Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[O:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:3]1[N:4]([C:38]2[CH:39]=[N:40][C:35]([O:34][CH:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: OB(O)c1ccc(OC2CCOCC2)nc1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.52 g), [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronic acid (0.49 g), copper acetate (0.53 g), pyridine (0.6 mL), triethylamine (1 mL), molecular sieves 4 A (1 g) and methylene chloride (10 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.2 g, 26%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@H:18]([CH3:26])[C@@H:19]([O:21]S(C)(=O)=O)[CH3:20])[CH:11]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)O)=[CH:6][CH:5]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@:10]2([CH2:11][N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[C@@H:18]([CH3:26])[C@H:19]([CH3:20])[O:21]2)=[CH:6][CH:5]=1
Reactant: C[C@H]([C@H](C)OS(C)(=O)=O)[C@H](c1ccc(Cl)cc1)C(O)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@](Cn2cncn2)(c2ccc(Cl)cc2)[C@H]1C
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
28 mg (1.003 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 200 mg (0.59 mmole) of (2R*,3S*,4S*)-2-(4-chlorophenyl)-3-methyl-4-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)pentanol in 5 ml of dimethylformamide, and the resulting mixture was stirred for 1.5 hours. At the end of this time, the reaction mixture was treated in a similar manner to that described in Example 60, to afford 32.3 mg (yield 19.7%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(N)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(N)=O
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of (E)-3-[(2S,4S)-N-allyloxycarbonyl 4-tritylthiopyrrolidin-2-yl]acrylamide (60 g, 120 mmol) in methylene chloride (60 ml) were added trifluoroacetic acid (60 ml) and triethylsilane (20 ml, 125 mmol) under ice-cooling. The reaction mixture was stirred under icecooling for 10 minutes and for additionally 30 minutes at room temperature, and concentrated. The residue was dissolved in methylene chloride (100 ml), and the solution concentrated. The obtained residue was dissolved ethyl acetate (750 ml), and the solution washed with 1M sodium phosphate buffer (pH 5.5, 500 ml and 250 ml×3) and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (50 ml), treated with hexane (250 ml) to crystallize to give the title compound (30 g, 97.3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)(=[O:24])=[O:25]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 63.2 %

Procedure:
10 g (60.5 mmol) of ethyl 4-aminobenzoate and 13.7 g (60.5 mmol) of 2-naphthylsulfonyl chloride were reacted by the method of procedure 4b, affording 13.6 g (64%) of the product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccccc3)n2)cc1
Yield: 80 %

Procedure:
To a stirred solution of 2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added benzylamine (5 eq) and the resultant solution heated under reflux for 24 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography with cyclohexane:ethyl acetate (3:1). Concentration in vacuo of the combined fractions containing pure product gave the title compound as a white solid (0.090 g, 80%).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]1OC(=O)C)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1CCC=CC1OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)C1=CC=CCC1
Yield: 85.4 %

Procedure:
Crude butyl ester (a) (55.25 g, max 0.207 mol) was dissolved in dry tetrahydrofuran (320 ml) and cooled in an ice/salt bath. To this was added slowly, over 1 hour, potassium t-butoxide in tetrahydrofuran (1 M, 220 ml, 0.22 mol). After 0.5 hour water and petroleum ether were added and the mixture filtered quickly through kieselguhr. The phases were separated and the aqueous extracted with more petroleum ether (×2). The combined organic extracts were washed with brine, dried and evaporated to give a mobile orange oil (31.85 g, 86%), which was used immediately without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCOC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 8c was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 364. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.15 (s, 1H) 8.72 (br s, 1H) 8.35 (m, 2H) 8.07 (d, 1H) 7.65 (m, 1H) 7.18 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 4.35 (q, 2H) 3.5 (m, 2H) 2.78 (m, 2H) 1.35 (t, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46](C)=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:50]C1C=C(Cl)C=CC=1N>>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:50])=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(S(C)(=O)=O)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Reactant: Nc1ccc(Cl)cc1Cl
Product: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1

Procedure:
The 1-[3-(tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one was prepared in a manner analogous to that for 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one of Example 53(d) using 2,4-dichloroaniline in place of 2-chloro-6-methylaniline.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])C.Cl>O>[Cl:20][C:19]1[C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[N:15][CH:16]=[C:17]([CH2:21][CH3:22])[CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(CC)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cnc(-n2ncc(C(=O)O)c2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
Water (4 ml) and 4N aqueous solution of sodium hydroxide (4 ml) were added at room temperature to a solution of 1-(3-chloro-5-ethylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (454 mg), and stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution was added. The precipitated solid was collected by filtration to give the titled compound (314 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:25]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:29])[C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:25]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sccc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
Combine (S)-6,7-difluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (207.2 mg, 0.55 mmol), formaldehyde (48.9 μL, 0.60 mmol, 37% in water), and dichloromethane (8.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (174.0 mg, 0.82 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 176.2 mg (82%) of the title compound: mass spectrum (ion spray): m/z=393.2 (M+1).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:23])[F:22].[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[N:34]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:33]=2)[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:22])[F:23]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)nc1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc(Cl)nc3)n2)c1
Temperature: 25 °C

Procedure:
9.22 g (43.8 mmol)of 3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is suspended in 88 ml of 2-propanol. 11 g (43.8 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 1.93 g (48.4 mmol) of sodium hydroxide are added and the reaction mixture is boiled under reflux for 19 h. After cooling to RT, the product is isolated by filtration, washed with 2-propanol and water and dried at 50° under HV. N[3(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamine is obtained; FAB-MS: 399 (M+ +H), m.p. 182°-184°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.FC1C=CC(S(N(CC)C(=C)C(NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=O)(=O)=O)=CC=1>C(O)C.ClC1SC(S(N(CC)C(=C)C(NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=O)(=O)=O)=CC=1>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Agent: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Solvent: CCO
Product: N#Cc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
2,6-dichloropyridine-4-carbonitrile 24 (4 gr, 23.13 mmol) was dissolved in 100 ml of ethanol. To the solution were added TEA (1 equiv., 3.22 ml), morpholine (1 equiv., 2 ml) and the mixture was stirred at 70° C. for 4 hours. (TLC AcOEt 3/petroleum ether 7). The solvent was evaporated and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (4.6 g, 89% yield) 1HNMR (DMSO, 400 MHz) δ 3.58 (4H, m), 3.64 (4H, m), 7.10 (1H, s), 7.32 (1H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].C(OC1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Agent: CC(C)Oc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was treated with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (prepared from 4-isopropoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-{7-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-{7-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([O:31]CC)=[O:30])[C:14]3=[O:34])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([OH:31])=[O:30])[C:14]3=[O:34])=[CH:11][CH:12]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetate (12.0 mg, 0.023 mmol) in EtOH (0.5 mL) is added 1N NaOH aqueous solution (115 μL, 0.12 mmol). The mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H22ClF3N2O4 (M+H+) 491.1, found 491.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[N:13]=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[N:13]=[N:12]1
Reactant: CCn1nnn(-c2cc(OC)c(F)cc2Cl)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCn1nnn(-c2cc(O)c(F)cc2Cl)c1=O
Yield: 93.7 %

Procedure:
In the manner of Example 11, Step A, the reaction of 0.9 g (0.0033 mole) of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one with 2.5 g (0.01 mole) of boron tribromide in 15 mL of methylene chloride produced 0.8 g of 1-(2-chloro-4-fluoro-5-hydroxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([NH2:28])=[O:18])[CH2:15][N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 11.1 %

Procedure:
To a solution of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.090 g) in N,N-dimethylformamide (6 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.034 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.049 g), and the mixture was stirred at 50° C. for 45 min. 28% Aqueous ammonia (2 ml) was added to the reaction, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=100:0-90:10), and recrystallized from hexane-ethyl acetate to give the title compound (0.010 g, yield 11%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]1[CH:14]=[C:15]([C:22](Cl)=[O:23])[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12.Cl.O>N1C=CC=CC=1>[F:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([C:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:13][CH:14]=1)=[O:23]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=C(Cl)c1cnc2ccccn12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C

Procedure:
A solution of methyl 3-amino-4-fluorobenzoate (5 g, 29.6 mmol) in pyridine (200 ml) was treated with imidazo[1,2-a]pyridine-3-carbonyl chloride.HCl (step 1) (6.43 g, 29.6 mmol) and the mixture was stirred at RT for 2 days. The mixture was poured into water (30 ml) and a small exotherm was observed. After cooling to RT, the resulting precipitate was filtered and dried in a vacuum oven to afford the title compound;
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][OH:9].[CH2:10]([C:14]1[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH:11]([CH3:13])[CH3:12]>CO>[OH:9][NH:8][C:18](=[NH:19])[C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([CH2:10][CH:11]([CH3:12])[CH3:13])=[N:15][CH:16]=1
Reactant: NO
Reactant: Cc1cc(C#N)cnc1CC(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cnc1CC(C)C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of potassium tert-butylate (3.04 g, 27.1 mmol) in MeOH (60 mL), hydroxylamine hydrochloride (1.62 g, 23.2 mmol) is added at 0° C. To this suspension, 6-isobutyl-5-methyl-nicotinonitrile (1.35 g, 7.75 mmol) is added. The mixture is refluxed for 3 h, cooled to rt, filtered and the filtrate is evaporated to dryness. The residue is suspended in a small amount of water and then extracted with EA. The org. extract is concentrated and dried under high vacuum to give N-hydroxy-6-isobutyl-5-methyl-nicotinamidine (1.53 g) as a pale yellow oil; LC-MS: tR=0.68 min, [M+1]+=208.22; 1H NMR (D6-DMSO): δ 0.91 (d, J=6.8 Hz, 6H), 2.06-2.17 (m, 1H), 2.29 (s, 3H), 2.61 (d, J=7.0 Hz, 2H), 5.85 (s br, 2H), 7.76 (s, 1H), 8.60 (s, 1H), 9.68 (s, 1H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 93.6 %

Procedure:
A solution of 1.25 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 80 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16hours. The catalyst was removed by filtration and the filtrate was evaporated to give 0.844 g of 1-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide as a pale yellow gum; MS: m/e 348 [M+H]+.