Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[N:3]=1.O.[CH3:29][N:30](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:29]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[N:3]=1)#[N:30]
Reactant: CCN1CCN(c2nc(Cl)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCN1CCN(c2nc(C#N)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
A mixture of methyl 4-chloro-2-(4-ethylpiperazin-1-yl)-6-(m-tolylamino)pyrimidine-5-carboxylate (152.6 mg, 0.391 mmol), tetrakis(triphenylphosphine)palladium (40.8 mg, 0.035 mmol) and zinc(II) cyanide (25.2 mg, 0.215 mmol) in DMF (3 mL) was stirred at 90° C. for 3 h. Water was added and the resulting mixture was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2 hexanes/EtOAc=5/1) to give the title compound as a yellow oil (51.1 mg, 34%). 1H NMR (500 MHz, CDCl3) δ ppm 1.12 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.44-2.49 (m, 6H), 3.81-3.98 (m, 7H), 6.95-6.96 (m, 1H), 7.23-7.26 (m, 1H), 7.37-7.47 (m, 2H), 10.46 (s, 1H). [M+H] calc'd for C20H25N6O2, 381. found, 381.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc2ccccc2c1CCN
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
0.45 g (2.23 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, is introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 0.47 cm3 (3.37 mmol) of triethylamine dried over potassium hydroxide is introduced, followed by 0.28 cm3 (2.69 mmol) of butyryl chloride. After the introduction of the reactants, the ice bath is removed and reaction is allowed to proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.29 g (1.07 mmol) of N-[2-(2-methoxynaphthyl)ethyl]butyramide (white solid) is obtained, equivalent to a yield after purification of 48%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9]O)[CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][N:15]2[C:14](=[O:16])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:21])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCO)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
45.6 g (262 mmol) of diethyl azadicarboxylate (DEAD) was added dropwise to a solution of 30.0 g (219 mmol) of 2-(6-methyl-2-pyridyl)ethanol, 38.6 g (262 mmol) of phthalimide and 68.6 g (262 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran at a temperature of 15° to 25° C. The mixture was stirred overnight. Water was added to the mixture. After extraction with ethyl acetate, the organic layer was washed with water After extraction with 2N hydrochloric acid, a 3N sodium hydroxide solution was added to the aqueous layer at 0° C. to make it alkaline. White crystals thus formed were collected by filtration to give 39.04 g (yield: 67%) of the intended compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O=S(Cl)[Cl:12].[CH3:14]O>>[ClH:12].[CH3:14][O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)CC(C)C
Product: Cl
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of (L)-leucine, (315 g, 2.4 mol) in MeOH (3.2 L) at −15° C. was added SOCl2 (315 mL, 4.32 mol, 1.8 equiv.) dropwise at such a rate that the temp. of the reaction did not exceed 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was concentrated under reduced pressure and Et2O (3 L) was slowly added to the residue to produce a precipitate. The mixture was cooled with an ice bath, then treated with additional MeOH (3 L) relatively rapidly. After 1 h at 0° C., the crystals were collected and dried to give (L)-leucine methyl ester HCl salt as a white crystalline solid (394 g, 86%): mp 147-149° C.; 1H-NMR (CD3OD) δ0.78-0.98 (m, 6 h), 1.58-1.72 (m, 3H), 3.76 (g, 3H), 3.92 (t, J=7.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=3)=[N:11][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1C=C(Cl)C=C(C(OO)=O)C=1.[S:38](S([O-])=O)([O-:40])=[O:39].[Na+].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:38]([CH3:27])(=[O:40])=[O:39])=[CH:15][CH:14]=3)=[N:11][C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc(-c3ccccc3)nn2-c2ccc(Cl)cc2)cc1
Reactant: O=S([O-])S(=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2nc(-c3ccccc3)nn2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-5-(4-methylthio-phenyl)-3-phenyl-1H-1,2,4-triazole (130 mg, 0.34 mmol) in CHCl3 (5 ml) were added 2 equivalents of MCPBA (200 mg, 6.88 mmol). The reaction mixture was stirred for two days at room temperature, then sodium hydrosulfite was added and the resulting mixture was neutralized with concentrated NaOH. After extraction with chloroform, the organic phase was washed with water and dried over sodium sulfate. Evaporation under pressure and crystallization from ethanol yielded a white solid (50 mg, 36%) m.p. 170° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:45](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:20]=[N:19][N:18]([CH3:45])[N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 0.5 g, 0.85 mmol), methyl iodide (0.3 g, 2.1 mmol) and potassium carbonate (0.29 g, 2.1 mmol) were stirred at 50° C. in acetonitrile (20 ml) for 2 hours. Concentrated in vacuo then partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 20, 50 and 75% ethyl acetate/iso-hexanes to afford the title compounds: isomer A (0.25 g, 49%) and isomer B (0.17 g, 33%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[N:46]7C(OC(C)(C)C)=O)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[NH:46]7)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3nc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)cnc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2cc1-c1cnc2cc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 156.6 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (30 mg, 0.044 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed under vacuum and the residue was triturated with Et2O to yield a TFA salt of 2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline (32.7 mg) as yellow solid. LC-MS retention time 1.33 min; m/z 475 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.47 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.31 (dd, J=8.8, 1.8 Hz, 1H), 8.26 (dd, J=8.5, 1.3 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 4.85-4.97 (m, 1H), 4.67 (dd, J=10.8, 7.5 Hz, 1H), 3.45-3.57 (m, 2H), 2.77-2.86 (m, 1H), 2.65-2.74 (m, 1H), 2.52-2.65 (m, 2H), 2.02-2.15 (m, 2H), 1.18-1.30 (m, 2H), 0.95-1.09 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[C:12]([O:23][CH3:24])(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:24][O:23][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 85 °C
Yield: 69.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.5 g, 2.33 mmol), methyl vanillate (0.6 g, 3.30 mmol), anhydrous potassium carbonate (1.0 g, 7.25 mmol), and DMF (40 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stifling to react for 8 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.35), filtering to obtain filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain solid, 0.51 g white crystalloid of 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3-methoxybenzoic methyl ester, a yield is 69.3%, m.p. 129.8-130.4° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:30]([N:12]3[C@H:13]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C@H:14]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[N:15]=[C:11]3[C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=3[O:33][CH2:34][CH3:35])=[O:31])[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCCC2)CC1

Procedure:
[1,4′]Bipiperidinyl-1′-yl-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-methanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-piperidinopiperidine (Aldrich) in an analogous manner as described in example 25. HR-MS (ES, m/z): observed 661.3071, calculated for C38H47Cl2N4O3 [(M+H)+] 661.3071.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([CH3:19])[C:13]=1[CH2:20][OH:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([CH:20]=[O:21])=[C:14]([CH3:19])[N:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Cc1nc(Cl)cc(Cl)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc(Cl)cc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A dry flask was charged with DCM (59.9 mL) and oxalyl chloride (3.15 mL, 35.9 mmol) and cooled to −78° C. Dimethyl sulfoxide (3.40 mL, 47.9 mmol) was added and the reaction was stirred for 30 min. A solution of (4,6-dichloro-2-methylpyridin-3-yl)methanol (4.60 g, 23.95 mmol) in DCM (2 mL) was then added. The reaction was stirred for 30 min then triethylamine (6.74 mL, 71.9 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction was warmed to 0° C. and stirred for 1 h. The reaction was then quenched with sodium bicarbonate, diluted with water, and the aqueous layer extracted with EtOAc. The organic phase was washed with sat. sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo to afford 4,6-dichloro-2-methylnicotinaldehyde, which was carried onto the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.37 (s, 1H), 2.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:20][CH:19]([CH2:21][OH:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:6]=2[CH:17]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:3]2[O:20][CH:19]([C:21]([OH:25])=[O:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:6]=2[CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A portion (4.5 g) of the 5-chloro-3-(2-chlorophenyl)7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 13 was dissolved in 200 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (4.9 g), water (10 ml) and concentrated sulfuric acid (6.9 g) was added dropwise over time, and the resulting mixture was stirred for 8 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the solution was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 2.6 g of 5-chloro-3-(2-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 220°-221.5° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH2:12]([NH2:15])[CH2:13][CH3:14].[H][H]>CO.[Pd]>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([NH:15][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCN
Agent: [Pd]
Solvent: CO
Product: CCCNC1CCC2(CC1)OCCO2

Procedure:
To a solution of 9.36 g (60 mmol) 1,4-cyclohexanedione monoethylene acetal in 60 mL of methanol and 9.84 mL (120 mmol) of propylamine is added 0.6 g of palladium on carbon (10%). The mixture is stirred overnight under 4 bar hydrogen pressure. Filtration over Celite and concentration in vacuum provides the crude product in almost quantitative yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H]>C1COCC1.[Pd]>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(c1Cl)CC(C)O2

Procedure:
51.0 g of 1C was dissolved in 600 ml of THF. The solution was divided in half, and each half was hydrogenated (40-50 psig hydrogen pressure) in the presence of 1 g of palladium-on-charcoal catalyst. The reaction mixtures were filtered, the filtrates were combined, dried (MgSO4) and evaporated dryness, to give 7-amino-2,3-dihydro-2,5-dimethyl-4-chlorobenzofuran (1D).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][N:51]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][N:51]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-benzyl-2-oxoazocan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 45 (6.3 mg, 0.027 mmol) to give a white solid (9.5 mg, 62% yield). Anal. Calcd. for C45H56N4O6S m/z 780.7. found: 781.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.03 (m, 16H), 6.81 (d, J=7.4 Hz, 1H), 5.34 (t, J=4.6 Hz, 1H), 5.13 (d, J=6.1 Hz, 1H), 5.07 (d, J=14.7 Hz, 1H), 5.03-4.93 (m, 1H), 4.92-4.80 (m, 1H), 4.06 (d, J=14.7 Hz, 1H), 3.77 (t, J=13.2 Hz, 1H), 3.68 (s, 3H), 3.25-3.04 (m, 2H), 2.92-2.64 (m, 5H), 2.47-2.29 (m, 2H), 2.12-1.95 (m, 2H), 1.90-1.09 (m, 18H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Cc1cc(N)no1
Product: Cc1cc(NC(=O)c2c(C(F)(F)F)nc3c(C(F)(F)F)cccc3c2O)no1
Yield: 48.6 %

Procedure:
Using the procedure of Example 2, 27.2 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride and 6.38 g of 3-amino-5-methyl-isoxazole were reacted to obtain 12.8 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(5-methyl-isoxazol-3-yl)-3-quinoline-carboxamide melting at 216° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19])=[CH:28][CH:27]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (0.9 g--see Preparation 4), N-methyl-4-chlorophenethylamine (0.51 g, see CA 61:15224h), anhydrous potassium carbonate (0.83 g) and acetonitrile (40 ml) was heated under reflux for 24 hours then partitioned between dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 40%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum yield, 0.25 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)cn2)CC1
Yield: 99.9 %

Procedure:
Compound 32 (391 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10 mL), and 1-methylpiperazine (0.56 mL, 5.00 mmol) was added thereto, followed by stirring under heating and reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium chloride was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:1) to afford the entitled Compound 35 (454 mg, 100%).