Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)([O:22][CH3:23])=[O:21].N1CCCC1.O1CCCC1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:20]([O:22][CH3:23])=[O:21])[CH:25]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Solvent: C1CCOC1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of 17 g of 6-benzyloxy-4-chromanone, 11.3 g of 3-carbomethoxybenzaldehyde, 14.4 g of pyrrolidine, 100 ml of tetrahydrofuran and 300 ml of methanol was stirred at room temperature overnight. The volatiles were evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel eluting with dichloromethane. The product fractions were combined and concentrated to an oil which crystallized upon trituration with methanol to give 17.2 g of title product, m.p. 109-112° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][C:12]1([C:19](Cl)=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:19]([C:12]3([CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC1CCCC(C)(C(=O)Cl)C1
Product: CC1CCCC(C)(C(=O)c2c[nH]c3ncc(Br)nc23)C1

Procedure:
(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1,3-dimethyl-cyclohexyl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and 1,3-dimethyl cyclohexanecarbonyl chloride (Journal of Organic Chemistry (1951), 16 920-9) following general procedures as described in these Examples. M+H=336.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1CCC(F)(F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.213 g DTAD was added into a solution of 5-fluoro-2-nitro-phenol, 0.105 g 4,4-difluorocyclohexanol, 0.25 g triphenylphospine in 2 ml of anhydrous methylene chloride at rt. The reaction mixture was stirred at rt overnight when TLC analysis indicated the consumption of the 5-Fluoro-2-nitro-phenol. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 10% potassium carbonate solution. The aqueous layer was extracted with methylene chloride (2×25 ml) and the combined organics washed with sodium hydrogecarbonate solution (25 ml). The organic layer was passed through a phase separator and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 iso-hexane/EtOAc).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:10][F:11])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].Cl.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[F:1][CH2:2][C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:20]=1)([CH3:9])[CH2:10][F:11]
Reactant: CC(CF)(CF)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(CF)(CF)c1cc(N)n(-c2ccccc2)n1
Temperature: 95 °C
Yield: 59.7 %

Procedure:
According to the procedure described in Example 161B Step 2, 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (0.81 g, 5 mmol) and phenylhydrazine hydrochloride (0.868 g, 14 mmol) in EtOH were heated at 95° C. for 2 hours, to afford 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine as solid (0.75 g, 52%). LC-MS (ESI) m/z 252 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:39][CH3:40]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][O:39][CH3:40])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: COCc1ccccc1CI
Product: COCc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 1-iodomethyl-2-methoxymethylbenzene analogous to Example 57, step B.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[Cl:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[Cl:12][CH2:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: O=CCCNCCl
Reactant: C=CCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(CCl)CCC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-chloromethylamino-propionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-chloromethyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH2:16])[CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:16][C:21](=[O:22])[CH2:20][CH2:19][Cl:18])[CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)=[O:22]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc2c(=O)c3cc(N)ccc3[nH]c2c1
Product: O=C(CCCl)Nc1ccc2c(=O)c3cc(NC(=O)CCCl)ccc3[nH]c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2,6-Diamino-9(10H)-acridone (AR-ACO-8, 8.40 g, 37.3 mmol was suspended in 3-chloropropionyl chloride (100 mL), stirred at room temperature for 1 hr, at 90° C. for 1 hr, and at reflux for 6 hr. Allowed to stand at room temperature overnight and then chilled with ice-water. The product was collected and washed with acetone (2×30 mL) followed by toluene (3×30 mL), acetone again (4×30 mL), ethanol (2×30 mL), dry ether (2×30 mL) and finally hexane (2×30 mL). The product was dried over P2O5 under vacuum to yield a yellow solid AR-ACO-09 (12.96 g, 86%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][OH:14])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>O1CCCC1>[CH2:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:13][OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: N[C@H](CO)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Yield: 73.04 %

Procedure:
To a 250 mL three-neck round bottom flask, 9.65 g (0.0497 mol) (R)-2-amino-N-benzyl-3-hydroxypropionamide, 120 mL tetrahydrofuran, and 7.58 g (0.0749 mol) triethylamine were added in sequence, the mixture was stirred to obtain a solution. At a normal temperature, 6.01 g (0.0554 mol) ethyl chlorocarbonate was added. After the reaction was completed, the solvent was evaporated, and the residue was added with 100 mL water, and stirred uniformly. The solution was extracted with 50 mL×3 ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated, to obtain a white solid of 9.67 g (0.0363 mol). The molar yield was 73.04%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH3:35])[C:25]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1.C([O-])(O)=O.[Na+]>CCO>[Br:21][C:22]1[CH:23]=[C:24]([CH3:35])[C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[CH3:20])[N:3]=3)[C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1
Reactant: Cc1cc(Br)cnc1N1CCN[C@H](C)C1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-chloro-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (1.30 g, 4.44 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (1.2 g, 4.44 mmol), and NaHCO3 (0.71 g, 8.46 mmol) in EtOH at 50° C. for 20 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[CH2:12]([Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C)([Cl:17])[Cl:16])[CH:13]=[CH2:14]>>[Cl:16][Si:15]([Cl:17])([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:13]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:14].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: C=CC[Si](Cl)(Cl)CCCCCC
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CCCCC[Si](Cl)(Cl)CC(C)[c-]1cccc1
Reaction time: 2 h
Yield: 26 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 0.60 g(3.22 mmol) of ferrocene was reacted with 1.45 g(6.44 mmol) of allyl -n-hexyldichlorosilane under the dry nitrogen atmospheric pressure for 2 hrs. After the addition of the catalyst solution, the reaction mixture was stirred for 2 hrs to complete the alkylation. The solvent was distilled off at atmospheric pressure and the products were then extracted with 20.0 mL of hexane. By vacuum distillation of the reaction products at 300° C. and at 0.5 torr, (3,3-dichloro-1-methyl-3-silaoctyl)ferrocene [yield: 26%(based on the reacted ferrocene), bp:(165-170° C./0.5 torr)] was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].Cl[C:11]([F:18])([F:17])C(OCC)=O.[F-:19].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]([F:18])([F:19])[F:17])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: [F-]
Reactant: Cc1ccc(I)cc1Cl
Reactant: CCOC(=O)C(F)(F)Cl
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 116 °C
Reaction time: 70 h
Yield: 135.7 %

Procedure:
2-Chloro-4-iodotoluene (22.0 g) was dissolved in N,N-dimethylformamide (110 ml), and copper(I) iodide (49.8 g), ethyl chlorodifluoroacetate (37.8 g) and potassium fluoride (15.2 g) were added. The mixture was stirred at internal temperature of 116° C. for 70 hr. The reaction mixture was filtered through celite. Water (11 ml) and diethyl ether (110 ml) were added to the filtrate under ice-cooling and the mixture was filtered through celite. The filtrate was separated and the aqueous layer was extracted again with diethyl ether (110 ml). The organic layers were combined and washed with saturated brine (110 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-chloro-4-trifluoromethyltoluene (23.0 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([OH:19])[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:4].Cl.[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CS(C)=O.O>[Cl:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][O:19][C:8]1[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=[C:12]2[C:7]=1[CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[N:5]([CH:3]=[O:4])[CH2:14][CH2:13]2
Reactant: ClCc1cccc(CCl)c1
Reactant: COc1cccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CC2c3c(cc(OC)c(OC)c3OCc3cccc(CCl)c3)CCN2C=O)c1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (80 mg, 1.96 mmole, 60%) in dimethyl sulfoxide (1 ml) was added a solution of intermediate 2 obtained in Referential Example 2 (350 mg, 0.98 mmole) at room temperature under nitrogen, and the reaction mixture was stirred for 10 minutes. The resulting mixture was added dropwise to a solution of α,α'-dichloro-m-xylene (172 mg, 0.98 mmole) in dimethyl sulfoxide (1 ml) at room temperature, and stirred for 2 hours. The reaction mixture was chilled in ice, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel/ethyl acetate) to give the desired compound (387 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[N:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[N:26][CH:25]=1>>[CH:30]([OH:32])=[O:31].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:28]3[CH:27]=[N:26][CH:25]=[C:24]([O:23][CH2:22][C:21]([F:34])([F:33])[F:20])[N:29]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: O=C(O)c1cncc(OCC(F)(F)F)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cncc(OCC(F)(F)F)n3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white solid. MS (ISP): m/z=478.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:16]1[C:17]([Cl:33])=[CH:18][C:19]([F:32])=[C:20]([N:22]2[C:26](=[O:27])[N:25]([CH2:28][CH2:29][CH2:30][F:31])[N:24]=[N:23]2)[CH:21]=1.[ClH:34]>C(#N)C.[Cu](Cl)Cl>[Cl:34][CH:2]([CH2:3][C:16]1[CH:21]=[C:20]([N:22]2[C:26](=[O:27])[N:25]([CH2:28][CH2:29][CH2:30][F:31])[N:24]=[N:23]2)[C:19]([F:32])=[CH:18][C:17]=1[Cl:33])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cl
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(Cl)Cc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cold, stirred mixture of 5.54 g (0.0553 mole) of ethyl acrylate, 10 mL of acetonitrile, 0.43 g (0.0042 mole) of tert-butyl nitrite, and 0.45 g (0.0033 mole) of copper (II) chloride was added a solution of 0.80 g (0.0028 mole) of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one (which may be prepared as described in International patent publication WO 87/03873, Example 1 A-E) in 10 mL of acetonitrile. The reaction mixture was stirred at room temperature for five hours and then was diluted with 2N hydrochloric acid. The acidic mixture was extracted with three portions of diethyl ether. The extracts were combined and dried over anhydrous magnesium sulfate. The dried organic phase was filtered and the filtrate was evaporated leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-heptane: ethyl acetate (2:1) to yield 1.1 g of ethyl 2-chloro-3-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazol-1-yl]phenyl]propionate as an oil, compound 3 of Table 1.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[O:16]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:12][O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: CC(=O)Oc1ccc(C2=COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(C2=COc3ccccc3O2)cc1
Yield: 77.4 %

Procedure:
A mixture of 4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (270 mg, 1.0 mmol) in MeOH:THF (5 mL:3 mL) and K2CO3 (167 mg, 1.2 mmol) was stirred for 30 min at rt. The solvent was removed under reduced pressure and water was added. The solution was neutralized by dilute HCl and the solid was isolated by filtration, washed well with water and dried to give 175 mg of 4-(benzo[b][1,4]dioxin-2-yl)phenol (77%). MS (ES) m/z: 225.97 (M), 224.93 (M−1); Mp. 137-140° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([O:3][CH3:4])=[O:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]([OH:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
3β-Carbomethoxyandrost-5-ene-7,17-dione (42) (0.5 g, 0.0014 mol) was dissolved in a mixture of dichloromethane (5 mL) and methanol (10 mL). The mixture was stirred at room temperature and finely powdered sodium borohydride (0.16 g, 0.004 mol) was added slowly. After 15 min the reaction mixture was quenched with water and the product was extracted with methylene dichloride. The organic layer was washed, dried and solvent removed. The product was crystallized from acetone-petroleum ether to afford 0.35 g (70%) of 3β-carbomethoxyandrost-5-ene-7,17β-diol (49) as a white crystalline solid, m.p. 150-52° C. LC-MS and 1H NMR analysis of the product showed a 8:2 ratio of isomeric 7β-hydroxy and 7α-hydroxy compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CC(=O)O
Yield: 83.4 %

Procedure:
2.0 g of ethyl 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetate, 15 ml of methanol, 5 ml of water and 0.8 g of potassium hydroxide are treated in the same manner as described in Example 8. 1.50 g of 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][N:3]1[NH2:12].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH-].[Na+].[OH:28][CH2:29][C:30](OC)=O>CCO>[N:1]1[C:30]([CH2:29][OH:28])=[N:12][N:3]2[C:2]=1[C:11]1[N:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:5]=[CH:4]2
Reactant: N=c1c2ncccc2ccn1N
Reactant: COC(=O)CO
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1nc2c3ncccc3ccn2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of 8-imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzenesulfonate (1.2 g, 2.83 mmol) in EtOH (30 mL) was added NaOH (227 mg, 5.67 mmol). The mixture was stirred at 60° C. for 1 h. Then methyl 2-hydroxyacetate (773 mg, 8.50 mmol) was added. The resulting mixture was stirred at reflux for 2 h. The mixture was concentrated and purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give [1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol as a yellow solid (280 mg, yield 49%). ESI MS: m/z 201.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[C:7]([CH3:9])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:9])/[CH2:8][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: C=C(C)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OCC)OCC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1, E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:16]=3)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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.O>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28]5)[CH:16]=4)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]3)=[CH:4][CH:3]=2)=[CH:34][N:35]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1ccc(C2(c3ccc(Br)cc3)C=CC(=O)CC2)cc1OC1CCCC1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(C2(c3ccc(-c4cnc(N)nc4)cc3)C=CC(=O)CC2)cc1OC1CCCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 4-(4-bromophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cylohexen-1-one (1.39 g, 3.17 mmol) in Toluene (50 ml) was added tetrakis(triphenylphosphine)palladium(0) (417 mg, 0.36 mmol), followed by 2-(2-aminopyrimidin-5-yl)-4,4,5,5-tetramethyl-1,3-dioxaborolane (2.02 g, 6.1 mmol, prepared as described in Tatsuo Ishiyama; Miki Murata and Norio Miyaura, J. Org. Chem. 1995, 60, 7508-7510), ethanol (8 ml) and 2M sodium carbonate (8 ml). The reaction mixture was stirred under argon at 80° C. for 18 h. Water was added and the mixture extracted three times with ethyl acetate, the combined organic extract was washed with water then brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (silica gel, 73% ethyl acetate/27% hexane) provided the title compound as a white solid (1.2 g, 83% crude yield). MS (m/e): 456 [(M+1)+].