Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28].Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[OH:31][N:30]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28]
Reactant: NO
Reactant: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 75.6 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (293 mg, 0.80 mmol) obtained in Example 11 was dissolved in ethanol (20 mL), and hydroxylamine hydrochloride (167 mg, 2.41 mmol) and pyridine (254 mg, 3.21 mmol) were added thereto, refluxed for 3 hrs, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 230 mg of 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (yield: 75%). Subsequently, 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (230 mg, 0.60 mmol) thus obtained was dissolved in methanol (20 mL), and 10%-palladium (230 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 90 mg of the titled compound (yield: 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:19]=[CH:18]/[CH2:17][CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH3:9]
Reactant: C=CCCC(=O)OCC
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 82 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/094362 and ethyl pent-4-enoate, the reaction was carried out in the same manner as the method described in Example 4(4c) to give the title compound as a colorless oily substance (yield 82%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:47]=[CH:46][CH:45]=[CH:44][C:22]=4[O:23][CH:24]([CH2:41][CH2:42][CH3:43])[C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:47]=[CH:46][CH:45]=[CH:44][C:22]=4[O:23][CH:24]([CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)O
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of diphenylmethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanoate (2.30 g) in a mixed solvent of tetrahydrofuran (30 ml) and methanol (15 ml) was added 1N sodium hydroxide solution (6.8 ml) at room temperature. The solution was stirred for two hours and concentrated under reduced pressure. The residue was diluted with water and acidified with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanoic acid (901 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:28])([F:27])[CH2:23][CH2:24][CH2:25]I.O>CN(C)C=O>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:24][CH2:23][C:22]([F:28])([F:27])[F:21])[C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: FC(F)(F)CCCI
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cccc3c(Br)ccc(c23)N1CCCC(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solutiion of 6-bromo-benzo[cd]indol-2(1H)-one (1 g, 4 mmol) in N,N-dimethyl formamide was added K2CO3 (5.53 g, 40 mmol) and the resulting mixture was stirred for 0.5 hour under nitrogen. 4,4,4-trifluorobutyl iodide (915 mg, 4 mmol ) was next injected to the solution and the mixture was heated at 60° C. for 18 hours. The reaction media was next poured into 200 ml water and extracted with trichloromethane (3×100 ml). Column chromatography using gradient ethyl acetate in hexane (10˜20%) gave the desired product (1.225 g, 85%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:29][CH:28]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C)cc3)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C)cc3)c[nH]c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
671 mg (10.3 mmol) of potassium cyanide and 31.5 mg (0.26 mmol) of 4-N,N-dimethylaminopyridine were added to 2.08 g (5.15 mmol) of the compound from Example 109A in 112 ml of DMSO. The mixture was stirred at 120° C. for 1 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.92 g (99% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:24]2[C:29]3[CH:30]=[CH:31][S:32][C:28]=3[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]2[CH2:22][CH2:23][N:18]([C:24]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:20]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (1.0 g, 4 mmol) was added to a solution under N2 of commercially available 4-piperazine-1-yl-thieno[3,2-c]pyridine [CAS-Nr. 106261-27-2] (0.85 g, 4 mmol) in 1,2-dichloroethane (45 ml) and AcOH (0.22 ml, 4 mmol). The resulting reaction mixture was stirred 8 h at room temperature before addition of Na(AcO)3BH (1.2 g, 6 mmol). Stirring was continued over night at room temperature. Sat. aq. NaHCO3 sol. was added and the product was extracted with EtOAc (2×). The combined organic layers were washed with H2O and brine. After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 90:10) to yield trans-{4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (1.2 g, 72%), MS (ISP) m/z=445.3 [(M+H)+].
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][CH2:7]Cl.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(O)C>[CH:24]1([N:30]2[CH2:7][CH2:6][N:5]([CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[CH2:4][CH2:3]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Oc1cccc(CC(c2ccccc2)N(CCCl)CCCl)c1
Reactant: NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1
Reaction time: 24 h

Procedure:
In ethanol (60 ml) are dissolved dl-N,N-bis(2-chloroethyl)-1-phenyl-2-(3-hydroxyphenyl)ethylamine hydrochloride (3.7 g) and cyclohexylamine (1.4 g) and thereto is added sodium hydrogen carbonate (3.0 g). The mixture is refluxed with stirring for 24 hours. After the reaction, the solvent is distilled off. The the residue is added a diluted sodium carbonate aqueous solution and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue (crude free base) is dissolved in a small amount of methanol and the mixture is made acidic with a 25% hydrobromic acid-acetic acid solution and allowed to cool. The precipitated crystals are washed with a mixture of acetone and ether and recrystallized from methanol to give the desired compound as dihydrobromide (2.9 g), melting point: 268°-270° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C>[C:17]([CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)#[N:18]
Reactant: N#CCCl
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC#N)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of methyl 4-hydroxyphenylacetate (10 g, 0.06 mol) in DMF (100 ml) was added to 97% NaH (1.78 g, 0.072 mol) in DMF (60 ml) in an ice bath. The reaction mixture was stirred for 0.5 hours and then chloroacetonitrile (5.44 g, 0.072 mol) in DMF (50 ml) was added. The reaction mixture was stirred at room temperature for about 2 days, the solvent was removed in vacuo, and the residue was partitioned between water and ether. The organic layer was separated, washed with saturated Na2CO3 and then brine, and then was dried over MgSO4, filtered and concentrated in vacuo to afford 12.2 g of methyl 4-(cyanomethoxy)phenylacetate.
Reaction SMILES: [N:1]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.P(Br)(Br)[Br:25]>C(Cl)Cl.O>[Br:25][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Solvent: ClCCl
Solvent: O
Product: BrCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of [4-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)phenyl]methanol (1.5 g, 4.91 mmol) in DCM (50 mL) is added phosphorus tribromide (0.667 mL, 6.8 mmol). The reaction mixture is stirred for 15 minutes at 0° C. The reaction mixture is diluted with water (100 mL) at 0° C. and extracted with DCM (2×200 mL). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an off white solid (1.1 g, 61%). ESI/MS m/z 369 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[CH2:16]([OH:19])[CH2:17][CH3:18].CS(O)(=O)=O>C1(C)C=CC=C(C)C=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:16][CH2:17][CH3:18])[N:10]=[C:11]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:12]=[CH:13][NH:14]1
Reactant: CCCO
Reactant: Cc1ccc(-c2ncnc(Cl)n2)c(C)c1
Agent: CS(=O)(=O)O
Solvent: Cc1cccc(C)c1
Product: CCCOC1(c2ccc(C)cc2C)N=C(c2ccc(C)cc2C)N=CN1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 500 mL round-bottomed flask fitted with a condenser, a magnetic stirrer and a nitrogen atmosphere is charged with 5.48 g (0.0169 mol) of 4,6-bis-(2,4-dimethylphenyl-2-chloro-s-triazine, 10.2 g (0.169 mol) of n-propanol, 2,37 g (0.0246 mol) of methane-sulfonic acid and 25 mL of m-xylene. The mixture is stirred at 90° C. for one hour. The mixture is then allowed to cool to room temperature and vacuum filtered through a plug of silica gel which is subsequently washed with 95:5 heptane:ethyl acetate. The combined organic layers are vacuum filtered through another plug of silica gel. The solvent is removed under reduced pressure to afford 3.31 g of the title compound as off-white crystals melting at 86-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:3]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:4][CH:5]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:7]=1
Reactant: O=C(CSc1cccc(Cl)c1)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: Clc1ccccc1Cl
Product: O=C(CSc1ccc(S(=O)(=O)Cl)c(Cl)c1)Nc1ccccc1

Procedure:
A mixture of 250 g. (0.9 mole) of 5-chloro-2-(phenylthio)acetanilide and 116.52 g. (1.0 mole) of chlorosulfonic acid in 2.5 liters of o-dichlorobenzene is heated at 150°-160°C for 2 hours in an oil bath. The reaction mixture is cooled, washed with 1 liter of cold sodium carbonate solution, washed with water and then dried using magnesium sulfate. Removal of the solvent by distillation under vacuum yields the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32]([CH3:34])=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32]([CH3:34])=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([OH:13])=[O:12])=[O:6]
Reactant: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-[(3,4-difluorebenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (EXAMPLE 94, step 4; 505 mg, 0.959 mmol) in CH2Cl2 (2 mL) is treated with TFA (2 mL) and maintained at 0° C. for 30 min. The ice bath is removed, and after 1 h, the solution was diluted with CH2Cl2 and concentrated (3×). The residual oil is diluted with H2O (10 mL) and extracted into CH2Cl2 (3×25 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 430 mg (95%) of the title compound as a slightly yellow, amorphous solid:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36](O)=[N:37][CH:38]=1>>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1

Procedure:
The titled compound was prepared following the general procedure for Mitsunobu reaction using (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol and 5-Chloro-pyridin-2-ol. ES-MS m/e: 559.2 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH:37]3[CH2:39][CH2:38]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNCC4CC4)c23)ccc1OCc1ccccn1
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)CC1CC1
Yield: 23 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(cyclopropylmethyl)amino]ethoxy}quinazolin-4-amine (obtained as described in Example 15, preparation of starting materials) to give the title compound in 23% yield; NMR spectrum (DMSO-d6)-0.04-0.04 (m, 2H), 0.13-0.29 (m, 2H), 0.74-0.83 (m, 1H), 2.98 (d, 1H), 3.66-3.80 (m, 2H), 3.85-3.93 (m, 2H), 4.12-4.32 (m, 4H), 5.08 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.09-7.17 (m, 2H), 7.30-7.40 (m, 2H), 7.47-7.54 (m, 1H), 7.63-7.68 (m, 1H), 7.73-7.82 (m, 1H), 8.21-8.29 (m, 1H), 8.37 (d, 1H), 9.62 (s, 1H); Mass spectrum MH+ 534.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C:8]([C:10]1[C@@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][O:7][C:8]([C:10]1[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]([C:18]([O:20][CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][O:41]2)=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCCCO2)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 36 mg of (4S)-5-(2-acetamidoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid in 0.5 ml of tetrahydrofuran were added 7.7 mg of p-toluenesulfonic acid, and then 0.24 ml of 3,4-dihydro-2-H-pyrane. The mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified using preparative TLC to obtain 18 mg of the objective compound.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:27])/[CH:24]=[CH:25]/[CH3:26])=[CH:16][CH:15]=1>C(O)C.COCCOCCOC>[CH2:7]([O:6][C:4]([CH:3]1[CH:25]([CH3:26])[CH2:24][C:23](=[O:27])[N:22]([CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:2]1=[O:10])=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Solvent: COCCOCCOC
Product: CCOC(=O)C1C(=O)N(CCc2ccc(F)cc2)C(=O)CC1C

Procedure:
Sodium (1.5 g, 65.1 mmol) was dissolved in ethanol (50 mL) and the solution was concentrated under vacuum. The residue was suspended in toluene (50 mL) and bis(2-methoxyethyl)ether (30 mL). Diethyl malonate (4.0 mL, 26.5 mmol) was added, followed by a suspension of trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (5.00 g, 24.1 mmol) in bis(2-methoxyethyl)ether (20 mL). The mixture was heated at reflux for 6 hours. The cooled mixture was washed with 1.0 N aqueous hydrochloric acid, then with water, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% ethyl acetate in hexane, to provide a pale yellowish oil which slowly crystallized (5.81 g, 75%). This appeared to be a mixture of cis and trans isomers (approximately 15% cis). 1H NMR (300 MHz, CDCl3) δ7.20 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.28 (m, 2H), 4.00 (m, 2H), 3.66 (d, J=5 Hz, 0.15H), 3.27 (d, J=10 Hz, 0.85H), 2.82 (m, 3H), 2.53 (m, 1H), 2.33 (dd, J=17, 10 Hz, 1H), 1.34 (m, 3H), 1.09 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 322.0 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Br)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:27])[Cl:25])=[O:21])=[C:15]([CH3:17])[CH2:19][S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 73.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (0.54 g.), chloroform (5 cc) and pyridine (0.16 g.) was heated under reflux for 2.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated. The residue was crystallized from ether to yield crystals (0.34 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161° - 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][CH:37]1[CH2:39][O:38]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:36][CH:37]3[CH2:39][O:38]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cn(CC2CO2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.00 g, 2.47 mmol) in N,N-dimethylformamide (10 mL), Cs2CO3 (970 mg, 2.977 mmol) was added and stirred for 10 minutes at room temperature. Then 2-(chloromethyl)oxirane (2.28 g, 24.64 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 14 hour at room temperature and diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (60/40) to give 500 mg (44%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24), [M+H]+=461.1, RT=1.30 min.