Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: O=C(CBr)c1cnc2cc(Br)ccc2n1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
DIPEA (0.040 mL, 0.227 mmol) was added to a solution of 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.152 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (37.9 mg, 0.167 mmol) in acetonitrile (1.5 mL) and the mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was partitioned between EtOAc (20 mL)/aq. sat. NaHCO3 (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield crude (1R,3S,5R)-3-(2-(6-bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (63 mg) as orange solid. LC-MS retention time 2.74 min; m/z 476 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm 510. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1]([C:9]([OH:11])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][N:17]([C:9](=[O:11])[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH2:16][CH2:15]1
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CN(C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
Benzoylformic acid (1.0 g, 6.7 mmol), dimethylpiperidin-4-ylamine (854 mg, 6.7 mmol), DIPEA (3.5 mL, 20.0 mmol), and 1-hydroxybenzotriazole (1.4 g, 10 mmol) were dissolved in 20 mL of methylene chloride, then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.53 g, 7.99 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with a 1.0 N NaOH solution, then the organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (10-30% MeOH in methylene chloride gradient) to give intermediate (5a) (501 mg).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C@@:17]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]2=3)[C:14]([OH:16])=[O:15])[N:6]=1.[C:36](O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH3:36][O:15][C:14](=[O:16])[C@@H:13]([O:12][C:7]1[N:6]=[C:5]([CH3:4])[CH:10]=[C:9]([CH3:11])[N:8]=1)[C@@:17]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](Oc1nc(C)cc(C)n1)[C@@]1(c2ccccc2)NCC(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Sodium methylate (10.14 g, 186 mmol) is added at 0° C. to a solution of (±)-(1S*, 9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (5.0 g, 12 mmol, Example 49) in methanol (250 ml). The solution is stirred at rt for 3 h, poured into a solution of citric acid (12.6 g, mono hydrate) in water (600 ml) and extracted three times with EA. The organic phase is washed with brine, dried over MgSO4 and evaporated to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid methyl ester (5.04 g) as a white foam. LC-MS1: tR=0.94 min, [M+1]+=447.07.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1.Cl>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:18][C:17]([CH3:25])([CH3:16])[CH2:22][CH:21]([CH3:23])[CH:20]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: Cl
Solvent: CCCCCC
Product: CC1C=C(c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)CC(C)(C)C1
Reaction time: 24 h
Yield: 43 %

Procedure:
A mixture consisting of 30.9 g (0.15 mol) of 2,4-di-tert-butylphenol and 10.5 g (0.075 mol) of 3,3,5-trimethylcyclohexanone is melted together and is then saturated, with stirring, with hydrochloric acid gas at 35° C. After 24 hours, the reaction mixture is again saturated with hydrochloric acid gas and is then stirred for 20 hours. Subsequently, the green reaction mixture is diluted with hexane and washed with water and sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=49:1, giving 10.6 g (43%) of 2,4-di-tert-butyl-6-(3,5,5-trimethylcyclohexen-1-yl)phenol as a thick yellowish oil (compound (106), Table 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].[Li]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH:24]([C:23](=[O:28])[CH3:22])[C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: ICCC=CCCc1ccc(OCc2ccccc2)cc1
Agent: [Li]
Product: CC(=O)C(CCC=CCCc1ccc(OCc2ccccc2)cc1)C(C)=O

Procedure:
[I; Ar is 3-C6H5CH2OC6H4, R0 is H, R' and R" are CH3CO, Y is CH=CHCH2CH2 ] was prepared by reacting 6-(4-benzyloxyphenyl)-3-hexenyl iodide (Preparation D16) with lithium pentane-2,4-dione. The product was chromatographed on activated magnesium silicate and eluted with benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]1.[Br:24]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:24][C:19]#[C:18][C:16]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14][N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C#CBr)c(C(F)(F)F)n2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)4ethynyl-3-trifluoromethylpyrazole (3.1 g) in acetone (25 ml) was added N-bromosuccinimide (1.4 g) and silver nitrate (0. 14 g). Stirring was continued at room temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between ether and water. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane and then dichloromethane: hexane (1:1). Combination and evaporation of appropriate fractions, followed by crystallisation from hexane, gave the title compound as a white solid m.p. 92-94° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)[CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(C2CCCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixed solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added cyclohexanecarbonyl chloride (0.18 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide. To 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL)) was added, and the precipitate was collected by filtration to give the title compound (252 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:19].O>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCCCCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In diethylether (200 mL), 10-phenyl-1-decanol (10 g) was dissolved, phosphorus tribromide (4.0 mL) was carefully added thereto, at 0° C., followed by stirring at room temperature for 6 hours. Water was added carefully to the reaction solution, followed by extraction with tert-buthylmethylether. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (7.0 g) having the following physical property values.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 66.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (step 1 of example 132) (700 mg, 0.9889 mmol) was deprotected with TFA/DCM (5/20 ml). This afforded 400 mg (66.6% yield) of the titled compound. MS: m/z=608.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)(=O)C.CCCCCC>[CH2:26]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21

Procedure:
A suspension of 15.0 g (57.8 mmol) of 3,7-dimethoxyphenothiazine, 31.9 g (0.231 mmol) of powdered potassium carbonate, 61.29 g (0.289 mol) of 1 -iodohexane and 1.6 g (5.0 mmol) of tris-[2-(2-methoxymethoxy)ethyl]amine was heated to 110° for 64 hours. The working up was effected analogously to that described in Example 4.1.1.b. After chromatography on silica gel with ethyl acetate/hexane (1:4) 18.33 g (91.8%) of 10-hexyl-3,7-dimethoxy-phenothiazine were obtained as a brownish oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][NH2:10].Cl.O.[C:13]([OH:17])(=[O:16])[CH:14]=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][N:10]=[CH:14][C:13]([OH:17])=[O:16]
Reactant: O=CC(=O)O
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: O
Product: O=C(O)C=NNc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of (2-bromo-5-fluorophenyl)hydrazine (2.15 g, 10.5 mmol) and concentrated HCl (1.2 mL) in water (30 mL) was added glyoxylic acid hydrate (1.06 g, 11.5 mmol). The resulting mixture was stirred at room temperature for 2 h. The precipitate that formed was collected by filtration, washed with water and dried at reduced pressure to afford the title compound as a yellow solid (2.67 g, 98% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 12.57 (1H, s), 10.65 (1H, s), 7.65 (1H, s), 7.56 (1H, dd, J=8.7, 5.9 Hz), 7.31 (1H, dd, J=11.4, 3.0 Hz), 6.73 (1H, td, J=8.5, 3.0 Hz); LCMS (+ESI, M+H+) m/z 261-263.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)#[N:2].C(=O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].[H-].[Na+]>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][CH:35]=1)(=[O:40])=[O:41])=[O:9])#[N:2]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1OC(C(=O)O)c1ccccc1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2cc(OCc3ccsc3)ccc2C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 2 (0.73 g) in dry dichloromethane (50 ml) was treated with N,N' carbonyidilmidazole (0.36 g) and stirred at 25° C. for 2 hours, when evolution of carbon dioxide was complete. A solution of 4-isopropylbenzenesulphonamide (0.60 g) in dry dimethylformamide (20 ml) was treated with sodium hydride (0.13 g, 60% dispersion in mineral oil) and stirred at 25° C. for 2 hours. This solution was then treated dropwise with the solution of acylimidazole prepared above and stirring was continued at 25° C. for 8 hours. The reaction mixture was evaporated, the residue diluted with water (50 ml) and extracted twice with ethyl acetate. The extracts were washed with water, dried and evaporated to give an orange oil which was purified by flash chromatography on silica eluting with ether. Fractions homogenous in the required product were combined and evaporated. The residual pale yellow solid (0.35 g) was recrystallized from a mixture of ethyl acetate and pentane affording the title compound (0.20 g) as colourless crystals, m.p. 187-189° C. [Elemental analysis:- C,63.7; H,4.79; N,5.12%. Calculated:- C,63.7; H,5.17; N,5.17%].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:33]=[O:34])[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a cooled solution of 4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added anhydrous N,N-dimethylformamide (150 μL, 1.94 mmol) at −78° C. After being stirred at −78° C. for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 410 mg of the crude product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 428.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: O=Cc1ccccc1F
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=Cc2ccccc2F)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[N:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]1([C:8]2[CH:9]=[N:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 59.6 %

Procedure:
Trityl chloride (1.58 g, 5.67 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (1 g, 5.15 mmol) and triethylamine (1.04 g, 10.3 mmol) in DCM (12 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic phase collected was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 2% EtOAc in hexane as eluent) to afford 1.9 g (84.4% Yield) of 4-iodo-1-trityl-1H-pyrazole. Na2CO3 (727 mg, 6.86 mmol) was added to a stirred solution of 4-iodo-1-trityl-1H-pyrazole (1.5 g, 3.43 mmol) in toluene: H2O (4:1, 20 mL). Pd(PPh3)4 (790 mg, 0.686 mmol) and phenylboronic acid (838 mg, 6.86 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated to in vacuo. Purification by column chromatography (using neutral alumina and 5% EtOAc in hexane as eluent) afforded 790 mg (59.4% Yield) of 4-phenyl-1-trityl-1H-pyrazole. 1H NMR (300 MHz, CDCl3): δ 7.96-7.94 (s, 1H), 7.64-7.6 (s, 1H), 7.46-7.4 (d, 2H), 7.36-7.0 (m, 11H), 7.24-7.16 (m, 7H). A solution of 4-phenyl-1-trityl-1H-pyrazole (785 mg, 2.03 mmol) in ether.HCl (15 mL) was stirred for 1 hr. The reaction mixture was then concentrated under reduced pressure and washed with hexane to afford 320 mg (87.4% Yield) of 4-phenyl-1H-pyrazole hydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 8.1-8.08 (s, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.22 (t, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])=[CH:11][C:10]=1[Br:30])C1C=CC=CC=1.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[Br:30][C:10]1[CH:11]=[C:12]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CC1(c2ccc(OCc3ccccc3)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 78.3 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-benzyloxy-3-bromo-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.10 g, 0.20 mmol) and BBr3 (0.59 mL, 1.0 M dichloromethane solution). After normal workup, the pure objective compound (65 mg, 78%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, CDCl3) δ 1.70 (s, 3H, CH3), 5.51 (br s, 1H, OH), 6.76 (d, J=1.6 Hz, 1H, ArH), 6.94 (d, J=8.6 Hz, 1H, ArH), 7.02 (d, J=2 Hz, 1H, ArH), 7.28 (dd, J=8.6, 2.4 Hz, 1H, ArH); m.p. 228-229° C.; MS(EI) m/e 413 [M+], 381, 336, 299, 226; HRMS m/e cacld. for C16H10NO3Br1Cl2 412.9221, found 412.9195.
Reaction SMILES: [CH:1]([N:4]1[C:8](Cl)=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2].[Na].[CH3:12][OH:13]>>[CH:1]([N:4]1[C:8]([O:13][CH3:12])=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)n1nc(O)nc1Cl
Agent: [Na]
Product: COc1nc(O)nn1C(C)C
Temperature: -70 °C

Procedure:
An amount of 166 g of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole is added to a solution of 115 g of sodium in 1000 ml of methanol; the mixture is then refluxed for 15 hours. After separation of filtration of the precipitated sodium chloride, and concentration of the filtrate in vacuo, the residue is taken up in dilute acetic acid and extracted twice with ether. The ether is evaporated off, and the partially crystalline residue dissolved in a little methanol. On cooling of the solution to -70° C, the product crystallises out. There is thus obtained 43.5 g of 1-isopropyl-3-hydroxy-5-methoxy-1,2,4-triazole in the form of white crystals, M.P. 102° -103° C.