Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C(OCC)(=O)C.Cl.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.C[Si](Cl)(C)C.[Zn]>[F:26][C:20]([F:27])([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc (962 mg) in tetrahydrofuran (25 mL), trimethylsilyl chloride (1 drop) and ethyl bromodifluoroacetate (2.2 mL) were added at room temperature, and the mixture was stirred for 5 minutes under reflux by heating. To the reaction mixture, 3-nitrobenzaldehyde (695 mg) was added, and the mixture was stirred for 30 minutes under reflux by heating. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added to the mixture. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 60% hexane in ethyl acetate) to obtain ethyl 2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)propanoate (C29, 1.02 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]=O)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:29][OH:30]>C(Cl)Cl>[Cl:1][C:2]1[C:3](/[CH:17]=[N:29]/[OH:30])=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: NO
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(C=O)c21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(/C=N/O)c21
Temperature: 60 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-Chloro-2-hydroxy-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridine-7-carbaldehyde (20 mg) was dissolved in 3 mL of CH2Cl2. DIEA (130 uL, 10 eq.) and hydroxylamine hydrochloride (51.5 mg, 10 eq.) were added, and the resulting solution was stirred at 60° C. for 2 h. The solvent was evaporated, and the crude was purified by reversed phase HPLC using an acetonitrile/water gradient to give 15 mg of the desired product in 71.4% yield. m/z=283.20 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[O:32])=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc(C)c(OC)nc3[nH]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccnc(CS(=O)c2nc3cc(C)c(OC)nc3[nH]2)c1C
Temperature: -30 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine (784 mg, 2.37 mmol) was dissolved in a mixture of methanol (6 ml) and toluene (54 ml). Metachloroperbenzoic acid (566 mg) in a mixture solution of methanol (3 ml) and toluene (3 ml) were added thereto at −40° C. under nitrogen flow, and the reaction mixture was stirred at −20 to −40° C. for 2 hours. After the reaction was completed, a sodium bicarbonate solution was added, and the organic layer was separated. The aqueous layer was extracted with chloroform (40 ml), combined with the organic layer and dried over sodium sulfate, the solvent was evaporated and the residue was obtained which was then precipitated as a solid from a mixture of chloroform and ether, thereby yielding the title compound (654 mg, 1.89 mmol, 80%) as a purple gray solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH:1][CH:2]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]4)(=[O:36])=[O:37])=[CH:33][CH:34]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3cnnc4cc(Cl)ccc34)cc2)C1
Temperature: 3 °C
Reaction time: 0.75 h

Procedure:
3-Amino-1-ethylpiperidine (0.4 ml) in chloroform (15 ml) was treated with anhydrous sodium carbonate (2.94 g) in water (15 ml) and cooled to 3° C. The mixture was vigorously stirred and treated with 4-(7-chloro-4-cinnolinylamino)benzenesulphonylchloride hydrochloride (1.0 g). The dark orange mixture was stirred at 3° C. for 15 minutes, then at room temperature for 45 minutes. During this period the colour lightened considerably. The chloroform layer was separated and dried over magnesium sulphate. The residue on evaporation solidified when triturated with methanol, to give the title compound (0.5 g), m.p. 213°-15° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:18]1=[O:19].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:17][C:18](=[O:19])[CH:20]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2ccccc2o1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Oc2ccccc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (1.54 mL, 0.00600 mol) in methylene chloride (0.50 mL) was added to a mixture of coumarin (0.731 g, 0.00500 mol) and of trifluoroacetic acid in DCM (1M, 10 mL) at rt. The resulting mixture was stirred at rt for 1 h and was then washed with NaHCO3 (2 mL) and brine (2 mL) successively. The organic phase was dried (over Na3SO4), filtered, and concentrated. The residue was purified by CombiFlash (ethyl acetate/hexane 20%) to give the desired product (0.99 g).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1>O1CCOCC1>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:26])[CH2:20]4)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=3)=[CH:44][CH:43]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCCN(C(=O)OCc5ccccc5)C4)n3)cc2)CC1
Reaction time: 3 h
Yield: 57.2 %

Procedure:
A mixture of benzyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.404 g, 0.805 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.220 g, 1.00 mmol) and pTsOH monohydrate (0.167 g, 0.879 mmol) in dioxane (8 mL) was stirred at 100 C for 3 h. The mixture was then purified by HPLC to give benzyl 3-((2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate 45 (0.270 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.N12CCCN=C1CCCCC2>CC#N>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(CCl)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O

Procedure:
A solution of ethyl acetoacetate and 4-methoxybenzyl chloride is stirred under an argon atmosphere with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature in CH3CN. The mixture is partitioned between 3 N HCl and EtOAc. The organic extract is washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][OH:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NO)c1ccc(Br)cc1O
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A solution of methyl 4-bromo-2-hydroxybenzoate (Intermediate 22) (0.7 g) in dioxan (5 ml) was added dropwise to a solution of hydroxylamine hydrochloride (0.32 g) and sodium hydroxide (0.42 g) in water (10 ml) then stirred at room temp. for 18 h. The dioxan was removed under vacuum and the residue was stirred with 2N hydrochloric acid to give a precipitate which was collected by filtration, washed with water and dried to give the title compound as an off-white solid (0.63 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC.[F-].[NH4+]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:14]([F:17])([F:16])[F:15])[O:8]2)=[CH:3][C:2]=1[CH:23]=[CH2:24]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 g (0.7 mmol) ethyl 6-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 16 mg (0.0139 mmol) tetrakis(triphenyl-phosphine)-palladium(0) in 4.2 mL of anhydrous toluene under nitrogen atmosphere was added 228 uL (0.785 mmol ) tributyl(vinyl)tin. The resulting solution was heated to 115° C. for three h. To the cooled reaction mixture was added 20 ml of 20% ammonium fluoride. After stirring for 15 min, the product was extracted three times with ethyl acetate. The combined organic extracts were washed twice with 20% ammonium fluoride, washed with brine and dried over anhydrous magnesium sulfate. The crude product was purified by silica chromatography with EtOAc/hexane (1:9) and used directly in the next step.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[N+:17]([O-])=O)[CH2:7][CH2:8][C:2]=12.CCO>C1COCC1.[Pd]>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[CH:6]1[N:3]2[CH:4]=[N:5][CH:1]=[C:2]2[CH2:8][CH2:7]1)[C:13]#[N:14]
Reactant: N#Cc1ccc(C2CCc3cncn32)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reaction time: 8 h

Procedure:
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile (0.054 g, 0.212 mmol) is dissolved in THF (2 mL) and EtOH (2 mL) and 5% palladium on carbon (wet) (15 mg) is then added. The mixture is placed under an atmosphere of hydrogen overnight. The mixture is then filtered and concentrated. The residue is purified via HPLC (reversed phase, CH3CN/H2O) to give 3-amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile as a solid. MS (ESI) m/z 225.0 (M+H); 1H NMR (400 MHz, CH3CN) (TFA salt) δ ppm 2.45-2.57 (m, 1H), 2.99-3.16 (m, 3H), 4.47 (br s, 2H), 5.68-5.75 (m, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.21 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:11][C:6]1([C:3]2([CH2:2][O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9][O:10]1
Reactant: CC1(C2(CO)CC2)OCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C

Procedure:
To a stirred and ice-cooled solution of 3 (5.0 g, 31.6 mmol), N,N-dimethyl-4-aminopyridine (386 mg, 8.16 mmol) and triethylamine (22 mL, 158 mmol) in dichloromethane (25 mL) was added p-toluenesulfonyl chloride (7.23 g, 37.9 mmol) portionwise and the mixture was stirred in a cold room at 4° C. overnight. The mixture was poured into ice water, and the organic layer was separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 16.70 g of crude 4, as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [OH-].[NH4+:2].Cl([O-])(=O)(=O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:15]=4[O+]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1.O>C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:28])([CH3:29])[CH2:23][C:15]=4[N:2]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1
Reactant: [NH4+]
Reactant: Cc1[o+]c2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Yield: 50 %

Procedure:
Aqueous ammonium hydroxide solution (3 mL) was added to a suspension of 9-fluoro-3,3,6-trimethyl-1-oxo-2,3,4,7-tetrahydro-1H-5-oxonia-7-aza-benzo[c]fluorene perchlorate of Example 3b (0.72 g, 1.88 mmol) in isopropanol (2 mL). The reaction mixture was refluxed for 1 h, cooled, and water (5 mL) was added. Aqueous ammonium hydroxide solution was added to the mixture to pH 9. The precipitate was filtered off, washed with water and dried. The crude product was dissolved in acetone, and 37% aqueous hydrochloric acid (0.2 mL) was added. The precipitate was filtered off, suspended in hot water, and the mixture was basicified with ammonium hydroxide to pH 9. The product was filtered off, washed with water, dried and crystallized from toluene to give 0.26 g (50%) of colorless crystals; m.p. 244-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1C(=O)ON=C1c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(Cl)cc2)noc1Cl
Temperature: 2.5 °C
Yield: 57 %

Procedure:
A suspension of methyl 3-(4-chlorophenyl)-5-oxo-4,5-dihydroisoxazole-4-carboxylate (518 mg, 2.04 mmol; building block is commercially available) in POCl3 (3 mL) was cooled to 0-5° C., and upon stirring, Et3N (0.3 mL) was added dropwise. The resulting mixture was heated to 100-110° C. and stirred at this temperature for 2-2.5 h, cooled to room temperature, poured into iced water and neutralized with aqueous NaOH (10%). The product was extracted with ether and purified by column chromatography (hexane:EtOAc 25:2) to give 320 mg of a yellow solid. Yield 57%. 1H NMR (DMSO-D6, CCl4): 3.79 (3H, s, OCH3), 7.50 (2H, AB-syst., CH-arom.), 7.65 (2H, AB-syst., CH-arom.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[C:16]([O:35][CH3:36])[CH:15]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:25][CH:26]=3)=[C:16]([O:35][CH3:36])[CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(CCCOS(C)(=O)=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 60 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 60%. Recrystallization from ethyl acetate-hexane gave colorless prisms, m,p.95-96° C.
Reaction SMILES: N1CCCCC1.[CH2:7]([CH2:10][NH2:11])[CH:8]=[CH2:9].[OH:12][C:13]1([CH:25]([CH3:38])[CH2:26]C2C=C(S([O-])(=O)=O)C=CC=2C)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:7]([CH2:10][NH:11][CH2:38][CH:25]([C:13]1([OH:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:26])[CH:8]=[CH2:9]
Reactant: C=CCCN
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CC(C)C1(O)CCCCC1c1ccccc1
Solvent: C1CCNCC1
Product: C=CCCNCC(C)C1(O)CCCCC1c1ccccc1

Procedure:
The procedure of Example II is followed except that piperidine is replaced by allylmethylamine. Starting with 12 g allylmethylamine and 30 g of tosylate (Compound III), 5.9 g of product is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Product: CN1CCN(Cc2cc(-c3ccc(S(C)(=O)=O)cc3)nn(CC3CC3)c2=O)CC1
Yield: 80.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.9%).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)N.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:5][C:4]1[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: C/C(N)=C\C#N
Reactant: NNc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(N)n(-c2ccccn2)n1
Reaction time: 0.17 h

Procedure:
3-Aminocrotonitrile (1.98 g, 24.1 mmol) was added to a stirred solution of 2-hydrazinopyridine (2.63 g, 24.1 mmol) in a mixture of concentrated hydrochloric acid (2.5 ml) and water (10 ml). After 10 minutes at room temperature, concentrated hydrochloric acid (5 ml) was added, and the mixture was heated for 30 minutes under reflux. The mixture was cooled and rendered basic by the addition of saturated aqueous potassium carbonate. The solid which precipitated was filtered off and dried to give the title compound, 2.43 g (58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was dissolved in ethanol. The solution was cooled and filtered to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)- 1-benzopyran-3-carbonitrile (5A), a solid. A mixture of 5A with 250 ml of methanol containing 2 ml of sulfuric acid, was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (5B), as light yellow needles, m.p.: 106°-109°.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[N:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:42][C:43]=1[CH3:44])[CH2:12][N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30](O)=[O:31])[C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>ClCCCl.CN(C)C=O>[CH3:44][C:43]1[O:42][C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:40][C:39]=1[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30]([Cl:4])=[O:31])[C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)Cl)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 mL of oxalyl chloride was added to the solution of 10.0 g of (±)-4-{9-[3-methoxy-4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-butyric acid prepared by the example 27 in 1,2-dichloroethane (100 mL), and then 5 drops of N,N-dimethylformamide was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was vacuum concentrated, and (±)-4-(9-(4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxybenzyl)-9H-carbazole-4-yloxy)-2-methylbutanoyl chloride was prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10]3[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=3[C:12](=[O:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 220 °C
Reaction time: 6 h
Yield: 28.9 %

Procedure:
To a mixture of 5-(4-fluorophenyl)cyclohexane-1, 3-dione (0.98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was refluxed for 14 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 6 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtoAc/hexane) to give oil of 7-(4-fluorophenyl)-4methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).