Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone in 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridinium dichromate. The reaction mixture is stirred at room temperature for 16 hours and then poured into 125 ml of water. The resulting precipitate is removed by filtration and the filtrate extracted with 9:1 chloroform-methanol. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo and combined with the precipitate above. The combined solids are purified by flash chromatography on silica gel by eluting with 1:1 ethyl acetate-hexanes to give 0.27 g of the desired product.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]1[C:22]2([CH3:23])[CH:9]([CH:10]3[CH:19]([CH2:20][CH2:21]2)[C:18]2[CH:17]=[C:16]([CH2:24][CH3:25])[C:15]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:14][C:13]=2[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:27]([O:26][C:15]1[C:16]([CH2:24][CH3:25])=[CH:17][C:18]2[CH:19]3[CH:10]([CH2:11][CH2:12][C:13]=2[CH:14]=1)[CH:9]1[C:22]([CH3:23])([C:6](=[CH:5][CH2:4][OH:3])[CH2:7][CH2:8]1)[CH2:21][CH2:20]3)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=C1CCC2C3CCc4cc(OCc5ccccc5)c(CC)cc4C3CCC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCO)CCC12
Reaction time: 6 h

Procedure:
A solution of (3-Benzyloxy-2-ethyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-ylidene)-acetic acid ethyl ester (0.92 g, 2 mmol) in 20 ml dry THF was cooled to 0° C. under nitrogen before LiAlH4 (0.15 g, 4 mmol) was added in a portion wise manner. After 6 hours at 0° C., the mixture was quenched with aq. NH4Cl, the organics were extracted with ethylacetate. The organic layer was washed with water, brine, dried over MgSO4 and the solvents were evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 15/1 to 6:1) to give 2-(3-Benzyloxy-2-ethyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-ylidene)-ethanol, 0.75 g (89%), as a white powder, mp=61-62° C.; 1H NMR (CDCl3, 270 MHz): 0.84 (s, 3H, CH3), 1.20-1.66 (m, 9H), 1.82-2.02 (m, 3H), 2.21-2.51 (m, 3H), 2.71 (q, J=7.4 Hz, 2H, CH2), 2.87 (m, 2H, H6), 4.16 (m, 2H, CH2OH), 5.07 (s, 2H, CH2Ph), 5.31 (m, 1H, CHCH2OH), 6.66 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.30-7.48 (m, 5H, Ph).
Reaction SMILES: CC1C=CC(S(O[CH:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=3)=[C:19]([O:31][CH3:32])[CH:18]=2)[C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[H][H]>C(O)C.[Pd]>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:18][C:19]=2[O:31][CH3:32])[N:25]=1
Reactant: [H][H]
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)ccc1Oc1cccc(F)n1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CC(F)(F)F)ccc1Oc1cccc(F)n1
Yield: 80 %

Procedure:
A solution of 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethyl 4-methylbenzenesulfonate (0.2 mmol; 96 mg) in ethanol (3 ml) containing a catalytic amount of Pd/C (10% wet; 0.014 mmol; 30 mg) was stirred for 16 h at rt under 2.5 atm of hydrogen. Purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) afforded the title compound (48 mg; 0.16 mmol; 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](Br)=[C:11]([Br:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]([CH3:21])[CH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:20][CH2:19][CH:18]([CH3:21])[CH3:17])=[C:11]([Br:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Br)c(Br)cnn1-c1cccc(Cl)c1
Reactant: CC(C)CO
Product: CC(C)COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 194B, starting with 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone (Example 207A) in place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone and substituting 2-methyl-1-propanol in place of methanol.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>>[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([C:19]4[CH:20]=[CH:21][C:22]5[N:23]([C:25]([C:28]([F:29])([F:31])[F:30])=[N:26][N:27]=5)[N:24]=4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C1NCN(c2ccccc2)C12CCN(c1ccc3nnc(C(F)(F)F)n3n1)CC2

Procedure:
A mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-phenyl-8-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17].C(O)(C)C>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([CH3:8])[NH:22][C:21]=1[NH2:23])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccco1
Yield: 78 %

Procedure:
Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 183°C (isopropanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=O.[H-].[Na+].C[Si](C=[N+]=[N-])(C)C.Cl.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>C(Cl)Cl.O.CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=1)=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cncc(Br)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOC(=O)C=C(OC)c1cncc(Br)c1
Temperature: 40 °C
Reaction time: 36 h
Yield: 53 %

Procedure:
A solution of methyl 5-bromonicotinate (15.0 g, 69.4 mmol) in ethyl acetate is treated with NaH (60% in mineral oil, 2.4 g) and gently heated at 40° C. until a mild exotherm occurs. After cessation of reflux, the reaction mixture is treated with additional NaH (2.27 g, 139 mmol total), heated at reflux temperature for 16 h, cooled to room temperature and diluted with CH2Cl2 and water. The organic phase is separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The resultant oil is dissolved in acetonitrile and methanol, treated with a 2M solution of trimethylsilyl diazomethane (TMSCHN2) in hexanes (70 ml, 140 mmol), stirred for 36 h and treated with 5% aqueous HCl. After cessation of nitrogen evolution, the phases are separated and the organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. The resultant residue is chromatographed through a plug of silica gel (4:1 hexanes:EtOAc) to give the title compound as a light brown solid, 10.1 g (53% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Si:9]([O:16][CH2:17][CH2:18][CH2:19]O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:9]([O:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:6])[CH2:7][CH2:8][NH:1][C:2]1=[O:3])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: O=C1CCNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)CCNC1=O

Procedure:
A mixture 5,6-dihydrouracil (4.45 g, 39.028 mmol), 3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-ol (3 mL, 13.01 mmol) and Cs2CO3 (16.95 g, 52.04 mmol) in dry DMF (120 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. Purified by chromatography on silica gel using ethyl acetate and hexane (60:40) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])=[CH:16][CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:40]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 489.23 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.O>CN1CCCC1=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Piperazine (12.9 g) was suspended in N-methyl-2-pyrrolidone (130 mL), and a solution of 2-chloro-5-trifluoromethylpyridine (9.08 g) in N-methyl-2-pyrrolidone (30 mL) was added dropwise. The mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give 1-(5-trifluoromethyl-2-pyridyl)piperazine (11.5 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:15])[CH:11]=[CH:12][CH:13]=1.[CH:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>C1(C)C=CC=CC=1.C(O)C.O>[CH:24]([C:26]1[CH:31]=[C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:15])[CH:9]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(NCCN1CCCC1)c1cccc(Br)c1
Reactant: O=Cc1cccc(OB(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2cccc(C(=O)NCCN3CCCC3)c2)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Palladium tetrakistriphenyl phosphine (735 mg) and 2 M aqueous sodium carbonate (21.2 ml) were added to a solution of 3-bromo-N-[2-(1-pyrrolidinyl)ethyl]phenylcarboxamide (6.31 g) in toluene (50 ml), and then a solution of 3-formylphenylboric acid (3.49 g) in ethanol (15 ml) was added thereto, and the mixture was stirred at 90° C. for 15 hours. The reaction solution was diluted with water and then extracted with diethyl ether. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (6.83 g) was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=2)[N:9]=1.[CH3:30]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1.O>[CH:27]([C:23]1[N:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][CH:12]=3)[C:8]([CH3:30])=[N:9]2)[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28]
Reactant: CB(O)O
Reactant: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A first flask was charged with 1,4-dioxane/H2O (30 mL/5 mL). The flask was cooled to 0° C. and vacuum was applied for 20 minutes. A second flask was charged with K2CO3 (2.92 g, 21.1 mmol), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (1.98 g, 5.28 mmol), diacetoxypalladium (0.0592 g, 0.264 mmol), methylboronic acid (0.948 g, 15.8 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.270 g, 0.528 mmol). The second flask was evacuated with vacuum and back filled with N2 for 3 times. The cold degassed dioxane/H2O was then added to the second flask, which was again evacuated with vacuum and back filled with argon 5 times. The reaction mixture was heated to 80° C. for 3 hours. The reaction was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO3, dried (Na2SO4) and concentrated to give the desired product, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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(OCC)(=O)C>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
In 1,2-dimethoxyethane(12 ml) were dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (566 mg, 2.00 mmol) and 3,4-methylenedioxyphenyl borate (465 mg, 2.80 mmol). To the mixture were added sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol), and the mixture was stirred at 80° C. for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was extracted with water (5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 15 g, ethyl acetate/hexane=1/19), and the desired fraction was concentrated under reduced pressure. To the residue was added diisopropylether, and the insoluble materials were filtered, which were washed with diisopropylether and dried under reduced pressure to give methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (434 mg, 1.34 mmol, 67%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=1.[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@@:25]([CH:30]([CH3:32])[CH3:31])([C:27](O)=[O:28])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1.CS(Cl)(=O)=O>>[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@:25]([C:27]([N:9]3[CH2:8][CH2:7][C:6]4[N:5]=[CH:4][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:12][C:11]=4[CH2:10]3)=[O:28])([CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: CS(=O)(=O)Cl
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1

Procedure:
N-((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)-N-[(cis-3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1, is synthesized by sequentially coupling three building block compounds 4, 5 and 6 (Schemes 3, 4 and 5, below). An amidation reaction between 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine, 5, and (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)1-isopropylcyclopent-2-ene-1-carboxylic acid, 4, is carried out in the presence of methanesulfonyl chloride to afford 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine. Deprotection of the pyrrole group was carried out at this stage using hydroxylamine as a through process to provide an amine salt. The amine salt and (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, are coupled through reductive amination, in the presence of a tributylamine buffer, and with NaBH(OAc)3 to afford (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2. The cyclopentene moiety of compound 2 was then hydrogenated to form free base compound 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ocnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 12.6 %

Procedure:
Combine 5-methyl-benzoxazole (0.5 g, 3.75 mmol), NBS (0.7 g, 3.93 mmol), AIBN (60 mg, 0.37 mmol), chloroform (10 mL) and reflux for 1 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain the title compound as a white solid (0.1 g, 13%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(OCCCC)(=O)C.[Br:21][CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>P([O-])([O-])([O-])=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC(C)=O>[Br:21][CH2:22][C@@H:23]([OH:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CCCCOC(C)=O
Product: COC(=O)C[C@H](O)CBr
Yield: 74.9 %

Procedure:
A solution was prepared by dissolving 75 g of glucose, 0.85 g of oxidized form of nicotine adenine dinucleotide phosphate, 0.11 g of glucose dehydrogenase (glucose amino 2; by Amano enzyme) in 1500 g of a phosphate buffer solution (pH 6.5) and 1300 g of butyl acetate and 37 g of methyl 4-bromo-3-oxobutanoate were added thereto, and then 150 g of the acetone-treated cells of Penicillium citrinum IFO 463described above were added to thereto under stirring. 15% aqueous sodium carbonate solution was dropwise added thereto so that the pH of the reaction solution is maintained within a range of from 6.5±0.5. After stirring for 24 hours, 90 g of celite were added thereto and filtered under reduced pressure. The organic layer separated from the filtrate was concentrated under reduced pressure to give 28 g of methyl (S)-4-bromo-3-hydroxybutanoate, Chemical Purity: 88%, Optical purity: 97% e.e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:25][CH3:26])(=O)=O.C(OCC)(=O)C.Cl>[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH3:26])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-t-butoxycarbonyl-L-tyrosine (II, EXAMPLE 1, (235 g, 835 mmol) is dissolved in sodium hydroxide (4N, 705 mL) at 20-25°. Diethyl sulfate (210 mL, 1.60 mol) is added over 15-20 min. The reaction mixture is stirred for 2 hr, then it is cooled with ice-bath (internal temperature around 15°). Ethyl acetate (1400 mL) is added, followed by slow addition of hydrochloric acid (3N, 1410 mL) for 1 hr. The ethyl acetate layer is separated, and the aqueous layer is extracted with ethyl acetate (1400 mL). The ethyl acetate phase is concentrated to about 200 mL, then hexane (1600 mL) is added. The mixture is stirred in an ice-bath for 2 hr, filtered, washed with hexane (800 mL) in 3 portions. The precipitate is dried to give the title compound. The filtrate is concentrated, suspended in ethyl acetate/hexane (80/450 mL) for 2 hr, filtered and washed with hexane (250 mL) in 3 portions and dried to give additional title compound, NMR (MeOH-d4) δ7.11, 6.80, 4.22, 4.05, 3.08, 2.86 and 1.36; CMR δ175.4, 159.3, 157.8, 131.3, 130.4, 115.4, 80.5, 64.4, 56.4, 37.9, 28.7 and 15.2.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][CH3:17])[N:11]=1)(C(C)(C)C)(C)C.CO.[OH-].[Na+]>C(O)C>[CH2:15]([N:12]1[CH:13]=[N:14][C:10]([CH2:9][OH:8])=[N:11]1)[CH2:16][CH3:17]
Reactant: CCCn1cnc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCn1cnc(CO)n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole (from Example 74, Step a) (2.97 g, 11.6 mmol) in ethanol (13 ml) and methanol (26 ml) was added 4 M aqueous NaOH (4.3 ml, 17.4 mmol) and the mixture was stirred at 45° C. for 2 days. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, EtOAc, then 10% MeOH/CH2Cl2) to leave 1.509 g (92%) of the title compound as a white solid: 1H NMR (250 MHz, CDCl3) δ 0.94 (3H, t, J=7.4 Hz), 1.92 (2H, sextet, J=7.4 Hz), 4.10 (2H, t, J=7.1 Hz), 4.76 (2H, s), 8.01 (1H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[CH3:11][NH2:12].Cl>C(O)C>[CH3:11][NH:12][C:5]1([C:8]([OH:10])=[O:9])[CH:6]=[CH:7][CH:2]=[N:3][NH:4]1
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: Cl
Solvent: CCO
Product: CNC1(C(=O)O)C=CC=NN1
Temperature: 100 °C

Procedure:
3-Chloropyridazine-6-carboxylic acid (2.5 g) (R. F. Homer, H. Gregory, W. G. Overend and L. F. Wiggins, J. Chem.Soc (1948) 2195-9) was treated with 8M methylamine in ethanol (2.16 ml) and heated at 100° C. in a sealed bomb for 18 hours. The solution was acidified to pH 4 with 5N HCl and the precipitate filtered off to provide title compound (0.58 g). MS (−ve ion chemical ionisation) ml/z 152 ([M-H]−, 100%).