Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1>C(NCCCC)CCC>[CH2:12]([N:13]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:14][CH2:19][CH2:18][CH3:17])[CH2:10][CH2:9][CH3:8]
Reactant: Cc1cccn2cc(C(=O)c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cn3cccc(C)c3n2)cc1
Yield: 197.7 %

Procedure:
A mixture of 2-(4-chloropropoxybenzoyl)-8-methylimidazo[1,2-a]pyridine (2.4 g, 6.0 mmol) in dibutylamine (30 ml) was stirred at reflux for 8 hours. The excess dibutylamine was removed by distillation and the resulting oil was flash chromatographed (silica gel, acetone) to give the free base of the title compound (2.5 g, 100% yield) as a thick oil. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the title compound in methanol, concentrated and recrystallized from methanol-acetone, mp 159° C. to 161° C. IR(KBr): 3420, 1650 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ 8.89 (s, 1H), 8.72 (d, J=6.6 Hz, 1H), 8.15 (d, J=8.9 Hz, 2H), 7.89 (d, J=7.3 Hz, 1H), 7.48 (t, J=6.9 Hz, 1H), 7.21 (d, J= 8.9 Hz, 2H), 4.29 (t, J=7 Hz, 2H), 3.26 (m, 6H), 2.73 (s, 3H), 2.33 (m, 2H), 1.79-1.35 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:12][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: NC1(C(=O)O)CCOCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(N)CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99 %

Procedure:
To a solution of 4-amino-4-carboxy-tetrahydropyrane hydrochloride (2 g) in methanol was added dropwise a solution of 2M trimethylsilyldiazomethane-diethylether (33 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo, and the resultant crude product was dissolved in hexane-diethylether (1 mL/1 mL), and thereto was added an aqueous 4N hydrochloric acid. The precipitates were collected by filtration to give 4-amino-4-methoxycarbonyl-tetrahydropyrane (2.13 g, yield: 99%) as white-crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:17]1[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][N:24]=2)[N:22]=1.O>CN(C)C=O>[CH2:3]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]2[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)[N:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CCCCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1ccc(Oc2nc(-c3ccncn3)cc(=O)n2C)cc1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 202 mg, 5.05 mmol) in N,N-dimethylformamide (1.0 ml) was added 4-hexylphenol (899 mg, 5.04 mmol) at room temperature, and stirred for one hour. 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (935 mg, 4.20 mmol) was added to the solution. The mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=50/50) to afford 2-(4-hexylphenoxy)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (1.14 g, 3.13 mmol, 75%).
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[N:15]=1.N1([CH2:35][OH:36])C2C=CC=CC=2N=N1>C1COCC1>[Br:13][C:14]1[N:15]=[C:16]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1
Reactant: OCn1nnc2ccccc21
Reactant: Brc1cccc(Cn2ccnn2)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OCC(c1cccc(Br)n1)n1ccnn1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of i-Pr2NH (370 μL, 2.59 mmol) in THF (3.0 mL) was cooled to −20° C., and n-butyllithium (970 μL, 2.43 mmol) was added dropwise. After stirring for 15 minutes at −20° C., the colorless solution was cooled to −78° C. before adding 2-bromo-6-(1H-1,2,3-triazol-1-ylmethyl)pyridine (200 mg, 0.84 mmol) in THF (2.0 mL) dropwise over 30 minutes. After stirring for an additional 30 minutes at −78° C., 1H-benzotriazole-1-methanol (250 mg, 1.67 mmol) in THF (5.0 mL) was added dropwise over 25 minutes. The solution was stirred at −78° C. for 2 h. The reaction was quenched (while cold) with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 79 %

Procedure:
Method E. Reaction of oxalyl chloride (195 λL, 2.2 mmol) and benzoic acid 4 (415 mg, 1.1 mmol) and subsequent coupling to 3-pyridinylmethylamine (125 λL, 1.2 mmol) gave benzamide 9 (406 mg, 79%) as a white powder: mp (EtOAc) 190-191° C.; 1H NMR δ 9.20 (t, J=5.8 Hz, 1 H, CONH), 8.57 (d, J=1.7 Hz, 1 H, H-2′), 8.47 (dd, J=4.8, 1.5 Hz, 1 H, H-6′), 8.00 (d, J=8.5 Hz, 2 H, H-2, H-6), 7.90 (d, J=8.4 Hz, 2 H, H-3, H-5), 7.74 (dt, J=7.8, 1.8 Hz, 1 H, H-4′), 7.67 (d, J=8.2Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.2Hz, 2 H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8Hz, 1 H, H-5′), 4.63 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 158.0, 149.9, 148.9, 148.1, 144.5, 135.6, 135.4, 135.2, 134.9, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 123.5, 53.0, 40.6, 21.0, 9.7; MS m/z 462.7 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.79; H, 5.03; N, 9.15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>COCCOC>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:10]2=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[C:11]2=[CH:12]1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)CCCn1cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c2ccccc21
Temperature: 25 °C

Procedure:
The mixture of 10.0 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 1.8 g of 50% sodium hydride in mineral oil and 250 ml of 1,2-dimethoxyethane is stirred at 100° until dissolution. It is cooled to room temperature and 15.0 g of 3-dimethylaminopropyl chloride in 10 ml of 1,2-dimethoxyethane are added. The mixture is stirred at 150° overnight, cooled, the supernatant solution decanted off and the residue treated with said solvent, to yield the 5-(3-dimethylaminopropyl)-2-(p-chlorophenyl)-pyrazolo-[4-3-c]quinolin-3-one melting at 189°-191°. Similarly the 5-(2-dimethylaminoethyl)-analog is obtained, m.p. 184°-186°.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1.O.[O:34]1CCOC[CH2:35]1>CO>[CH3:35][O:34][C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccnc1OCCOc1nccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
NaH (50% in mineral oil; 0.010 g, 2.1 mmol) was added to a stirred solution of the product from Step 1 (0.38 g, 0.87 mmol) in dioxane (8 mL) and MeOH (2 mL) in a reaction tube. As the gas evolution had ceased, the tube was sealed and the mixture was stirred at 100° C. for 15 min. The reaction was poured into water and extracted with toluene, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.178 g (47%) of the title product. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C20H28N6O5 (M)+ 432.2121, found 432.2126.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1
Reactant: O=C(CCc1ccccc1)N1CCC(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCc1ccccc1)N1CCC(CCCl)CC1
Temperature: 20 °C

Procedure:
A solution of thionyl chloride (15.7 ml) in dry chloroform (100 ml) was added dropwise to a stirred solution of the product from Example 35 (51.1 g) in dry chloroform (500 ml) over 45 minutes, keeping the temperature between 0° C. and 5° C. The solution was allowed to warm to 20° C. with stirring and then heated under reflux for 2.5 hours. The mixture was cooled to 20° C., washed (saturated sodium bicarbonate solution, water), dried, filtered and evaporated to give 4-(2-chloroethyl)-1-(3-phenylpropionyl)piperidine as oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][C:24]([CH3:33])([CH3:32])[CH2:23][N:22]3[CH:21]=1)=O>>[CH3:32][C:24]1([CH3:33])[CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]3[CH2:23]1)[CH:29]=[CH:28][CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)(C)C2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: CC1(C)Cc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(O[C:5]1[C:8](=[O:9])[C:7](=[O:10])[C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14][C:13]([CH3:24])([CH3:23])[CH:12]=1)(C)C.[CH3:25][NH2:26]>CC#N.CCO>[CH3:24][C:13]1([CH3:23])[CH:12]=[C:11]([C:6]2[C:7](=[O:10])[C:8](=[O:9])[C:5]=2[NH:26][CH3:25])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14]1
Reactant: CC(C)Oc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Reactant: CN
Solvent: CCO
Solvent: CC#N
Product: CNc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 437 mg (1.35 mmol) of 4-(2-isopropoxy-3,4-dioxo-cyclobut-1-enyl)-2,2-dimethyl-2H-chromene-6-carbonitrile in CH3CN 14 mL) was added dropwise 8.03M methylamine in EtOH. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with H2O (50 mL) and then was extracted into 20% THF-CH2Cl2. The combined organic extracts were dried (Na2SO4) and purified by flash chromatography (4% MeOH--CHCl3) and crystallization from CH2Cl2 -petroleum ether to give 210 mg (53% yield) of the title compound, mp 193°-194° C., as a white solid: 1H-NMR (DMSO-d6 ; 400 MHz; major rotamer) δ8.7-8.8 (br q, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.01 (d, 1H), 6.22 (s, 1H), 3.25 (d, 3H), and 1.46 ppm (s, 3H); IR (KBr) 2220, 1775, 1735, 1620 cm-1 ; mass spectrum (DCI+), m/e 2.95.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)[CH3:2].S(OC)([O:14][CH3:15])(=O)=O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:15][OH:14])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc[n+]([O-])cc1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1ccnc(CO)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-nitropyridine-N-oxide (12 g) was dissolved in ethanol, sodium ethoxide (8.8 g) was added to the mixture, and the mixture was stirred for 40 hours at 50° C. After allowing the mixture to be cooled to room temperature, the precipitates were filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-ethoxypyridine-N-oxide (11.8 g). To 4-ethoxypyridine-N-oxide (11.8 g) was added dimethyl sulfate (8.56 ml), and the mixture was stirred for 1 hour at 110° C. After diluting with methanol (180 ml), the mixture was heated to reflux for 1 hour, an aqueous solution (18 ml) of ammonium peroxodisulfate (20.6 g) was added dropwise to the solution under heat reflux, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-ethoxy-2-pyridinyl)methanol (2.8 g).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)C[C:8]([C:13]1[C:22]([N:23]3[C:32]4[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:34]([O:36]C)=[O:35])[CH:19]=3)[N:14]=1)=[CH:7]2>CO.O1CCCC1>[F:33][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:23]([C:22]1[C:13]([C:8]3[O:1][C:10]4[CH:11]=[CH:12][C:4]([F:3])=[CH:5][C:6]=4[CH:7]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:34]([OH:36])=[O:35])=[CH:17][CH:16]=3)[CH2:24][CH2:25][CH2:26]2
Reactant: COC(=O)c1ccc2nc(C3=Cc4cc(F)ccc4C3)c(N3CCCc4cc(F)ccc43)nc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Sodium hydroxide (15.6 mg, 0.39 mmol) was added to a solution of methyl 2-(5-fluoro-1H-inden-2-yl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinoxaline-6-carboxylate (59 mg, 0.13 mmol) in methanol (25 mL) and tetrahydrofuran (5 mL). The reaction was stirred overnight at room temperature, concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrogen chloride (3 N). The precipitate was collected by filtration to afford 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid (32.5 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.[H-].[Na+].O.O[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH2:22][O:23][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COCCN2CCOCC2)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester was dissolved in 5 ml N-(2-hydroxyethyl)morpholine. 10 mg sodium hydride were added and the reaction mixture stirred at 50° C. for one hour. 10 ml water was added and the reaction mixture extracted 50 ml ethyl acetate. The organic layer was separated and washed twice with 20 ml brine. The organic layer was dried over MgSO4 and the solvent was then removed in vacuo. The residue was purified by RP-HPLC to obtain 40 mg 2-chloro-4-[4-(2-morpholin-4-yl-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as its trifluoro-acetate salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCCC1=O>C(OCC)(=O)C.[Cu]I>[C:11]1([S:17]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1cnccc1Br
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Yield: 158.8 %

Procedure:
A mixture of 4-bromopyridine-3-carbaldehyde (0.90 g), benzenesulfinic acid sodium salt (4.0 g), copper (I) iodide (4.6 g) and 1-methyl-2-pyrrolidinone (50 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a yellow oil (1.9 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1cc(N3CCOCC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and morpholine were reacted to give 129bp. 1H NMR (400 MHz, CDCl3) δ: 7.27 (m, 1 H), 7.11-7.14 (m, 2 H), 6.90-6.98 (m, 3 H), 6.75 (s, 1 H), 5.09 (s, 2 H), 4.04 (m, 2 H), 3.38 (s, 3 H), 3.32 (m, 2 H). LCMS (ESI) m/z: 442.9
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH2:8].O>C(Cl)Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH:8][CH2:2][C:3]#[N:4]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#CCCl
Solvent: ClCCl
Solvent: O
Product: N#CCNc1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
Chloroacetonitrile (40 ml) and 2,4-dichloroaniline (81.0 g) were heated with stirring in a 250 ml round-bottomed three-necked flask at 120°-125° C. for 1.0 hour and then for approximately 1 hour at 140°-145° C. The reaction mixture was cooled, diluted with CH2Cl2, and then placed in a separatory funnel and water added. Shaking the mixture resulted in crystal formation. The mixture was filtered and 39.2 g of 2,4-dichloroaniline hydrochloride removed. The CH2Cl2 layer was then separated from the filtrate and the CH2Cl2 layer treated with diatomaceous earth and activated charcoal and then filtered. The CH2Cl2 was then evaporated off, leaving a black viscous gum which on cooling with stirring solidified. Recrystallization from carbon tetrachloride gave 21.5 g of 2,4-dichloroanilinoacetonitrile.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:24]=3[F:23])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(C(F)(F)F)c4F)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 2-fluoro-3-trifluoromethyl-benzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). The mixture was stirred at room temperature overnight then quenched with methanol (1 mL). The resulting suspension was filtered and the solid was washed with methylene chloride to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide (0.8 g, 72%) as a white solid: mp 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 min. (99%); 1H NMR (DMSO-d6) δ 2.04-2.11 (s, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.79-8.01 (m, 5H), 9.26 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.91, 38.46, 48.87, 117.03 (117.29, 117.45), 120.65 (124.26), 122.03, 125.09 (125.15), 125.45 (125.64), 127.22, 129.24 (129.29), 131.58, 132.97, 134.89, 138.41, 154.37 (157.77), 162.90, 166.91, 167.45, 169.80, 172.73; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.13; H, 2.95; N, 8.73; F, 15.69.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]1[NH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>O>[C:1]1([NH:7][C:8]([N:19]2[C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=[C:18]2[CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1C(=O)Nc1ccccc1
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A solution of 11.9 g. (0.1 mol.) of phenylisocyanate in 75 ml. of toluene is added dropwise to the stirred suspension of 15.2 g. (0.12 mol.) of 2-methyl-5-nitroimidazole in 60 ml. of water at 10° to 12° C. When the addition is complete, the mixture is stirred for further 4 hours. The separated product is filtered off, washed and dried. 20.4 g. (82.9%) of 1-phenylcarbamoyl-2-methyl-5-nitroimidazole are obtained; m.p.: 218°-220° C.