Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=S)[NH:26][CH2:27][CH2:28][CH3:29])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34]C(C)C)(C)C>C(O)(=O)C>[N:1]1([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25]([NH:26][CH2:27][CH2:28][CH3:29])=[O:34])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Reactant: CC(C)OC(C)C
Solvent: CC(=O)O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
Mercuric aoetate (I.8I g) dissolved in glacial acetic acid (35 cc) is added in the course of 20 minutes to a solution of 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinecarbothioamide (2.5 g) in acetic acid (25 cc), and the mixture is stirred for 45 minutes at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite, and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc). The organic phase is washed successively with normal sodium hydroxide (2×100 cc) and distilled water (3×100 cc) and with saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (2.1 g) is thereby obtained This residue is taken up with boiling isopropyl ether (80 cc). The small amount of insoluble matter is removed by filtration and crystallization is primed in the filtrate by cooling maintained with stirring. The crystals are filtered off on sintered glass to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinecarboxamide (1.29 g) in the form of an offwhite solid, m.p. 113° C.
Reaction SMILES: C1(S([N:10]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=3)=[O:16])=[CH:11]2)(=O)=O)C=CC=CC=1>CO.[OH-].[Na+]>[Cl:27][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:12]2[CH:13]=[CH:14][NH:10][CH:11]=2)=[O:16])=[CH:22][C:21]=1[S:23]([NH2:26])(=[O:24])=[O:25]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NS(=O)(=O)c1cc(C(=O)c2cc[nH]c2)ccc1Cl
Yield: 65.7 %

Procedure:
5-(1-Benzenesulfonyl-1H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide (0.1 g, 0.23 mmol) is dissolved in 3 mL of 2:1 (v:v) mixture of methanol and 5 N aqueous sodium hydroxide and heated at reflux for 20 minutes then the reaction mixture is allowed to cool down and the organic solvent is removed in vacuo. The aqueous solution is acidified with 5 N HCl to pH 3, thoroughly extracted with ethyl acetate, then the combined organic extracts are washed with water, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/methylene chloride provides 43 mg (66%) of the title compound as a white solid. 1H NMR (DMSO): δ 11.70 (s, 1H), 8.70 (m, 1H), 8.00 (m, 1H), 7.80 (m, 3H), 7.50 (m, 1H), 7.00 (m, 1H), 6.60 (m, 1H). MS (m/z): 285 (M+1) Analytics calculated For C11H9N2ClO3S: C, 46.40; H, 3.19; N, 9.84. Found: C, 45.84; H, 2.90; N, 9.41.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: NCc1ccccc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCc2ccccc2)c1

Procedure:
Example 132 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and benzylamine to give the title compound (0.008 g).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].I[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of pentane-2,4-dione (4.41 g, 40 mmol), 1-iodo-4-nitrobenzene (5 g, 20 mmol) and potassium carbonate (11 g, 80 mmol) were heated in DMSO (15 ml) at 120° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and then extracted with ethyl acetate. The organic layer was washed with water, brine and dried. Evaporation gave a residue which was chromatographed over silica gel eluting with ethyl acetate/pet ether (5:95) to give 3-(4-nitrophenyl)-pentane-2,4-dione (2.67 g, 60%) as solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]12[C:15]([O:18][CH3:19])([O:16][CH3:17])[C:10]([Cl:20])([C:11]([Cl:14])=[C:12]1[Cl:13])[CH:9]1[CH:5]2[O:6]C(=O)[O:8]1>O.C1COCC1.Cl>[Cl:3][C:4]12[C:15]([O:16][CH3:17])([O:18][CH3:19])[C:10]([Cl:20])([C:11]([Cl:14])=[C:12]1[Cl:13])[CH:9]([OH:8])[CH:5]2[OH:6]
Reactant: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C1OC(=O)OC12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(O)C2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Potassium hydroxide (112 g, 1.20 mol) in water (1 L) was treated with 1,7,8,9-tetrachloro-10,10-dimethoxy-3,5-dioxa-tricyclo[5.2.1.02,6]dec-8-en-4-one (358.3 g, 1.23 mol) in THF (500 mL) via addition funnel, producing a slight exotherm. The reddish solution was stirred overnight at room temperature. By morning, the solution became a murky dispersion, which was diluted with water (500 mL), and 12N HCl (20 mL) to pH 10. The product was extracted with EtOAc (1×1000 mL) and ether (1×500 mL). The combined organic layers were washed with 1N HCl (1×300 mL), water (1×300 mL), saturated aqueous NaHCO3 solution (1×300 mL) and saturated aqueous NaCl solution (1×300 mL), dried over Na2SO4, filtered and concentrated to give a light brown solid (310 g, 78%). (TLC 40% EtOAc/hexanes Rf 0.55); 1H NMR (400 MHz, CDCl3) δ 4.46 (s, 2H), 3.54 (s, 3H), 3.51 (s, 3H); GCMS m/z 322 (M)+, 287, 289 (M-Cl)+; mp 160–162° C.; Anal. Calcd for C9H10Cl4O4: C, 33.37; H, 3.11. Found C, 33.34; H, 3.16.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO.CCOC(C)=O>[Si:16]([O:15][C@@H:14]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate (99%). LCMS (m/z): 331.3 (MH+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:32]\[CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)/[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([OH:30])[C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:43].C(O)(=O)C.[OH-].[Na+]>O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:14]3[NH:43][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]([OH:30])[C:26]([CH3:27])([OH:29])[CH3:28])=[CH:23][CH:24]=4)=[CH:16][CH:15]=3)=[CH:32]\[CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC(C)(O)C(O)c1ccc(C(=O)CCC(=O)/C(=C/C2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(O)C(O)c1ccc(-c2ccc(/C(=C/C3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of (5E)-5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hex-5-ene-1,4-dione (4.79 g), ammonium acetate (3.40 g) and acetic acid (15 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was neutralized with 8N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was dissolved in tetrahydrofuran, and the solution was treated with activated carbon and concentrated. Cold ethyl acetate was added to the obtained residue to allow crystallization. The crystals were collected by filtration, washed with cold ethyl acetate and dried to give the title compound (3.38 g, yield 73%) as pale-yellow crystals. melting point 196-197° C. MS: 523 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.N1C=CN=C1.FC(F)(F)S(O[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.1 %

Procedure:
6-fluoro-2-methylquinolin-8-ol (19.0 g, 107 mmol) was dissolved in methylene chloride (300 mL) and treated with 1H-imidazole (10.9 g, 160 mmol) and triisopropylsilyl trifluoromethanesulfonate (33.1 mL, 123 mmol). The reaction was stirred at ambient temperature for 13 hours. The reaction mixture was quenched with saturated NH4Cl and separated. The organic layer was washed twice with saturated NH4Cl, dried over Na2SO4 and concentrated in vacuo to provide the desired product (35 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB(O)c1ccco1
Reactant: COc1cc(Br)cc(C#N)c1OC
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccco2)cc(C#N)c1OC
Temperature: 85 °C
Yield: 92.7 %

Procedure:
To a mixture of 5-bromo-2,3-dimethoxybenzonitrile (0.958 g, 4.0 mmol), 2-furylboronic acid (0.53 g, 4.7 mmol), dioxane (24 mL), H2O (8 mL) and Na2CO3 (1.1 g, 10.4 mmol) was added tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol). The mixture was degassed by alternately putting under house vacuum and argon three times for several minutes each then heated at 85° C. under argon for 16.5 hrs. After cooling to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-20% EtOAc-hexanes) provided 5-(furan-2-yl)-2,3-dimethoxybenzonitrile as a white solid (0.85 g, 94% yield).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([C:10]1[CH:11]=[C:12]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[F:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:18]3[CH2:19][CH2:20][CH2:21][CH:16]([C:14]4[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:47])=[O:3])[CH:11]=[C:12]([C:37]5[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=5)[CH:13]=4)[CH2:17]3)=[CH:28][CH:27]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Temperature: 78 °C

Procedure:
To compound 48a, 2-(5-{1-[4-(4-Fluoro-phenoxy)-benzyl]-piperidin-3-yl}-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester (52.3 mg, 0.08 mmol) in EtOH (5.0 ml) was added 2M KOH (0.40 ml, 0.8 mmol). The reaction was heated to 78° C. for 3 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (41 mg, 76%). 1H NMR (400 MHz, MeOD) δ ppm 0.90-0.96 (m, 6 H) 1.51 (ddd, J=13.08, 6.72, 6.60 Hz, 1 H) 1.68 (dt, J=13.76, 6.94 Hz, 1 H) 1.88-1.93 (m, 2 H) 1.95-2.03 (m, 1 H) 2.11 (s, 2 H) 3.06 (d, J=2.93 Hz, 2 H) 3.22 (t, J=12.96 Hz, 1 H) 3.48-3.57 (m, 2 H) 3.77 (t, J=7.70 Hz, 1 H) 4.33 (s, 2 H) 7.00-7.10 (m, 5 H) 7.14 (d, J=1.96 Hz, 1 H) 7.24-7.34 (m, 2 H) 7.44-7.50 (m, 2 H) 7.58 (s, 1 H) 7.74-7.83 (m, 4 H), Calcd for C37H37F4NO3 (M+H) 619.69, Found 620.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].C([Li])CCC.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([F:29])[CH:22]=1>C(OCC)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[OH:26])=[C:23]([F:29])[CH:22]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1C(O)c1ccc(Br)cc1F
Reaction time: 0.75 h

Procedure:
To a mechanically stirred solution of 1-bromo-2-(diethoxymethyl)benzene (266 g) in dry diethyl ether (1.5 ) cooled to −70° C. under nitrogen was added a 2.5M solution of n-butyl lithium in hexanes (414 mL) dropwise over 30 min. The reaction mixture was stirred at a temperature less than −60° C. for 45 min then a solution of 4-bromo-2-fluorobenzaldehyde in dry diethyl ether (1.5 ) was added dropwise over 1 h maintaining the low temperature. The cooling bath was removed allowing the reaction to warm to +10° C. over 3 h. The reaction was quenched by the addition of water (500 mL). Organic layer was separated and the aqueous layer washed with ethyl acetate (2×500 mL). Combined organic layers were washed with brine then dried over anhydrous sodium sulfate and evaporated to yield the title product (371.1 g) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2
Reactant: CCC(O)CCCCC1CCC2CC(=O)CC12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)CCCCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 13 substituting the starting material from Example 3, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (2.0 g, 8.4 mmoles) and pyridinium dichromate (4.7 g, 12.6 mmoles) in methylene chloride (10 ml). The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (1.7 g, 7.1 mmoles).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:38]1([C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: C1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)N2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2-[[(4-methylphenyl]sulfonyl]amino]6-[[(phenylmethoxy)carbonyl]amino]hexanoic acid (18.00g, 44.43 mmol), triethylamine (5.80 mL, 41.43 mmol) and piperidine (4.10 mL, 41.43 mmol) in anhydrous dimethylformamide (80 mL) was added dropwise diphenylphosphoryl azide (8.90 mL, 41.43 mmol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted three additional times with ethyl acetate. The combined extracts were then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid and brine prior to drying and solvent concentration. There was isolated in sufficiently pure state 20.90g (100%) of the title compound of as pale yellow oil; 1H NMR (CDCl3) δ 7.62 (d, J=8.2 Hz, 2H), 7.30-7.22 (m, 5H), 7.19 (d, J=8.1 Hz, 2H), 5.94 (d, J=8.9 Hz, 1H), 5.09-5.07 (m, 1H), 5.03 (s, 2H), 3.90-3.88 (m, 1H), 3.43-3.36 (m, 1H), 3.09-2.91 (m, 5H), 2.32 (s, 3H), 1.43-1.23 (m, 10H), 1.09-0.97 (m, 2H); 13C NMR (CDCl3) ppm 168.28, 156.09, 142.87, 136.43, 136.30, 128.98, 127.95, 127.43, 126.96, 65.81, 52.08, 45.70, 42.67, 40.14, 32.58, 28.72, 25.49, 24.65, 23.64, 21.71, 20.93; IR (KBr, cm-1) 3316, 2938, 2860, 1718, 1634, 1526, 1452, 1416, 1340, 1246, 1162, 1092; MS m/z (MH+) calcd 502.2376, obsd 502.2363.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:27](O)([CH3:29])[CH3:28])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH:26]=1>O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:17][C:13]3[C:12]([C:27]([CH3:29])=[CH2:28])=[CH:11][C:10]([OH:9])=[CH:26][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 2-[5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole-7-yl] propan-2-ol (114 mg, 0.36 mmol) and the reaction was stirred for 2 h. The mixture was cooled to room temperature, dissolved in water and extracted with EtOAc. The organic layers were combined and washed with HCl (1N), water then brine and dried over MgSO4. Evaporation and purification by flash chromatography (50%–60% EtOAc/petroleum ether) gave (40 mg, 41% yield) of the product as a light red-brown solid, m.p. 225–228° C.; MS m/e 268 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[C:32]([F:34])[CH:33]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:30]2[CH:31]=[C:32]([F:34])[CH:33]=[C:28]([Cl:27])[CH:29]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cc(F)cc(Cl)c1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)cc(Cl)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-chloro-5-fluorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.97 (2H, d, J=8.4 Hz), 7.88–7.80 (1H, m), 7.40 (2H, d, J=8.4 Hz), 7.10–7.02 (1H, m), 7.00–6.94 (1H, m), 6.87–6.80 (1H, m), 5.43–5.27 (1H, m), 1.68–1.55 (12H, m); MS (ESI) m/z 505 (M+H)+, 503 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24]O)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:37]1C=CC=C[CH:38]=1>>[CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24][C:38]#[N:37])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#CC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
11.24 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 40 ml of pyridine. 7.01 g of p-toluenesulfonyl chloride are added dropwise to the mixture of 5° C., and the mixture is stirred at the same temperature for 30 minutes. The mixture is evaporated under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with 5% HCl and water, dried and then evaporated to remove the solvent. The residue is dissolved in 50 ml of dimethylformamide, and the solution is added dropwise to a suspension of 2.21 g of sodium cyanide in 40 ml of dimethylformamide. The addition is carried out at 5° C. The mixture is stirred at the same temperature for 2 hours, and then at room temperature for 60 hours. The mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (Solvent; ethyl acetate:n-hexane=1:2). 3.78 g of (3S)-2-benzyloxycarbonyl-3-cyanomethyl-1,2,3,4-tetrahydro-β-carboline are obtained as pale red oil. Yield: 36%
Reaction SMILES: [CH3:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2nc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc2ccccc2nc1N1CCNCC1
Reaction time: 12.5 h

Procedure:
To a solution of 2-methyl-3-[4-(phenylmethyl)piperazin-1-yl]quinoxaline (Preparation 19, 1.68 g, 5.28 mmol) in methanol (106 ml) was added ammonium formate (1.66 g, 26.4 mmol) followed by palladium (10% w/w on carbon, 0.25 g) under a nitrogen atmosphere. After 12.5 h, more ammonium formate (0.83 g, 13.2 mmol) and palladium (0.12 g) were added. The reaction mixture was filtered through Celite® and evaporated to a yellow oil. The crude product was purified by flash chromatography using silica gel eluting with methanol:dichloromethane (5:95 and then 10:90). The title compound was obtained as a pale yellow oil which crystallised upon standing (0.46 g, 38%).