Chemical Industries, Ltd., and allowed to react at 40° C. for 7 hours. Thereafter, the reaction liquid was allowed to react at 65° C. for 3 hours, and then cooled. The reaction liquid was successively washed with aqueous sodium hydrogen carbonate solution and distilled water, and then concentrated. The concentrate was added with 3,600 ml of isopropanol, stirred for 30 minutes, added with 900 ml of distilled water, and further stirred for 30 minutes. Precipitated solid was collected by filtration, added with 1,800 ml of isopropanol, the mixture was stirred for 30 minutes, added with 450 ml of distilled water, and further stirred for 30 minutes. The resultant solid was collected by filtration, and dried, to thereby obtain 300 g of 2-bromomethylnaphthalene.