Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22]([C:23]([OH:32])([C:28]([F:31])([F:29])[F:30])[C:24]([F:25])([F:26])[F:27])=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12

Procedure:
The title compound was prepared using 1-bromo-4-(isocyanatomethyl)benzene, the product of Example 77A and the procedure described in Example 73B except that THF was used as solvent (white solid, 840 mg, 34%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C20H14BrF6N3O2; C, 46.00; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=O>O>[CH3:1][NH:2]/[C:4](=[CH:5]\[CH3:7])/[C:3]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: CN
Solvent: O
Product: C/C=C(\NC)C(=O)OC
Temperature: 20 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
At 5° to 10° C., 186 g (2.4 moles) of a 40% strength aqueous methylamine solution is dripped into a solution of 232 g (2 moles) of methyl acetoacetate in 150 ml of water. The mixture is then stirred for 12 hours at room temperature (20° C.). The product is then separated from the solution by suction filtration. After washing with ice water and drying under reduced pressure, there is obtained 212 g (82%) of a white solid; m.p.: 62°-63° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][O:5]1.C(N(CC)CC)C.[F:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[N:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])=[CH:21][CH:20]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N(CC)CCCl)C>CN(C)C=O.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[N:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([NH:2][CH2:3][CH:4]2[O:5][CH2:6][C:7](=[O:10])[NH:8][CH2:9]2)=[O:27])=[CH:33][CH:34]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: NCC1CNC(=O)CO1
Agent: CCN(CC)CCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1COC(CNC(=O)c2cccnc2Oc2ccc(F)cc2)CN1

Procedure:
A solution of 6-Aminomethyl-morpholin-3-one hydrochloride (0.200 grams, 1.2 mmole) and triethyl amine (0.150 grams, 1.5 mmole) in dimethylformamide was stirred at room temperature for 30 minutes. To the stirring solution 2-(4-Fluoro-phenoxy)-nicotinic acid (0.280 grams, 1.2 mmole), 1-hydroxybenzotriazole hydrate (0.237 grams, 1.755 mmole) and 2-diethylaminoethyl chloride hydrochloride (0.30 grams, 1.56 mmole) was added and stirred over night. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give a white solid which was purified by chromatography on silica eluting with 5% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave white crystals. (0.175 g); M.P. 157-159° C.; Anal. calcd. for C17H16N3O4F: C, 59.14; H, 4.67; N, 12.17. Found: C, 59.00; H, 4.69; N, 12.19.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[N:19][C:12]=3[N:11]=[C:10]2[C@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@@H:20]([C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[N:19][C:12]=2[N:11]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
Compound 1 (1.05 g, 2.68 mmol) was dissolved in CH2Cl2 (40 mL) and treated with TFA (40 mL). The resulting mixture was stirred for 1.5 h then concentrated in vacuo. The concentrate was re-dissolved in CH2Cl2 (100 mL) and washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional CH2Cl2 (3×50 mL). The combined extracts were dried over Na2SO4, concentrated and dried under high vacuum for 17 h to give B1 (767 mg, 98%), which was suitable for use without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:1])=[O:18])[CH:11]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: C=Cc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: Cc1cccc(NC(N)=O)c1

Procedure:
1.00 g (8.40 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask containing 10 ml of chloroform. After ten minutes of mixing, 1.12 g (8.41 mmol) of m-tolyl isocyanate (99% Aldrich) was added dropwise. Within seconds, a white, pinkish precipitate formed. Chloroform (20 ml) was added to aid stirring. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in a white powder (166 g, 78% crude yield, mp=203° C.).
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=C(CCl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[OH2:34]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:9]([CH2:8][N:4]([CH2:5][CH:7]([OH:34])[C:11]4[CH:33]=[CH:32][CH:14]=[CH:13][CH:12]=4)[CH3:1])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:32][CH:33]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CCN(C(C)C)C(C)C
Reactant: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccccc1
Temperature: 90 °C

Procedure:
N,N-Diisopropylethylamine (0.111 mL) and (x-(methylaminomethyl)-benzyl alcohol (0.094 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.095 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 118-121° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 7.41-7.35, 7.32-7.25, 7.22-7.18, 6.84, 5.10, 4.734.69, 4.55, 3.89, 3.73, 2.62-2.54, 2.32; MS (ESI+) m/z 480 (M+H)+. Anal. Found: C, 63.48; H, 5.56; N, 8.24; Cl, 6.94.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26]1([C:42]3=[CH:43][C:44]4OCO[C:45]=4[CH:49]=[C:41]3[O:40][CH2:39]1)C(=O)N2CCCCC.C1C2C3C=CC=CC=3OC=2C(B(O)O)=CC=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH:43]1[C:42]2[C:26]3[CH:25]=[CH:29][CH:30]=[CH:31][C:39]=3[O:40][C:41]=2[C:49]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)=[CH:45][CH:44]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cccc2c1oc1ccccc12
Product: O=C1Nc2cccc(-c3cccc4c3oc3ccccc34)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and dibenzo[b,d]furan-4-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (10%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.43-7.42 (m, 3H), 7.34-7.29 (m, 3H), 7.16 (t, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.25 (s, 1H), 5.69 (d, 2H), 4.41 (ABq, 2H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[CH3:16][O:17][C:18]1[C:19]([C:28](O)=[O:29])=[CH:20][C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:28]([C:19]3[C:18]([O:17][CH3:16])=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)=[O:29])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: COc1cc2c(cc1C(=O)O)OCCO2
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: COc1cc2c(cc1C(=O)Nc1cnn(Cc3c(C)noc3C)c1)OCCO2
Yield: 50 %

Procedure:
Prepared as in Example 4-73 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) and 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (example 4-95a). Yield 50%. MS M+H calculated 385.1, found 385.1. 1H NMR (400 MHz, DMSO): 2.136 (s, 3H), 2.410 (s, 3H), 3.851 (s, 3H), 4.214 (bs, 2H), 4.296 (bs, 2H), 5.120 (s, 2H), 6.688 (s, 1H), 7.290 (s, 1H), 7.6006 (s, 1H), 8.069 (s, 1H), 9.856 (s, 1H).
Reaction SMILES: [C:1]([O:20]C(C)C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCCCCCCCC.[CH2:24](O)CCCCCCCCCCCCCCCCC>>[CH3:24][C@@H:1]([OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCC[C@@H](C)O
Reaction time: 48 h
Yield: 72 %

Procedure:
To the distillation residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate, were added 90 g of stearyl alcohol and 3 g Lipase PL. After regulating the particle size of the enzyme by ultrasonication in the same manner as described above, interesterification was carried out at 85° C. for 48 hours. The reaction mixture was subjected to simple distillation at 90° C. and 3 mmHg to recover highly pure free (R)-(-)-2-decanol (yield: 72%; chemical purity: 99.6%; optical purity: 84% ee).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:24])=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 134.5 %

Procedure:
4-{[4-(Trifluoromethyl)phenyl]carbonyl}benzoic acid (200 mg, 0.68 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.496 mL, 6.8 mmol) added. The reaction mixture was heated at reflux for 1 h. Further thionyl chloride (0.496 mL, 6.8 mmol) was added and heating continued for 3 h. On cooling, the reaction mixture was concentrated in vacuo to give 4-{[4-(trifluoromethyl)phenyl]carbonyl}benzoyl chloride as an oily white liquid (0.286 g) which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (2 mL) and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.170 g, 0.53 mmol) and triethylamine (0.11 mL) in DCM (2 mL). The reaction mixture was stirred at room temperature under argon overnight then diluted with water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic layers were dried, concentrated and purified by column chromatography. Elution with 0-30% EtOAc/pentane gave the title compound as a colourless oil (0.244 g). MS (ES): MH+ 596.2. Description 124
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][C@H:10]([O:12]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9][N:8]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 82.5 %

Procedure:
A solution of (4S)-1-(tert-butyloxycarbonyl)-4-(p-nitrobenzoyloxy)-L-proline tert-butyl ester (575 mg, 1.32 mmol) in ethanol (13 mL) was treated with 0.4N sodium hydroxide (4.3 mL, 1.72 mmol) for 18 hours at room temperature. The solution was neutralized with several drops of glacial acetic acid, diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The residue was subjected to flash silica gel chromatography eluting with 5% acetone/dichloromethane. The title compound (313 mg) was obtained contaminated with some p-nitrobenzoic acid and used without further purification in the next step.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Br:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[Br-:36].[CH2:35]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 180 °C
Yield: 45.7 %

Procedure:
In a 100 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 8.6 g of triphenylphosphine and 10 g of n-hexadecyl bromide, and under nitrogen atmosphere, the mixture was heated at 180° C. for 10 hours on an oil bath. After cooling the reaction mixture to room temperature, precipitated solid material was pulverized in acetone and collected by filtration under reduced pressure. The resulting crystals were washed with acetone to obtain 8.5 g of the title compound. Melting point: 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C=O.Cl.[CH3:21][NH:22][CH3:23].[C:24](O)(=O)C>CCOCC.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:15][CH3:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OCC(=O)O)c(Cl)c1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCC(CN(C)C)C(=O)c1ccc(OCC(=O)O)c(Cl)c1

Procedure:
(2-Chloro-4-butyrylphenoxy)acetic acid (12.8 g., 0.05 mole), paraformaldehyde (1.65 g., 0.055 mole), dimethylamine hydrochloride (4.62 g., 0.056 mole) and acetic acid (1ml.) are combined and heated on a steam bath for three hours. The reaction mixture is treated with ethyl alcohol (75 ml.) and ether (125 ml.) which causes precipitation of 11.7 g. (69%) of [2-chloro-4-(2-dimethylaminomethylbutyryl)phenoxy]acetic acid hydrochloride which melts at 182° C. after recrystallization from 2-propanol (90 ml.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(#N)C.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:23][O:24][CH2:25][CH2:26][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mmol), K2CO3 (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled. The inorganics were filtered and rinsed with DCM. The organic solution was concentrated down to an oil (7 g). Purification on a flash chromatography column (SiO2, 45 g; eluted with methanol/DCM) gave a light yellow oil as product (4 g, 87%). This oil was dissolved into ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157°-158° (2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[NH:5][C:6]=1/[C:7](/[C:15]1[CH:20]=[CH:19][C:18](SC)=[C:17]([Cl:23])[CH:16]=1)=[CH:8]/[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O1CCC[CH2:31]1.O[O:36][S:37]([O-:39])=O.[K+].C(=O)([O-])O.[Na+]>O.CO>[Cl:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[NH:5][C:6]=1/[C:7](/[C:15]1[CH:20]=[CH:19][C:18]([S:37]([CH3:31])(=[O:39])=[O:36])=[C:17]([Cl:23])[CH:16]=1)=[CH:8]/[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CSc1ccc(/C(=C\C2CCOCC2)c2[nH]c(-c3ccccn3)nc2Cl)cc1Cl
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)c2[nH]c(-c3ccccn3)nc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-{4-chloro-5-[(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethenyl]-1H-imidazol-2-yl}pyridine (1.10 g) in a mixed solvent of tetrahydrofuran (10 mL), methanol (10 mL) and water (10 mL) was added Oxone (registered trade mark) (3.02 g) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in a mixed solvent of acetonitrile (20 mL) and water (10 mL) was added sodium percarbonate (772 mg) under ice-cooling. The reaction solution was warmed to room temperature, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) to give the title compound (0.471 g, yield 40%) as a colorless amorphous solid. MS: 478 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([Cl:27])=[O:18])=[CH:10]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(=O)n(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a suspension of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (795 mg) in CH2Cl2 (8 mL) were added DMF (0.025 mL) and ethanedioyl dichloride (603 mg) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. The volatile materials were removed by evaporation in vacuo to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarbonyl chloride (810 mg).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(N)CCC.C(N(CC)CC)C.[F:30][C:31]([F:35])=[C:32](F)F.CN(C)C=[O:39]>>[F:30][CH:31]([F:35])[C:32]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:39]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)F
Solvent: CCN(CC)CC
Solvent: CCCCN
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 13 h
Yield: 74 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.52 g, 2.0 mmol), n-butylamine (0.44 g, 6.0 mmol) and triethylamine (0.6 1 g, 6.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.3 liter/hr), with vigorous stirring at 50° C. for 13 hours. After cooled to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The ether layer was washed with 5% hydrochloric acid, water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.50 g, 1.5 mmol, yield 74%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=O)#[N:2].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(C#N)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light brown oily semisolid. MS (EI) 245 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CCN1C(=O)c2ccccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 81.8 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-ethyl-3-oxo-2,3-dihydroisoindol-1-yl)propionaldehyde (0.36 g) was treated with 4-(2-oxoperhydropyrimidin-1-yl)piperidine (0.183 g) as described in Example 8. The resulting material was purified by chromatography and was transformed into the hydrochloride to afford the title compound (0.23 g); mp 165°-170° C.; MS: m/z=557(M+1); NMR(CD3OD): 2.3 (m, 7), 2.9 (m, 10), 3.45 (m, 1), 4.0 (m, 1), 4.3 (m,1), 5.0 (m, 1), 7.25 (m,7). Analysis for C28H34Cl2N4O2 ·1.0 HCl ·1.2 H2O: Calculated: C, 57.23; H, 6.41; N, 9.53; Found: C, 57.16; H, 6.21; N, 9.28.