Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:9])[CH2:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(CC(=O)c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3'-dihydroxydeoxybenzoin (0.05 mol), ethyl bromoacetate (0.05 mol) ad K2CO3 (0.05 mol) in 50 mL of DMF is stirred at room temperature overnight. The reaction mixture is poured into water and extracted with EtOAc. The organic solution is dried and evaporated to dryness. The crude products are separtated by flash chromatography to give the ethyl 2-(3-(2-(3-hydroxyphenyl)-2-oxoethyl)phenoxy)acetate and the ethyl 2-(3-(2-(3-hydroxyphenyl)-1-oxoethyl)phenoxy)acetate.
Reaction SMILES: C(OCC(C)C[Br:9])(C)(C)C.[Mg:11].C1(C)C=CC(S(OCC[C@H](C)CCCC(C)C)(=O)=O)=CC=1.OS(O)(=O)=O.[C:38]([O:42][CH2:43][C@H:44]([CH3:56])[CH2:45]CC[C@H](C)CCCC(C)C)([CH3:41])([CH3:40])[CH3:39]>O1CCCC1.CCOCC>[C:38]([O:42][CH2:43][C@H:44]([CH3:56])[CH2:45][Mg:11][Br:9])([CH3:41])([CH3:40])[CH3:39]
Reactant: [Mg]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C
Reactant: CC(CBr)COC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCCC(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](COC(C)(C)C)C[Mg]Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-3-tert. butoxy-2-methyl-1-propylmagnesium bromide was prepared from 3.34 g. (0.016 mole) of the S-(+)- 3-tert. butoxy-2-methyl-1-bromopropane and 0.42 g. (0.0176 mole) of magnesium powder in a total of 14 ml. of dry tetrahydrofuran as described in Example 4. To a stirring solution of 2 g. (6.4 moles) of (R)-(+)-3,7-dimethyl-1-octyl p-toluenesulfonate in 6 ml. of dry tetrahydrofuran cooled to -78° C. was added 7 ml. (~8 mmoles) of this Grignard solution dropwise followed by 033 ml. of a 0.1 M Li2CuCl4 solution in dry tetrahydrofuran. The resulting mixture was stirred at -78° C. for 10 minutes then in an ice bath (0°-5° C) for 2 hours and finally at room temperature for 16.5 hours. The reaction mixture was treated with 1 N aqueous H2SO4 and the product was isolated by extraction with ether in the manner of Example 1. Chromatography of the crude product (1.7 g.) on silica gel (50 parts) afforded pure (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane (eluted with 49:1 parts by volume hexane-ether). Evaporative distillation gave 1.19 g. (68.8%) of (2R,6R)-(+)-1tert. butoxy-2,6,10-trimethylundecane as a colorless oil, b.p. 75°-80° C. (bath temperature) (0.05 mm Hg.); [α]25D + 1.29°(c 2.01, hexane).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24]1([NH2:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[C:24]1([NH:30][C:8](=[O:9])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Diphenylcarbamic chloride (23 g, 0.1 mol, Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) was added to a solution of 10.1 g of triethylamine and 9.3 g (0.1 mol) of benzeneamine in 150 ml of chloroform. The resulting solution was heated under reflux overnight. The solution was cooled to room temperature and washed three times with 100-ml portions of brine solution, dried over anhydrous magnesium sulfate, and evaporated to give an off-white solid which was triturated with diethyl ether to give triphenylurea as a white solid, mp 136°-138° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:18]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
By substantially following the procedures of Example 1,A, 25.0 g (194 mmol) of nipecotic acid was protected with benzylchloroformate under basic conditions to afford 18.0 g (68 mmol; 35%) of analytically pure N-Cbz-nipecotic acid as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncccn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-2-ylcarbamate (200 mg, 0.739 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (190 mg, 70.4%) as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccoc1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccoc1
Yield: 42.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.48 g of 3-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.30 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-])=O)[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]=2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CCOC(C)=O.[Pt]>[NH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([O:6][C:5]1[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:8]([CH3:25])[N:9]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c(N)cccc21

Procedure:
The product from step (iii) (1.0 g) was dissolved in EtOAc (20 ml), triethylamine (1.1 ml) added, followed by 5% Pt/C (50 mg) and hydrogenated at 1 atm and RT for 6 h. The catalyst was filtered off and the filtrate evaporated to give a light brown solid. Yield 800 mg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH:12](OC)=[O:13]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][CH:12]=[O:13]
Reactant: COC=O
Reactant: CO[Si](CCCN)(OC)OC
Product: CO[Si](CCCNC=O)(OC)OC
Reaction time: 3 h

Procedure:
A mixture of 7 parts (39 mmol.) of 3-aminopropyltrimethoxysilane and 20 parts (330 mmol.) of methyl formate was heated under reflux in a nitrogen atmosphere. The reaction was monitored by gas chromatography and was found to be complete after 3 hours. Volatiles were then removed in vacuum, yielding the desired N-(3-trimethoxysilylpropyl)formamide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a solution of ethyl [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (4 g) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added 1N aqueous sodium hydroxide solution (17.4 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and water was added to the residue, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and crystallized from ethyl acetate and diethyl ether to give the title compound (2.2 g, yield 59%) as yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:15])=[N:7]2.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:7]2
Reactant: COc1c(Br)cc(Br)c2ccc(C)nc12
Reactant: O=Cc1ccccc1
Solvent: CO
Product: COc1c(Br)cc(Br)c2ccc(C=Cc3ccccc3)nc12
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 5,7-dibromo-2-methyl-8-methoxyquinoline (10.29 g) and benzaldehyde (15.84 g) is heated at reflux for 18 hrs. Upon cooling to room temperature, a precipitate forms. Methanol is added, and the reaction mixture is sonicated. The solid material is then collected by filtration. Crystallization from hot absolute ethanol yields 10.872 g of the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([N:8]2[CH:14](C)[CH2:13][C:12]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:11]=3[C:10]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[N:9]2)=[N:5][N:4]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.[Cl-].[Na+]>CN(C)C=O>[CH:32]1([NH:35][CH2:2][C:3]2[S:7][C:6]([N:8]3[CH2:14][CH2:13][C:12]4[CH:16]=[C:17]5[O:22][CH2:21][O:20][C:18]5=[CH:19][C:11]=4[C:10]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[N:9]3)=[N:5][N:4]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nnc(CCl)s1)OCO3
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2=NN(c3nnc(CNC4CC4)s3)CCc3cc4c(cc32)OCO4)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of 5 ml of dimethylformamide, 0.44 g (0.96 mmol) of (±)-7-(5-chloromethyl-1,3,4-thiadiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (Example 34) and 0.37 ml (5.31 mmol) of cyclopropylamine was stirred at 70-80° C. for 1 h. Then the reaction mixture was poured into 20% sodium chloride solution and, the precipitated crude product was extracted into ethyl acetate. The solution was washed with water, dried and after evaporation yielded 0.39 g (85%) of the title compound, as solid foam.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][N:17]([CH3:26])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (100 mg, 0.252 mmol) in DMF (1.5 mL), followed by the addition of K2CO3 (70 mg, 0.504 mmol) and MeI (60 mg, 0.423 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc, washed with water, brine, dried using anhydrous Na2SO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford 5-bromo-1-tert-butyl-2-[2-(1-methyl-1H-[1,2,4]-triazol-3-yl)-phenyl]-1H-benzimidazole (37 mg, 36%) as a light brown solid. LCMS (ESMS): m/z 410.58, 412.51 (M++1)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:24].ClC1[N:27]([C:41]2[CH:46]=CC(F)=CC=2)[C:28]2C(C(=O)C=1C(O)=O)=CC(F)=C[CH:29]=2.[NH:48]1CCSCC1>CN1CCCC1=O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:48]4[CH2:46][CH2:41][NH:27][CH2:28][CH2:29]4)[CH:11]=3)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: O=C(O)c1c(Cl)n(-c2ccc(F)cc2)c2ccc(F)cc2c1=O
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)cc32)cc1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)cc32)cc1
Temperature: 115 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
To a solution of 3.36 g of 7 chloro-1-p-fluoro-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (the product of Example 4(b)) in 35 ml of 1-methyl-2-pyrrolidinone at 115° C. is added 4.13 g of thiomorpholine. After stirring at 115° C. for 20 hours, the solvent is removed by reduced pressure to dryness. Methanol is added to the residue and the resulting mixture is filtered and washed with ethylacetate and then washed with water. The solid is dried, yielding 2.51 g 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid (9) ##STR36## R=p-fluorophenyl) in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.[Ar].Cl[C:23]([O:25][CH3:26])=[O:24].C(OCl)=O>ClCCl>[ClH:1].[CH3:26][O:25][C:23](=[O:24])[NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Reactant: COC(=O)Cl
Agent: O=COCl
Agent: [Ar]
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Product: Cl
Reaction time: 5 h
Yield: 230.5 %

Procedure:
Under stirring and argon 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (15 mg, example 35) was dissolved in dichloromethane (1.5 ml) and methyl chloroformate (4.6 mg) dissolved in dichloromethane (0.5 ml) was added. After stirring for 6 h and standing over night additional chloro formate (2.3 mg) was added. Stirring was continued for 5 h, then the solvent was removed and the residue was dissolved in water/2N hydrochloric acid and freeze dried to give 20 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A dimethyl sulfoxide (10 mL) solution of 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (13.58 g, 43.9 mmol) and triethyl amine (18.35 mL, 131.7 mmol) was cooled to 0° C. Pyridine sulfur trioxide (21.0 g. 131.7 mmol) in dimethyl sulfoxide (80 mL) was added in a steady stream. The cooling bath was removed and the reaction stirred 1.5 hours. The reaction was poured into 130 mL ice water and extracted with diethyl ether (2×180 mL and 100 mL). The combined organic portion was washed sequentially with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was chromatographed on silica gel (900 mL) eluting with ethyl acetate/hexanes (1:4), to give the title compound as a clear, colorless oil (9.20 g, 70%). MS (CI) m/z 208.0 (M−99).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1)(=[O:24])=[O:23]
Reactant: OCc1nnc(-c2ccccn2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)-pyridine (6 gm), and triethylamine (13.1 ml) in dichloromethane (150 ml) was added methanesulfonylchloride (5.31 gm) at 0° C. The reaction mixture was stirred at 0° C. over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (50 ml×2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide title compound in 7.5 gm quantity (88%) as oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].ClCCl>O>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Yield: 107.6 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (2.2 g) prepared in the Examples 1-3, triethylamine (1.2 g), methanesulfonylchloride (1.25 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated Na2SO4, and then condensed by filtration to obtain 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (3.2 g, yield 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)/[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:28]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[N:12][N:11]=[C:9]12)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCn1/c(=N/NC(=O)CCc2nnc(-c3ccccc3)o2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Yield: 66.7 %

Procedure:
The mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanohydrazide (485 mg, 1.11 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was concentrated to yield the desired product (310 mg, 66.7%). LCMS calculated for C21H23N8O2 (M+H): 419.2. found 419.2.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23]N[CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH:28]1CCNCC1>>[OH:27][CH:28]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24][CH2:23]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: OC1CCNCC1
Product: O=c1c2c[nH]c3ccc(N4CCC(O)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 4-hydroxypiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.39 (2H, brm), 1.83 (2H, brm), 3.15 (1H, d, J=5.22 Hz), 3.71 (1H, m), 4.19 (2H, m), 4.74 (1H, d, J=4.40 Hz), 7.16 (1H, tt, J=7.40, 1.10 Hz), 7.21 (1H, d, J=9.34 Hz), 7.42 (2H, m), 7.78 (1H, d, J=9.34 Hz), 8.21 (2H, ddd, J=7.69, 1.92, 1.10 Hz), 8.52 (1H, s). m/z 362.4 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: COc1cccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and m-anisoyl chloride (85 mg; 0.50 mmol; 2.0 eq.). Crude was purified on SPE NH2 column and the title compound was isolated as a white powder (26.9 mg, 32%). HPLC, Rt: 3.32 min. (purity 89.0%). LC/MS, M+(ESI): 306.4.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[C:23]([C:17](=[CH:16][NH:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:24]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1csc(-c2ccccc2)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1csc(-c2ccccc2)c1
Yield: 11.6 %

Procedure:
A mixture of 5-phenyl-3-thienylamine (1.00 g, 5.7 mmol) and ethyl (ethoxymethylene)cyanoacetate (950 mg, 5.7 mmol) in 20 mL of toluene is heated at reflux for 45 minutes. The reaction mixture is filtered while warm and the collected solid is washed with diethyl ether to provide 198 mg of ethyl 2-cyano-3-[(5-phenyl-3-thienyl)amino]-2-propenoate as white crystals, mp 190-193° C.; MS 296.9 (M−H)−.