Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:25])[NH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14](=[O:25])[NH:15][C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccccc1
Reactant: Oc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-bromo-pyridin-3-ol (0.3 g, 1.7 mmol), (2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (0.41 g 1.7 mmol), and triphenylphosphine (0.52 g, 2 mmol) in THF (15 mL) was stirred at 0° C. for 30 min. To the mixture was added a solution of di-t-butyl azidodicarboxylate (0.46 g, 2 mmol) in 5 ml of THF. The mixture was allowed to warm to room temperature then stirred at room temperature for 20 h. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:2 ethyl acetate/hexane. Recovered 0.82 g of a mixture of product and di-tert-butyl azidodicarboxylate. MS (ESI) m/z 395 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][C:31]3[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: FC(F)(F)c1ccc(CBr)o1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(C(F)(F)F)o3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-(bromomethyl)-5-(trifluoromethyl)furan. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.51-7.61 (m, 1H) 7.39-7.47 (m, 2H) 7.32-7.39 (m, 1H) 7.08-7.15 (m, 1H) 6.65-6.73 (m, 1H) 6.43-6.51 (m, 1H) 5.94-6.00 (m, 1H) 5.75-5.91 (m, 2H) 5.26 (s, 1H) 3.63 (s, 3H) 0.96 (s, 9H); LC/MS (m/z) ES+=537 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCN(C)CC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mmol) and 1-methyl-piperazine (0.08 mL, 0.9 mmol) in dry ethyl acetate was stirred overnight at 25° C., treated with water and extracted with ethyl acetate. The organic layer was washed with dil aqueous HCl (10%, 50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.180 g, (80%) 1H NMR (DMSO-d6): δ 2.20 (s, 3H, CH3), 2.30 (s, 4H, CH2), 2.80 (s, 3H, CH3), 3.00 (s, 4H, CH2), 5.40 (s, 2H, CH2), 8.00 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 2H, Ar). MS: m/e (ES+) 501 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:17][O:18][CH3:19].C([Li])CCC.CN([CH:28]=[O:29])C.Cl>C1COCC1>[C:12]([C:4]1[C:3]([O:16][CH2:17][O:18][CH3:19])=[C:2]([CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)[CH:28]=[O:29])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.5 h

Procedure:
46.00 g (140.0 mmol) of the compound obtained in Example 13 (a) and 500 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 61.5 ml (154.00 mmol) of an n-butyllithium solution (2.5M in hexane) are added dropwise at −78° C. and the mixture is stirred for 30 minutes at this same temperature. 13.0 ml (168.0 mmol) of DMF are then added dropwise and the mixture is allowed to return to room temperature. The reaction mixture is acidified with hydrochloric acid (1N) and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 46.00 g (100%) of the expected compound are collected in the form of an orange oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[C@H:22]([NH:21][C:19]([C:18]1[CH:30]=[CH:31][C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[CH:16][CH:17]=1)=[O:20])[CH2:23]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(I)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (20.9 mg, 0.11 mmol) was added to a flask charged with (S)-4-iodo-N-(quinuclidin-3-yl)benzamide (35.6 mg, 0.1 mmol), cesium carbonate (81.5 mg, 0.25 mmol) in 2 ml of Acetonitrile and 2 ml of water. The mixture was degassed by sonication for 20 minutes followed by charging catalytic amount of Palladium (II) acetate and place under nitrogen to stirred for 3 hours. The reaction mixture was filtered through pad of celite and washed with acetone, solution was concentrated under vacuum to oil. Preparative HPLC instrument was used to obtain pure (S)—N-(quinuclidin-3-yl)-4′-(trifluoromethyl)biphenyl-4-carboxamide (24.5 mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.80 (d, J=8 Hz, 2H), 7.63 (m, 4H), 7.58 (d, J=8 Hz, 2H), 6.33 (d, 1H), 4.11 (m, 1H), 3.38 (m, 1H), 2.80 (m, 4H), 2.56 (ddd, J=6, 14, 6 Hz, 1H), 2.00 (m, 1H), 1.65 (m, 3H), 1.47 (m, 1H). C21H21F3N2O=374.16 LCMS (M+H): m/z 375
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccsc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccsc3)c2c1
Yield: 95 %

Procedure:
This compound was prepared from 6b using 3-thiopheneboronic acid according to method P. Orange powder; Yield: 95%; mp>160° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.06 (t, J=8.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.50 (dd, J=4.9, 1.2 Hz, 1H), 7.82 (dd, J=4.9, 3.0 Hz, 1H), 7.90-7.95 (m, 4H), 8.06 (dd, J=13.0, 2.1 Hz, 1H), 9.97 (s, 1H), 10.19 (s, 1H); MS (ESI) m/z 336 ([M−H]−), 338 ([M+H]+); Anal. Calcd for C19H12FNO2S: C, 67.64; H, 3.59; N, 4.15. Found: C, 66.81; H, 4.14; N, 3.58.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(S(F)(F)[F:22])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:22])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Process A: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (1.97 g) was dissolved in dichloromethane (50 mL). While this solution was chilled in an ice water bath, diethylaminosulfur trifluoride (1.90 mL) was added dropwise and the mixture was stirred at room temperature for 19 hours. Subsequently, while the reaction mixture was chilled in an ice water bath, a saturated aqueous solution of sodium bicarbonate (40 mL) was added and the dichloromethane layer was separated. The dichloromethane layer was then washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow-brown tar (1.64 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[CH:43]=[CH:42][S:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccsc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccsc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 36 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37 g) and 3-(chloromethyl)thiophene (0.21 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained. By the reaction and treatment of this compound (0.11 g), in the same manner as in Example 133, 5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.054 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]([C:15]2[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=2)=[O:14])[N:11]=[C:10]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[Cl-].[Cl-].[Al+3]>CN(C=O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([C:13]([C:15]3[S:19][C:18]([C:20]4[N:28]=[N:29][NH:30][N:21]=4)=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nn[nH]n2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}thiophene-2-carbonitrile (0.300 g, 0.60 mmol) in DMF (5 mL) was added sodium azide (0.120 g, 1.80 mmol) and aluminum trichloride (0.240 g, 1.80 mmol). The reaction mixture was allowed to stir at 100° C. overnight and then concentrated. The residue was purified by column chromatography to give 2-(3-pyridin-3-yl-1-{[5-(2H-tetrazol-5-yl)-2-thienyl]carbonyl}-4,5-dihydro-1H-pyrazol-5-yl)phenol (I-226). LCMS: (FA) ES+ 436, ES-434.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)methanol (3.0 g, 16.04 mmol) and imidazole (1.42 g, 20.85 mmol) in dichloromethane was added tert-butyl dimethylsilyl chloride (3.14 g, 20.85 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with water, extracted with ethyl acetate (2×) and concentrated. The residue was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 4.68 (s, 2H), 0.94 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16]C(=O)OC(C)(C)C)=[O:10].[O:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH2:35][CH2:34][CH2:33]1>>[NH2:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:33]1[O:32][CH2:37][CH2:36][CH2:35][CH:34]=1)=[O:10]
Reactant: CC1(C)OB(C2=CCCCO2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1=CCCCO1
Yield: 8 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate and 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester gave 102 as a white solid (25 mg, 8% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.18 (s, 1H), 7.34-7.28 (m, 1H), 7.06-6.98 (m, 2H), 6.13 (s, 2H), 5.11 (t, J=3.9 Hz, 1H), 4.25 (t, J=5.1 Hz, 2H), 3.89 (s, 3H), 2.32-2.26 (m, 2H), 2.03-1.96 (m, 2H). LCMS (ES+) m/z 418 (M+1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH2:9](I)[CH3:10]>[Ag]=O.CN(C=O)C>[CH2:9]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 20 g of (s)-(-)-ethyl lactate, 100 ml of N,N'-dimethylformamide, 38 g of ethyl iodide and 30 g of silver oxide was stirred at room temperature for 40 hours. The insoluble materials were separated by filtration and water and hexane were added to the filtrate to separate N,N'-dimethylformamide. The aqueous layer was subsequently extracted twice with hexane, and the hexane layers were dried over anhydrous sodium sulfate. The product was distilled under reduced pressure to give 18.5 g of a fraction having a boiling point of 86°-88° C./75 mmHg. Nuclear magnetic resoanance spectroscopy led to the determination that this fraction was the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[C:38]([NH:41][NH2:42])(=[O:40])[CH3:39].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[C:38]([NH:41][NH:42][C:34]([C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1)=[O:35])(=[O:40])[CH3:39]
Reactant: CC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)NNC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), acetohydrazide (0.09 g), 1-hydroxybenzotriazole (0.19 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C([O-])c1ccc(O)cc1O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(OC(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
154.0 g of potassium 2,4-dihydroxybenzoate and 122.3 g of vinylbenzyl chloride were added to 500 ml of dimethylsulfoxide, and stirred at 40° C. for 3 days to react. Then, 1,000 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from a benzene-hexane mixture solvent yielded 140 g of vinylbenzyl 2,4-dihydroxybenzoate (m.p. 52°-54° C.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>Cl>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Agent: Cl
Product: CC(C)C(=O)NC1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 84.3 %

Procedure:
Combine p-fluorophenylhydrazine hydrochloride (5.00 g, 30.7 mmol) and N-(4-oxo-cyclohexyl)isobutyramide (5.64 g, 30.7 mmol) in ethanolic HCl (125 mL) and heat at reflux under nitrogen for 18 h. Concentrate the reaction in vacuo to remove most of the EtOH, dilute with water and extract with EtOAc. Wash the EtOAc extracts with water and brine, dry over Na2SO4, and evaporate to give 7.1 g (56%) of a beige solid. MS (ES): m/z 275 (M+1); 1H NMR(DMSO-d6): δ 10.79 (s, 1H, NH), 7.81 (d, 1H, J=7.5 Hz), 7.19 (dd, 1H, J=8.6, 4.6 Hz), 7.07 (d, 1H, J=10.1 Hz), 6.79 (dt, 1H, J=8.9, 1.8 Hz), 4.00 (m, 1H), 2.85 (dd, 1H, J=15.0, 5.3 Hz), 2.76 (m, 2H), 2.39 (m, 2H), 1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, J=6.6 Hz).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.CO.[NH3:31]>>[C:24]([O:23][C:21](=[O:22])[NH:20][C@@H:5]([C:4](=[O:3])[NH2:31])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: N
Reactant: CCOC(=O)[C@@H](CCCc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(OC(C)(C)C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-2-tert-Butoxycarbonylamino-5-(4-tert-butoxy-phenyl)-pentanoic acid ethyl ester (179 g, 460 mmol) is dissolved in 7M NH3 in MeOH (400 ml, 2800 mmol) and stirred at room temperature for 4 days. The reaction is concentrated in vacuo keeping the temperature below 30° C. to afford [(R)-4-(4-tert-Butoxy-phenyl)-1-carbamoyl-butyl]-carbamic acid tert-butyl ester [M+H]+ 364
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([OH:32])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(OCC)C>[C:7]([Cl:2])(=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus pentachloride (0.123 mol, 25.6 g) was added gradually to a solution of nervonic acid (available from Aldrich Chemicals) (0.123 mol, 45.0 g) in dry ethyl ether (225 mL, C=200 g.L−1). The mixture was stirred at room temperature under nitrogen for 3 h and concentrated to dryness to yield z-15-tetracosenoyl chloride as pale yellow, fairly viscous oil.
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:19]=2C(O)=O)=[CH:13][CH:12]=1)C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:19]=2[C:33](=[O:32])[CH3:34])=[CH:13][CH:12]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Reaction time: 3 h

Procedure:
Methyllithium (210 ml, 1.25M methyllithium-lithium bromide complex in ether) (0.263 mole) was added dropwise to a solution of 25.49 g (0.0732 mole) of 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid in 226 ml of tetrahydrofuran cooled to 0°-5° C. The reaction mixture was stirred for 3 hours at 0°-5° C. Ethyl acetate was then added and the mixture poured into ice and saturated ammonium chloride solution. The aqueous suspension was extracted with ether, the ether extracts dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from toluene to give 16.1 g of 1-[2-(4-benzyloxyphenylamino)-5-methoxyphenyl]ethanone, yellow-orange solid, m.p. 80°-81.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:18]4[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3ccc(F)nc3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3ccc(F)nc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[O:19]([CH2:26][CH2:27]O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([CH2:26][CH2:27][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCOc1ccccc1
Product: O=C(O)CNC(=O)c1ccc(OCCOc2ccccc2)cc1
Yield: 77.1 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 2-phenoxyethanol (163 μL, 1.19 mmol) to give 241 mg of the title compound