Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20](Br)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[O:35][N:34]=1.[F-].[Cs+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:47])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(Br)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)noc4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (320 mg, 1.44 mmol), cesium fluoride (437 mg, 2.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.06 mmol) in dioxane (20 mL) was degassed with nitrogen, then stirred at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (253h, 400 mg, 78% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].Cl.C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:26][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Temperature: 75 °C

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol, Example 7, Step 1), glycine ethyl ester•HCl (97 mg, 0.69 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial for 30 h. The reaction was allowed to cool to rt, concentrated, and purified by silica gel chromatography (3:2→1:4; hexanes:ethyl acetate) to give ethyl 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetate: 1H NMR (400 MHz, DMSO-d6): δ 7.93 (t, 1H), 7.68 (d, 1H), 7.08 (d, 1H), 4.92 (s, 1H), 4.80 (m, 1H), 4.13 (q, 2H), 4.10 (d, 2H), 3.86 (s, 3H), 1.90-1.45 (m, 8H), 1.20 (t, 3H); MS (ESI): 361.9.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].Cl[C:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[N:13]=1>C(N(CC)CC)C>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[N:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN)C(C)C
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C#N)c(NCCN(C(C)C)C(C)C)n1
Temperature: 90 °C
Yield: 101.1 %

Procedure:
A mixture of N,N-diisopropyl-1,2-diaminoethane (10.8 g, 75 mmol) and 2-chloro-3-cyano-4,6-dimethylpyridine (12.5 gm, 75 mmol) in triethylamine (20 ml) is heated at 90° C. for 17 hours. The excess triethylamine is removed under vacuum and the residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate and evaporated to give essentially pure product (20.8 g) which is used in subsequent reactions. The title A product can be crystallized from methanol to give 13.6 g; m.p. 65°-68° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:30])([F:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1>CCOCC.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:30])([F:29])[C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)C(C)(C)C)cc1)C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)C(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension (70 ml) of zinc chloride (4.94 g, 36.2 mmol) in ether was added sodium borohydride (2.74 g, 72.4 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3-chlorophenyl)-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-3-oxopropionate (7.59 g, 18.1 mmol) in ether (50 ml), and the mixture was stirred at room temperature for 1 hr. The reaction was quenched with 1N hydrochloric acid, and the mixture was diluted with ethyl acetate, washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1, 10:1, 5:1) to give ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionate (6.12 g, 80%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:27][NH2:28]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:28][CH3:27])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: CN
Solvent: CCO
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccccc1C
Temperature: 170 °C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(300 mg, 0.79 mmol) was dissolved in ethanol(1.0 ml) and aqueous solution of methylamine(40%, 5 ml) was added. The reaction mixture was refluxed in the pressure tube at 170° C. for 20 hours, and the solvent was removed by distillation under low pressure. The residue was diluted in dichloromethane(20 ml), washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 240 mg of desired compound as solid in 81% of yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Yield: 103.2 %

Procedure:
A mixture of 1-bromo-4-trifluoromethoxybenzene (2.0 g, 8.3 mmol), 4-amino-1-benzylpiperidine (1.73 g, 9.13 mmol), palladium acetate (37 mg, 0.17 mmol), (R)-(+)-BINAP (155 mg, 0.25 mmol) and sodium tert-butoxide (1.2 g, 11.6 mmol) in toluene (30 ml) was refluxed under a nitrogen atmosphere for 5 hours. Ethyl acetate and water were added to the reaction mixture while stirring, the insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyllacetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford (1-benzylpiperidin-4-yl)-(4-trifluoromethoxyphenyl)amine (3.0 g, yield 99%) as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:91]=[CH:90][C:6]([CH2:7][O:8][C@@H:9]([C@@H:84]([CH3:89])/[CH:85]=[CH:86]\[CH:87]=[CH2:88])[C@@H:10]([CH3:83])[C@H:11]([O:75][Si:76]([C:79]([CH3:82])([CH3:81])[CH3:80])([CH3:78])[CH3:77])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([CH3:74])[C@@H:17]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:18]([CH3:65])/[CH:19]=[CH:20]\[C@@H:21]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:22][C@H:23]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:24]([CH3:48])/[CH:25]=[CH:26]/[CH2:27][O:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]([C@@H:84]([CH3:89])/[CH:85]=[CH:86]\[CH:87]=[CH2:88])[C@@H:10]([CH3:83])[C@H:11]([O:75][Si:76]([C:79]([CH3:82])([CH3:81])[CH3:80])([CH3:77])[CH3:78])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([CH3:74])[C@@H:17]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:18]([CH3:65])/[CH:19]=[CH:20]\[C@@H:21]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:60])[CH3:59])[CH2:22][C@H:23]([O:49][Si:50]([C:53]([CH3:54])([CH3:55])[CH3:56])([CH3:52])[CH3:51])[C@H:24]([CH3:48])/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:90][CH:91]=1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/CO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 177769.8 %

Procedure:
The procedure for 45 was used with 74 (0.58 g, 0.22 μmol), ZnBr (0.25 g, 1.11 mmol) to yield 75 (0.42 g, 89%) after flash column chromatography (EtOAc/hexane 3:17) as a colorless oil: IR (CHCl3) 3402, 2956, 2929, 2856, 1614, 1514, 1471, 1251, 1085, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.04-7.01 (m, 2H), 6.76 (ddd, J=16.8, 10.6, 10.5 Hz, 1H), 6.19 (t, J=11.0 Hz, 1H), 5.87-5.72 (m, 3H), 5.59 (t, J=10.0 Hz, 1H), 5.45 (dd, J=10.9, 8.3 Hz, 1H), 5.35 (d, J=16.8 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.75-4.65 (m, 3H), 4.22 (d, J=4.5 Hz, 2H), 4.09 (m, 1H), 3.94 (s, 3H), 3.83 (m, 1H), 3.56 (m, 1H), 3.51 (m, 1H), 3.17 (m, 1H), 2.77 (m, 1H), 2.57 (m, 1H), 1.95 (m, 1H), 1.85 (m, 1H), 1.78-1.55 (m, 8H), 1.53-1.40 (m, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.56-1.06 (m, 45H), 1.01 (d, J=6.7 Hz, 3H), 0.29-0.22 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 158.9, 134.8, 134.5, 132.8, 132.4, 132.3, 131.2, 129.2, 129.1, 128.9, 117.1, 113.6, 84.3, 80.2, 75.0, 72.4, 72.2, 66.5, 63.6, 55.1, 42.3, 41.5, 40.5, 37.9, 35.7, 35.2, 33.8, 28.1, 26.2, 25.9, 25.6, 19.3, 18.8, 18.4, 18.2, 18.0, 14.6, 13.0, 9.2, −3.0, −3.5, −3.7, −3.9, −4.3, −4.4, −4.5; LRMS (ESI) 1095.7 [M+Na]+, 809.6, 677.5, 537.4, 413.2; HRMS (ESI) calcd for C61H116O7Si4Na 1095.7696 [M+Na]+, found 1095.7712; [α]20D+4.8 (c 1.7, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([O-:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1.C[NH3+:35].C(OCC)(=O)C.Cl.O>[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([O-:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1.[NH4+:35]
Reactant: C[NH3+]
Agent: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: [NH4+]
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (10 g) was added to ethyl acetate (125 ml). The mixture was cooled to 5° C. and 1M hydrochloric acid in saturated brine (20 ml) was added, followed by water (30 ml) to obtain a two-phase solution. The aqueous phase was separated off and the organic phase was washed with water (30 ml) and dried over anhydrous magnesium sulphate. Aqueous ammonia (1.7 ml) was added, followed by ethyl acetate (80 ml), and the solution was concentrated under vacuum and diluted with ethyl acetate (60 ml). The mixture was stirred at 0° C. to 5° C. for 90 minutes and the product was isolated by filtration and dried at 30° C. under vacuum to give ammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (6.33 g) as white crystals. The X-ray powder diffraction spectra for a typical sample of the crystalline ammonium salt is shown in FIG. 1 hereinafter. The ten most prominent peaks in the XRD occur at about 2-theta=12.9, 15.2, 18.0, 18.2, 18.5, 20.2, 22.4, 23.0, 24.0 and 27.2°.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=O)[OH:3].S(=O)(=O)(O)O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:3][CH:2]1[CH2:4][C:5](=[O:7])[O:8][C:1]1=[O:9])(=[O:17])[CH3:16]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1CC(=O)OC1=O
Temperature: 140 °C
Yield: 60 %

Procedure:
250 g (1.86 mole) of malic acid are dissolved in 500 ml of acetic anhydride and a further 1 ml of concentrated sulphuric acid is added thereto. The mixture is then heated at 140° C. for four hours. Finally, it is concentrated in vacuo and the residue is fractionally distilled. 2-acetoxysuccinic acid anhydride is obtained in a 60% yield. Boiling point at 0.01 torr: 108° to 113° C.; melting point: 56° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CN1CCOCC1.Cl.[C:41]([N:45]1[N:49]=[N:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([NH:70][C:71](=[O:82])[C@H:72]([C:78]([CH3:81])([CH3:80])[CH3:79])[NH:73][C:74]([O:76][CH3:77])=[O:75])[CH2:58][C@H:59]([OH:69])[C@@H:60]([NH2:68])[CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:52][CH:51]=2)=[N:46]1)([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.C(Cl)Cl>[C:41]([N:45]1[N:49]=[N:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([NH:70][C:71](=[O:82])[C@H:72]([C:78]([CH3:81])([CH3:80])[CH3:79])[NH:73][C:74]([O:76][CH3:77])=[O:75])[CH2:58][C@H:59]([OH:69])[C@@H:60]([NH:68][C:10](=[O:11])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:52][CH:51]=2)=[N:46]1)([CH3:43])([CH3:42])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 54 mg (0.308 mmol) of N-methoxycarbonyl-(L)-valine and 92 mg (0.308 mmol) of TPTU in 1 ml of DMF and 101 μl (0.91 mmol) of NMM are stirred at room temperature for 10 min. 190 mg (0.308 mmol) of 1-[4-(2-tert-butyl-2H-tetrazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-amino-2-N-[N-methoxycarbonyl-(L)-tert-leucyl]amino-6-phenyl-2-azahexane hydrochloride (Example 34g) in 2 ml of DMF are added thereto and the mixture is stirred at room temperature overnight to complete the reaction. The reaction mixture is diluted with methylene chloride and washed with brine. The aqueous phases are extracted 2× with methylene chloride; the organic phases are filtered through cotton wadding, concentrated by evaporation and chromatographed (SiO2; methylene chloride/methanol 30:1): TLC: Rf=0.21 (methylene chloride/methanol 19:1); FAB MS (M+H)+=738.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
A mixture of 4,4'-difluorobenzophenone (25.2 g, 115.5 mmol), 3-hydroxybenzoic acid (8.0 g, 57.9 mmol), and anhydrous potassium carbonate (16.0 g) in dry dimethylsulfoxide (120 ml, distilled under reduced pressure from calcium hydride) was stirred at 120° C. under nitrogen for 48 hours. At the end of this period the reaction mixture was poured into water, and the suspension thus obtained was filtered through Celite. The clear filtrate was cooled, then carefully acidified with conc. hydrochloric acid until strongly acidic. The white precipitate that formed was filtered and recrystallized from aqueous ethanol. Two recrystallizations gave 9.5 g (48%) of 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid with m.p. 158.5°-160° C. A sample with m.p. 159°-161.5° C. could not be purified further by recrystallization.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(#N)C.ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc[nH]n1)c1ccccc1Cl
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a solution of 1H-pyrazol-3-amine (166 mg, 2 mmol, Aldrich) in acetonitrile (8 ml) was added triethylamine (0.558 ml, 4.0 mmol, Aldrich) and the stirred solution was cooled in an ice-water bath. To the mixture was added a solution of 2-chlorobenzoyl chloride (0.253 ml, 2.0 mmol, Aldrich) in acetonitrile (7 ml). The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (approximately 30 ml) and water (approximately 30 ml). The layers were separated and the aqueous phase was washed with further ethyl acetate (2×20 ml). The combined organic layers were filtered through a hydrophobic frit and the filtrate concentrated in vacuo to give the crude material (0.47 g). The sample was loaded in dichloromethane and purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (0.198 g); LCMS: (System 4) MH+=222, tRET=1.54 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
To a stirred solution of dehydroepiandrosterone (2.88 g, 10 mmol) in methylene chloride (100 mL) is added dropwise benzylchloroformate, over a period of 30 min following the known procedure (F. Reber and T. Reichstein, Helv. Chim. Acta, 28, 1164, 1945). After stirring for 3 h, the mixture is washed with water and evaporated to dryness. The residue is then dissolved in acetone and precipitated in iced water. After 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccccc12
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: C=CC(=O)c1ccc2c(C)cccc2c1
Yield: 86.2 %

Procedure:
1-methylnaphthalene (142 mg), acryloyl chloride (100 mg), and aluminium chloride (150 mg) were reacted in carbon disulfide (0.5 mL) at from −20° C. to room temperature for 1 hour. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (169 mg) in a viscous liquid form.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:16][C:15]1[C:10]([CH:8]([NH2:7])[CH3:9])=[N:11][CH:12]=[C:13]([F:17])[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(N)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To tert-butyl-1-(3,5-difluoropyridin-2-yl)ethylcarbamate (Method 16; 0.10 g, 0.39 mmol) in DCM (2 ml) was added HCl (0.8 ml, 3.12 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed and 10 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (5×30 ml), dried over sodium sulfate and concentrated to give the title compound (0.06 g, 95%) as pale yellow oil. MS: Calcd.: 158. Found: [M+H]+ 159.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.CCN(CC)CC.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:17](=[O:18])[CH3:19])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of (5-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol) in DCM (10 mL) was added Et3N (405 mg, 4.0 mmol) and AcCl (250 mg, 3.18 mmol) at 0° C. The mixture was then warmed to room temperature for 2 h when the reaction was quenched with water and extracted with DCM. The organic layer was concentrated to give the crude product which was used in next step without further purification. (540 mg, Yield 90%). LCMS (m/z): 229.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncccc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ncccc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-2-methylpyridine (Synchem-OHG), the title compound was obtained as a yellow sticky solid after purification by preparative HPLC.