Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].Cl>CCO.O>[Cl:1][C:2]1[N:12]=[C:9]2[CH:8]=[CH:7][CH:6]=[N:11][N:10]2[CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cn2ncccc2n1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Chloro-imidazo[1,2-b]pyridazine (10-1) was synthesized as shown in scheme 10, wherein chloracetaldehyde (55% in water, 126 ml, 880 mmol) was added to a solution of 6-chloro-pyridazin-3-ylamine (25.43 g, 196 mmol) and NaHCO3 (28 g, 334 mmol) in EtOH (600 ml) and then the reaction mixture was heated to reflux while stirring for 14 hours. The resulting dark brown reaction mixture was then concentrated under vacuum and the resulting residue reconstituted with dichloromethane (DCM). This solution was filtered through a celite pad and the solid washed with DCM and the solvent was then removed to yield a dark brown oil. 2M HCl (290 ml) and water (300 ml) was added to the residue and the resulting slurry was stirred at room temperature for 15 minutes. The solution was filtered through a celite pad and the filter cake was washed with water. The filtrate was extracted with diethyl ether (3×200 ml). The aqueous layer was cooled to 0° C. (ice bath) and neutralized using NaOH (24 g). The resulting slurry was extracted with diethyl ether (6×300 ml), dried using sodium sulfate and the diethyl ether was removed using a rotary evaporator to yield chloro-imidazo[1,2-b]pyridazine (10-1) as a light orange solid. MS: 155.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19].O>C(OCC)C>[F:16][C:17]([F:23])([F:22])[S:18]([O:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([F:11])([F:12])[F:10])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(Cl)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(OC(c1ccc(Cl)cc1)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (1.20 g, 5.70 mmol) was dissolved in diethyl ether (80 mL), and the resulting solution was cooled to 0° C. Then, 63% sodium hydride (217 mg, 5.70 mmol) was added thereto, and the resulting mixture was stirred for 1 hour. Thereafter, trifluoromethanesulfonyl chloride (0.910 mL, 8.55 mmol) was added dropwise thereto. Then, the temperature of the reaction solution was raised to room temperature, and the reaction solution was stirred for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 93:7 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (495 mg, yield: 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a well stirred solution of (+)-5-(benzyloxycarbonyl) -1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N-dimethylamino)pyridine (1.69 g, 13.80 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate (2.78 g, 13.80 mmol) at room temperature. The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2×50 mL). The organic layer was separated and dried (Na2SO4). The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20%-50%) as the eluent to give (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (5.37 g, 92%) as a viscous oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[S:17]([CH3:20])(=[O:19])=[O:18])C.O>O1CCCC1>[CH3:20][S:17]([N:12]1[CH2:13][C@H:14]([OH:16])[CH2:15][C@H:11]1[CH2:10][OH:9])(=[O:19])=[O:18]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C[C@H](O)C[C@H]1CO
Reaction time: 3 h
Yield: 87 %

Procedure:
To 360 ml of tetrahydrofuran was added 3.98 g (0.105 mol) of lithium aluminum hydride, and the mixture was stirred. To this mixture was slowly added dropwise a solution of 16.6 g (0.07 mol) of (2S,4R)-N-methanesulfonyl-4-hydroxyproline ethyl ester [III] in 200 ml of tetrahydrofuran under agitation and ice-cooling. After stirring the suspension at 0° C. for 3 hours and then at room temperature for 3 hours, 14 ml of water was added dropwise in small portions to the suspension under ice-cooling, and thereafter the mixture was stirred for 30 minutes. Any insoluble matter was removed by filtration and the filtrate was concentrated until dryness under reduced pressure whereby 11.9 g (yield: 87%) of an oily substance was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:25]/[N:24]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OCCO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 21 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)ethanol in 21% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD2Cl2) δ ppm 9.40 (s, 1H), 8.91 (m, 1H), 8.18 (d, 2H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.45 (dd, 1H), 6.13 (s, 2H), 4.46 (t, 2H), 3.97 (t, 2H), 2.39 (s, 3H). LCMS (method A): [MH]+=364, tR=4.28 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:11]([O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH3:12].CCCCCC>C(Cl)(Cl)Cl.CCOCC>[CH2:11]([O:13][C:14]([NH:16][C:17]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[S:18])=[O:15])[CH3:12]
Reactant: CCOC(=O)N=C=S
Reactant: COC(=O)c1sccc1N
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)NC(=S)Nc1ccsc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methyl 3-amino-2-thiophenecarboxylate (5.0 g (32 mmol) was dissolved in 16 mL of chloroform and to this solution 4.17 g (32 mmol) of ethoxycarbonyl isothiocyanate was added slowly with stirring at ambient temperature. A precipitate began to appear after a few minutes and after 20 min the volatile components were removed by evaporation under reduced pressure. The tan solid residue obtained was diluted with 20 mL of ether and allowed to stir for about 20 min and then 100 mL of hexane was added. The insoluble solids were recovered by filtration and dried to obtain 8.51 g of the title compound as a tan solid melting at 165°-167° C.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:9][C:8]=1[CH3:38])C.[Li+].[OH-].Cl>C1COCC1>[CH3:38][C:8]1[CH:9]=[C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2ccccc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2ccccc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of {2-methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid ethyl ester (210 mg, 0.37 mmol) in THF (3 mL is added LiOH (1.0 M, 2 mL). After stirred at room temperature for 2 hrs, it is acidified with 5 N HCl, extracted with ether, dried over sodium sulfate. Concentration gave the title compound (200 mg). MS (ES): 544.2 (M++1); the structure is also confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C@H:13]2[C:23]([O:25]C(C)(C)C)=[O:24])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C@H:13]2[C:23]([OH:25])=[O:24])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN1C[C@@H](C(=O)OC(C)(C)C)[C@@H](NC(=O)c2ccc(Cl)c(Cl)c2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C[C@@H](C(=O)O)[C@@H](NC(=O)c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
The tert-butyl ester of Example 9 (145 mg, 0.327 mmol) was dissolved in 5 ml of trifluoroacetic acid and stirred for 16 h at room temperature after which time the reaction was concentrated in vacuo. The resulting material was radially chromatographed on silica gel eluting with EtOH/CH2Cl2 /HOAc (5/95/1) to give the title compound (89 mg, 77%) as a colorless solid. Anal calcd for C17H20N2O4Cl2 : C, 52.73; H, 5.20; N, 7.23. Found: C, 52.43; H, 5.32; N, 7.02. DSC=204.6°-210.2° C.@54.8 J/g. MS M+1 calcd for C17H20N2O4Cl2 387, found 387.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[N:7]([CH:13]3[CH2:15][CH2:14]3)[C:6]=2[N:16]=1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:20][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([F:17])[C:2]([Cl:1])=[N:16][C:6]=2[N:7]([CH:13]2[CH2:15][CH2:14]2)[C:8]1=[O:12]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(Cl)c(F)cc12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(Cl)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of 3.83 g (15 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 23i) in 50 mL of dimethylformamide-dioxane (1:1) is cooled to 0° C. and treated portionwise with 0.8 g (20 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred to room temperature for 30 minutes, re-cooled to 0° C. and 3.2 g (16 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 300 mL with ice and water and stirred at 5° C. for 1 hour. The precipitate is removed by filtration, washed with water, ether and dried in vacuo to give 2.65 g of the title compound, mp 192–194° C. A second crop, (0.6 g) could be isolated by evaporating the filtrate and triturating the residue with petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:33]>O1CCCC1>[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([N:34]([C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH3:33]
Reactant: COC(=O)[C@H](C)NCc1ccc(F)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g, 195 mmol) in dry tetrahydrofuran (250 mL) at 0° C. was added 4-methyl morpholine (21.5 mL, 195 mmol) followed by isobutylchloroformate (25.3 mL, 195 mmol). The reaction was allowed to warm to ambient temperature and stirred for two hours. This was followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (43.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:33])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1.1 g) in dimethylformamide (13 ml), under an atmosphere of nitrogen, was treated with sodium hydride (117 mg of a 55-60% dispersion in mineral oil) in one portion, at -10° C. After 30 min at -10° C., iodomethane (174 μl) was added in one portion and the solution allowed to reach 0° C. over 1 h. The solvent was then removed in vacuo and the crude residue partitioned between water (100 ml) and dichloromethane (100 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed on silica, using 1:1 petrol:ethyl acetate as the eluant, to afford the title compound (0.75 g) as a white solid. Mp 205°-207° C. 1H NMR (360 MHz, CDCl3) δ 1.03-2.04 (10H, m), 2.76 (1H, m), 3.36 (3H, s), 5.10 (3H, m), 6.52 (1H, d, J=8 Hz), 7.25-7.55 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:22]COC)[C@H:12]([O:18]COC)[C@@H:13]([CH2:15][O:16][CH3:17])[O:14][C@H:8]3[N:7]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:6]=2[CH:33]=1.C(Cl)(Cl)Cl.CO>CO.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:22])[C@H:12]([OH:18])[C@@H:13]([CH2:15][O:16][CH3:17])[O:14][C@H:8]3[N:7]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:6]=2[CH:33]=1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](COC)O[C@H]21
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](COC)O[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
The compound (26) 63 mg obtained in Example 25 was dissolved in 1 ml of methanol saturated with hydrogen chloride and 3 ml of methanol, and the solution was stirred for 2.5 hours at room temperature. The solution was concentrated under reduced pressure, the resulting residue was poured into 0.5N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride successively. The solution was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (manufactured by Fuji Silicia Company), and 47.2 mg (yield 78.5%) of the title compound was obtained from the fraction of chloroform-methanol (19:1).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:14]([Li])(C)(C)C.IC>>[Cl:1][C:2]1[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cc(I)cnc1Cl
Reactant: [Li]C(C)(C)C
Solvent: CI
Product: Cc1cnc(Cl)c(C(=O)N(C)C)c1
Temperature: -90 °C
Yield: 62.9 %

Procedure:
A solution of 2-chloro-5-iodo-N,N-dimethylnicotinamide (0.385 g, 1.24 mmol), prepared as in Example 14, in 10 mL of THF was distilled to remove volatile gases. The residual solution was cooled -90° C. and then tert-butyllithium (1.9 mL, 2.48 mmol) was added over 3 to 5 minutes. Iodomethane (0.23 mL, 3.72 mmol) was added and the mixture was allowed to warm to room temperature. The mixture was partitioned between aqueous sodium carbonate (pH 10) and hexanes and the aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried (Na2 SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (3:1) to give 2-chloro-N,N,5-trimethylnicotinamide (0.152 g, 0.78 mmol), m.p. 117°-119° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20]Cl)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12
Solvent: Cc1ccccc1
Product: COc1c(NC(C)=O)c(OCCN2CCN(C)CC2)c(OC)c2occc12

Procedure:
A solution of 15.5 g (0.05 mole) of 5-acetamido 6-(2-chloro ethoxy) 4,7 dimethoxy benzofuran prepared in the preceding example and 15 g (0.15 mole) of N-methyl piperazine was brought to reflux for 8 hours in 100 ml of toluene. It was filtered and the filtrate evaporated under vacum the residue was taken up again in alcohol and hydrochloric alcohol was added. It was filtered and recrystallized in absolute alcohol.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[NH2:3].[C:13](/[C:15](=[CH:21]\OCC)/[C:16]([O:18][CH2:19]C)=[O:17])#[N:14].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH3:19][O:18][C:16]([C:15]1[CH:21]=[N:3][N:2]2[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6](=[O:8])[NH:14][C:13]=12)=[O:17]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCO/C=C(\C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h then cooled. Water (5 mL) was added and the mixture was stirred at ambient temperature for 1 h then filtered. The solid was washed with H2O, EtOH and Et2O then dried.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+].O.CCOCC>C(O)(C)C>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[CH2:9][OH:10])=[CH:21][CH:22]=1
Reactant: O=CC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
(4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetaldehyde, 124 (0.02 mol) was dissolved in isopropanol (20 mL) and sodium borohydride (0.02 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was dried and concentrated, and the residue was chromatographed to afford the title compound 125. 1H-NMR (DMSO, 400MHz): δ 7.75-7.24 (m, 8H), 5.59 (μs, 1H), 5.22 (m, 1H), 3.70 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccccc2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccc2)cs1
Yield: 57 %

Procedure:
4-Phenyl-3H-thiazol-2-one (5 g, 28.2 mmol) was dissolved in POCl3 (30 mL), and the mixture was refluxed overnight. The mixture was concentrated in vacuum, and the residue was purified by column chromatography to give 2-chloro-4-phenylthiazole (3.1 g, 57%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Se](=O)=[O:22].O1CCOCC1>O>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]=[O:22])=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(C)=O)cc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(C(=O)C=O)cc1

Procedure:
A mixture of 11.56 g. of 4'-(decyloxy)acetophenone, 4.6 g. of selenium dioxide, 150 ml. of dioxane and 4 ml. of water was refluxed overnight, filtered through diatomaceous earth, washed with dioxane and the filtrate evaporated to dryness. The residue was triturated with water, dried and crystallized from 150 ml. of hot acetone giving the desired product as an off-white solid, m.p. 81°-83° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=O)[CH3:12].O1C[CH2:27][CH2:26][CH2:25]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH3:12]/[C:11](/[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[CH:25]/[CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC/C=C(/C)c1ccc(C(=O)OC)cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Ethyltriphenylphosphonium bromide (4.2 g, 11.2 mmol) was dissolved in tetrahydrofuran (15 mL), and then potassium bis(trimethylsilyl)amide (11.2 mmol, 11.2 mL of a 1M solution in tetrahydrofuran) was added dropwise in the mixture at room temperature under stirring. After 10 minute, methyl 4-acetylbenzoate (1 g, 5.6 mmol) dissolved in toluene (30 mL) was dropwise and heated to 110° C. for 3 hours. The mixture was cooled and evaporated, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to get (Z)-methyl 4-(pent-2-en-2-yl)benzoate (610 mg, 56%). LRMS (M+H+) m/z: calcd 204.12. found 204.