Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][OH:14])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:14][CH2:13][CH2:12][C:8]1[C:9](=[O:11])[O:10][C:5]2[CH:4]=[C:3]([O:17][CH3:18])[C:2]([O:1][CH3:21])=[CH:16][C:6]=2[C:7]=1[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1OC

Procedure:
40.0 g (160 mmol) of 6-hydroxy-3-(2-hydroxyethyl)-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 41), 45.4 g (320 mmol) of methyl iodide and 66.3 g (480 mmol) of potassium carbonate in 500 ml of DMF are stirred for 22 hours at 60° to 80° C. The reaction solution is evaporated, extracted with chloroform, and the organic phase is washed with dilute sodium hydroxide and with water, dried with Na2SO4, and re-evaporated. Yield 31.6 g (75%); m.p. 184°-187° C. (from isopropanol).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([O:28][CH2:29][P:30]([CH3:33])([CH3:32])=[O:31])=[O:27])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:33][P:30]([CH2:29][O:28][C:26]([C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18][CH2:19][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:35][CH:34]=1)=[O:27])([CH3:32])=[O:31]
Reactant: CP(C)(=O)COC(=O)c1ccc(N)cc1
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CP(C)(=O)COC(=O)c1ccc(-n2c(-c3ccccc3)cc3c2-c2ccccc2CC3)cc1

Procedure:
A mixture of 2.6 g. (0.01 mole) of 2-phenacyl-1-tetralone, 2.3 g. (0.01 mole) of dimethylphosphinylmethyl p-aminobenzoate, 0.4 g. of p-toluenesulfonic acid, and 250 ml. of dry toluene was heated under reflux for 73 hours, concentrated to about 100 ml., diluted with 25 ml. of cyclohexane, and cooled. The solid which separated was collected to provide 2.6 g. (57%) of solid, m.p. 171°-173°. Recrystallization from cyclohexane-benzene gave pale yellow crystals, m.p. 180°-181°.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH2:24]([O:23][C:22]1[C:17]2[N:18]([C:2]([CH3:15])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][C:11](=[O:13])[NH:10][C:9]=4[CH:14]=3)[N:16]=2)[CH:19]=[CH:20][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Product: Cc1c(-c2ccc3oc(=O)[nH]c3c2)nc2c(OCc3ccccc3)cccn12
Yield: 27.7 %

Procedure:
5-(8-Benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-benzoxazolinone (0.8 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-2-benzoxazolinone (2.1 g) and 2-amino-3-benzyloxypyridine (4.8 g). mp. 264°-265° C. (dec.).
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1.C(O)C.Cl.[NH2:20][OH:21]>O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:20][OH:21])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(O)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
115.2 g (1.405 moles) of sodium acetate, 108.9 g (0.800 mole) of p-hydroxyacetophenone and 1000 ml of ethanol were added to a solution of 56.8 g (0.817 mole) of hydroxylamine hydrochloride in 1000 ml of water, and then the mixture was refluxed for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to a volume of about 500 ml, and the concentrate was allowed to cool at room temperature for 23 hours to precipitate crystals. The crystals were washed with 500 ml of water, and dried in air for 24 hours and in vacuo for a further 6 hours to give 102.1 g (84.5%) of p-hydroxyacetophenone oxime in the form of colorless needles melting at 145°-146°.
Reaction SMILES: [Li].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Cl-:13].[Cl-].[Cl-].[Cl-].[CH:17]1([Nb+4:22])[CH:21]=[CH:20][CH:19]=[CH:18]1>O1CCCC1>[Cl-:13].[Cl-:13].[Cl-:13].[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][Nb+3:22][CH:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: [Nb+4]C1C=CC=C1
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C1=CC([Nb+3]Oc2cccc3cccnc23)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.01 moles of the lithium salt of 8-hydroxyquinoline in 30 mL of tetrahydrofuran (prepared as described in Example 3) is added dropwise to a solution of 0.01 moles of cyclopentadienyl niobium tetrachloride in 50 mL of tetrahydrofuran at −78° C. After warming to room temperature and stirring overnight, the suspension is filtered and the solvent evaporated under vacuum. The product is recovered by extraction with toluene and then isolated by evaporating the toluene. Polymers may be produced using this catalyst by following the procedure of Example 4.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[S:8][C:7]2=[C:9]([C:12]([O:14]CC)=[O:13])[N:10]=[CH:11][N:6]2[CH:5]=1>CO>[Br:3][C:4]1[S:8][C:7]2=[C:9]([C:12]([OH:14])=[O:13])[N:10]=[CH:11][N:6]2[CH:5]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A 2 M aqueous solution (10 ml) of potassium hydroxide was added to a solution of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (265 mg, 0.96 mmol) in methanol (20 ml), and the mixture was stirred at room temperature for 18 hr. Methanol was removed by distillation under the reduced pressure, and the reaction solution was poured into 2 M hydrochloric acid (30 ml) under ice cooling to precipitate a solid. The resultant solid was washed with water, and a mixed solvent composed mainly of ethanol and toluene was added thereto. The solvent was removed by distillation under the reduced pressure, and the residue was thoroughly dried to give 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (236 mg, quantitative) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:19](=[O:20])[N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 50 ml of chloroform was dissolved 10.2 g (0.05 mole) of 1-(4-acetylphenyl)-piperazine at room temperature, and 6.8 g (0.05 mole) of diethylcarbamoyl chloride was dropped to the solution over a period of 30 minutes. The mixture was stirred at room temperature for 5 hours, and the insoluble substance was removed. The filtrate was subjected to distillation under reduced pressure and the residue was made alkaline by 4 N aqueous solution of sodium hydroxide and extracted with 100 ml of toluene. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a benzene-hexane mixed solvent to obtain 1-(4-acetylphenyl)-4-diethylcarbamoylpiperazine having a boiling point of 72° to 76° C. The so obtained free base was dissolved in chloroform, and the solution was saturated with gaseous hydrogen chloride and stirred for a certain time. Then, the solution was subjected to a post treatment according to customary procedures to obtain 8.6 g of 1-(4-acetylphenyl)-4-diethylcarbamoylpiperazine hydrochloride having a melting point of 145° to 152° C.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:53](Cl)(OC1C=CC=CC=1)[O:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(OCC)(=O)C.O>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:53]([O:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(Oc3ccccc3)nc12
Reaction time: 5 h
Yield: 11 %

Procedure:
To a mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (140 mg) and sodium carbonate (14 mg) in ethyl acetate (1.5 ml) was added dropwise a solution of 1,1-dichloro-1,1-diphenoxymethane (67 mg) in ethyl acetate (1 ml) in water bath and the mixture was stirred at same temperature for 5 hours. The reaction mixture was evaporated in vacuo and dissolved in chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phenoxy-1H-benzimidazol-4-yl)carbonylaminobenzamide (18 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(F)c1)c1cccc(F)c1

Procedure:
A solution of 1,1-bis(3-fluorophenyl)-2-methoxyethanol (156.7 g) (obtained by the reaction of 3-fluorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (160 cc) is heated to reflux for 16 hours, cooled and poured into a mixture of saturated sodium carbonate solution (800 cc) and ethyl acetate (500 cc). The organic phase is washed with water (2×500 cc) and with saturated sodium chloride solution (500 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-fluorophenyl)acetaldehyde (144.5 g) in the form of a yellow oil.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH3:12])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1
Reactant: CSC(=S)NN=Cc1c[nH]c(C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncc2cn[nH]c(=S)n12

Procedure:
A mixture of 53.9 gm. of 3-(2-methyl-4-imidazolyl-methylene)dithiocarbazic acid methyl ester and 200 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 280.5°-284° C.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]2[N:5]([C:9](=[S:21])[NH:10][C:11]=2[C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][N:8]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([S:21][C:9]1[N:5]2[CH:6]=[CH:7][N:8]=[C:3]([NH2:2])[C:4]2=[C:11]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nccn2c(=S)[nH]c(-c3cc4ccccc4[nH]3)c12
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(SCc3ccccc3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
A solution of 8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazine-3(2H)-thione hydrobromide (10 mg, 0.04 mmol) and benzyl bromide (5.1 uL, 0.043 mmol) in DMF (1.0 mL) was charged with N,N-diisopropylethylamine (18 uL, 0.11 mmol) and stirred at rt for 2 h. The solvent was then removed in vacuo and the crude product was dissolved in purified by preparative TLC eluting with 3% NH3/MeOH in DCM to afford 2.5 mg 3-(benzylthio)-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, MeOD) δ ppm 4.25 (s, 2H), 6.76 (s, 1H), 6.92 (d, J=5.05 Hz, 1H), 7.06-7.14 (m, 3H), 7.14-7.23 (m, 4H), 7.28 (d, J=5.05 Hz, 1H), 7.48(d, J=8.08 Hz, 1H), 7.63 (d, J=8.08 Hz, 1H); MS (ES+): m/z 373.35 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12](O)=O)=[N:9][NH:10][CH:11]=1)=[O:5].[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:28][C:29]=3[N:34]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A mixture of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid (75 mg, 0.25 mmol), 4-morpholin-4-ylmethyl-benzene-1,2-diamine (52 mg, 0.25 mmol), EDC (58 mg, 0.3 mmol) and HOBt (41 mg, 0.3 mmol) in DMF (4 ml) was stirred at ambient temperature for 48 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion washed with saturated aqueous NH4Cl, dried (MgSO4) and reduced in vacuo. The residue was taken up in AcOH and heated at 100° C. for 14 hours. cooled to ambient temperature and reduced in vacuo. The residue was purified via flash column chromatography eluting with CH2Cl2-MeOH (20:1-10:1) to give 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (30 mg) as a pink solid. (LC/MS: Rt 2.12, [M+H]+ 471.14).
Reaction SMILES: [OH:1][C:2]1([C:18]([F:21])([F:20])[F:19])[CH2:6][S:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=O)[S:11][C:12]=2[CH3:13])=[N:3]1.NC(NC1C=C(C(OC)=S)SC=1C)=[S:24].BrCC(C(F)(F)F)=O>>[OH:1][C:2]1([C:18]([F:21])([F:20])[F:19])[CH2:6][S:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[S:24])[S:11][C:12]=2[CH3:13])=[N:3]1
Reactant: COC(=O)c1cc(NC2=NC(O)(C(F)(F)F)CS2)c(C)s1
Reactant: COC(=S)c1cc(NC(N)=S)c(C)s1
Agent: O=C(CBr)C(F)(F)F
Product: COC(=S)c1cc(NC2=NC(O)(C(F)(F)F)CS2)c(C)s1
Yield: 54 %

Procedure:
Methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiophene-2-carboxylate: Using a procedure similar to Example 204, step (a), 56 mg (0.21 mmol) of methyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate was allowed to react with 40 mg (0.21 mmol) of bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, Wis.) to afford 40.3 mg (54%) of methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C11H11F3N2O3S3, 373.00 (M+H), found 373.0.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][CH:24]1[NH:25][CH2:26][CH2:27][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:29]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC1CNCCN1
Product: CC1CN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CCN1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2-methylpiperazine to give 264. MS: (ESI+)=396.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:14]([CH3:17])([O-:16])=[O:15].Cl.CN.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:17]/[N+:14]([O-:16])=[O:15]
Reactant: O=Cc1ccc(C(F)(F)F)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)cc1Cl
Reaction time: 12 h
Yield: 33.1 %

Procedure:
2-chloro-4-(trifluoromethyl)benzaldehyde (400 mg, 1.92 mmol) was diluted with nitromethane (727 μl, 13.4 mmol) followed by the addition of methylamine hydrochloride (77.7 mg, 1.15 mmol) and sodium acetate (94.4 mg, 1.15 mmol). After stirring for 12 hours, the reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield (E)-2-chloro-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (160 mg, 0.636 mmol, 33.2% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.CCCCCC.[CH:27]([C:29]1[CH:41]=[CH:40][C:32]([C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)=[O:28]>O1CCCC1.C(O)C.ClCCl>[Si:6]([O:5][C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[CH:27]([C:29]1[CH:41]=[CH:40][C:32]([C:33]([N:35]([CH2:36][CH3:37])[CH2:38][CH3:39])=[O:34])=[CH:31][CH:30]=1)[OH:28])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: -78 °C
Yield: 52.3 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (61.7 g, 0.21 mol), prepared as in Example 1, was dissolved in 500 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butyllithium in hexane (132 mL, 0.21 mol) was added dropwise at a rate to maintain the temperature below -70° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred via cannula to another vessel containing a cold (-78 ° C.) solution of 4-formyl-N,N-diethylbenzamide (44.1 g, 0.21 mol), from above, in 500 mL of dry tetrahydrofuran under nitrogen. The transfer rate was monitored to maintain the temperature below -70° C. After stirring for one hour at -78° C., the reaction was quenched with saturated aqueous ammonium chloride, warmed to room temperature and diluted with diethyl ether. The ethereal layer was washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane: ethanol (0-1%) gave 45.4 g (52%) of 4-(3-(tert-butyl dimethylsiiyloxy)-α-hydroxybenzyl)-N,N -diethylbenzamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: OB(O)c1ccc(F)nc1
Product: O=C(O)c1ncc(-c2ccc(F)nc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and 6-fluoro-3-pyridineboronic acid, the title compound was obtained as white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH2:28][CH2:29][CH2:30][O:31][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: O=S(=O)(CCCO)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.2 %

Procedure:
tert-Butyldimethylchlorosilane (508 mg) and diisopropylethylamine (587 μL) were added to a solution of 3-(4-bromophenylsulfonyl)propan-1-ol (784 mg) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2.5 hours. tert-Butyldimethylchlorosilane (127 mg) and diisopropylethylamine (147 μL) were added to the reaction solution, and the mixture was stirred at room temperature for further two hours. tert-Butyldimethylchlorosilane (254 mg) and diisopropylethylamine (1.17 mL) were added to the reaction solution, and the mixture was stirred at room temperature for further 30 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→33:1→19:1→9:1) to give the title compound as a white solid (720 mg, 65%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(OCC)C>[ClH:1].[CH3:20][C:18]1[O:17][N:16]=[C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[N:19]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)no1

Procedure:
20 mL 4 mol/L HCl solution in dioxane was added to 3.35 g 4-(5-methyl-(1,2,4) oxadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 20 mL dioxane was stirred over night. The mixture was diluted with diethylether and the precipitate was filtered and washed with diethylether to give 2.5 g of the desired product.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])(=[O:6])=[O:5])[CH2:2][CH3:3].[Br:33][CH2:34][CH2:35]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)C>CN(C=O)C.O>[CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[O:13][CH2:35][CH2:34][Br:33])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCBr
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of trans-2-(3-n-propylsulfonyl-4-hydroxy-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (4.66 g, 10 mmol), 1,2-dibromoethane (1.84 mL, 20.5, mmol) and K2CO3 (4.0 g) in DMF (20 mL) was heated with stirring at 80° C. for 1 h. The reaction mixture was cooled and partioned between ethyl ether and water. The organic layer was separated, dried, and evaporated to a crystalline mass. Recrystallization from ethyl ether-hexane afforded the title compound, mp 135°-136° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]([OH:14])=O)=[O:5])[CH3:2].S(Cl)([Cl:17])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]([Cl:17])=[O:14])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Product: CCOC(=O)c1cnn(C)c1C(=O)Cl
Yield: 110.7 %

Procedure:
A mixture of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (6.00 g) and thionyl chloride (82.8 g) was refluxed for 4 h. Excess thionyl chloride was removed under educed pressure; the obtained crude product (7.26 g, assumed purity ˜60%, 66%) was used in the next step without further purification.