Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([O:28][CH3:29])(=[O:27])=[O:26])(=[O:18])=[O:17])SC)[N:4]=1.[CH3:30][O:31][NH2:32].Cl>O1CCOCC1>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([O:28][CH3:29])(=[O:26])=[O:27])(=[O:18])=[O:17])=[N:32][O:31][CH3:30])[N:6]=1
Reactant: COc1nc(NC(=NS(=O)(=O)c2ccccc2S(=O)(=O)OC)SC)nc(OC)n1
Reactant: CON
Agent: Cl
Solvent: C1COCCO1
Product: CON=C(Nc1nc(OC)nc(OC)n1)NS(=O)(=O)c1ccccc1S(=O)(=O)OC
Temperature: 0 °C
Reaction time: 96 h
Yield: 32.5 %

Procedure:
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) S-methylisothiourea (4.63 g) was dissolved in dioxane (100 ml), and O-methylhydroxylamine (2.35 g) was added to the solution. The mixture was stirred at room temp. for 4 days. The reaction mixture was poured into ice water, and adjusted to pH 3 with hydrochloric acid. The precipitated crude crystals were collected by filtration, and recrystallized from acetonitrile to give 1.5 g of the desired N-(4,6-dimethoxy-1,3,5-triazin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) N"-(methoxy)guanidine represented by the following formula. mp. 148°-150° C. ##STR22## By the same method as in Example 1 or 2, the compounds of the invention shown in Table 1 below were synthesized.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:35]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:35]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 20 °C

Procedure:
15 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid were dissolved at -15° C. in a solution of 5 g of sodium acetate in 100 ml of methanol and 3 g of activated carbon were added thereto. The solution was filtered and the filtrate was heated to 20° C. to obtain crystals of a methanol solvate of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate identical to the product of Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[Na+].[F:18]F>C(#N)C>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:18][N+:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1cccc(Cl)n1
Reactant: FF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[n+]1c(Cl)cccc1Cl
Temperature: -40 °C

Procedure:
A 100 ml (milliliters) 3-necked round bottom flask was equipped with a magnetic stirring bar, a fluorine-helium inlet tube, and a gas outlet tube connected to a granular alumina trap and then to a 5 percent aqueous caustic trap. A 1.0 g (gram) (6.8 mmol (millimole)) sample of 2,6-dichloropyridine, 1.03 g (6.0 mmol) of sodium trifluoromethanesulfonate, and 40 ml of anhydrous acetonitrile were added and the mixture cooled to -40° C. A 1:9 mixture of fluorine and helium then was passed into the mixture with stirring at the rate of 30 ml per minute until 15 mmol of fluorine had been added. The fluorine gas mixture was replaced with nitrogen gas and the mixture was allowed to warm to ambient temperature. The mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to obtain 0.75 g (40 percent of theory) of the title compound as a yellowish solid. The compound had 19FNMR absorptions (CD3CN, CFCl3 standard) at 31.6 ppm (s) N-F and -78 ppm (s) CF3 in a 1:3 ratio as required by the structure.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][O:6][C:7]1[C:8]([CH:23]=C)=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:43].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:3][CH:2]([CH3:1])[CH3:33])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)=[O:43]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@@H](COc1cc2c(cc1C=O)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (300 mg, 0.664 mmol) (prepared as described in Example 46, Part A) osmium tetroxide (2.5% in 2-methyl-2-propanol) (4.17 μl, 0.013 mmol), and 2,6-dimethylpyridine (0.155 mL, 1.329 mmol) in 1,4-dioxane (5 mL) and water (2 mL), cooled to 0° C., was stirred for 15 min. Sodium metaperiodate (568 mg, 2.66 mmol) was added and the reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth (Celite®), eluting with EtOAc. The EtOAc layer was washed with saturated aqueous NaHCO3, H2O, then brine. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to afford (S)-tert-butyl (1-((9-formyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.353 mmol, 53% yield) as a gummy solid. LC/MS (ESI) m/e 454.1, [(M+H)+, calcd for C25H32N3O5, 454.2].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O.CC(C)=O>[CH2:10]([O:17][C:18]([N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[NH2:9])[CH2:3][CH2:2]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of piperidine-4-carboxamide (5 g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol) in a mixture of water (30 mL) and acetone (40 mL), NaOH 1N (39 mL, 39 mmol) was added dropwise, while maintaining the pH between 6 and 8. The mixture was stirred at r.t. for 3 h; then acetone was evaporated and the resulting precipitate filtered and dried at 70° C. under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][O:54][C@@H:55]1[C@@H:61]([CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=2[Cl:72])[O:60][C@H:57](OC)[C@:56]1([CH3:74])[OH:73]>CC#N.O.C(Cl)Cl>[O:1]([CH2:9][CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[N:13]([C@@H:57]2[O:60][C@H:61]([CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=3[Cl:72])[C@@H:55]([O:54][CH2:53][C:47]3[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=3[Cl:45])[C@@:56]2([CH3:74])[OH:73])[CH:12]=1)[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ncnc(Cl)c12
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
Compound 2.3 (2.5 g, 8.00 mmol) was suspended in CH3CN (50 mL), and powdered 85% KOH, (1.3 g, 19.73 mmol) followed by TDA -1 (tris[2-(2-methoxyethoxy)ethyl]amine) (0.2 mL, 0.62 mmol) were added. After stirring at room temperature for 10 min, a freshly prepared solution of bromo sugar 2.4 (prepared from commercially available 3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-1-O-methyl-α-D-ribofuranose; (i) Helv. Chim. Acta, 1995, 78, 486; (ii) WO 02/057287, 2002) (10.1 mmol) in anhydrous acetonitrile (50 mL) was added via cannula, and the reaction stirred for 24 hr at room temperature then cooled in an ice/water bath and treated with CH2Cl2 (100 mL) and water (80 mL). The aqueous material was extracted three times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered and evaporated The crude product was purified on a silica gel column using 20% ethyl acetate/hexanes as eluent to give the desired nucleoside 2.5 (1.03 g, 13%). Further elution with 25% EtOAc/hexanes as eluent gave a mixture of the desired nucleoside 2.5 and starting base 2.3 (350 mg).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[C:37]([C:41]1[CH:73]=[CH:72][C:44]([C:45]([NH:47][C:48]2[N:49]=[CH:50][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[N:52][CH:53]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:73]=[CH:72][C:44]([C:45]([NH:47][C:48]2[N:49]=[CH:50][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[N:52][CH:53]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:39])([CH3:38])[CH3:40]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3cnc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3cnc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Yield: 31 %

Procedure:
The compound of example 505 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 504.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC>O.COCCOC>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1csc(-c2ccncc2)c1
Temperature: 140 °C
Yield: 2.9 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid ethyl ester (5.26 mmol), 4-pyridylboronic acid (5.26 mmol), caesium carbonate (7.9 mmol) and palladium (0) tetrakis-triphenylphosphine (0.53 mmol) were dissolved in a mixture of water (10 mL), IMS (20 mL) and DME (50 mL). The reaction mixture was heated by microwave irradiation to 140° C. for 10 minutes, and then ether (100 mL) and water (20 mL) were added. The organic solution was washed with water, dried with anhydrous magnesium sulfate, filtered and the solvent evaporated to give brown oil. The residue was purified by flash chromatography on silica. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.035 g) as an off-white solid. LCMS m/z 234.04 [M+H]+ R.T.=2.10 min. (Analytical Method 5).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13](C(O)(C)C)[CH:14]=[CH:15][CH:16]=1)[CH3:9].S(Cl)(Cl)=O.N1C=C[CH:30]=[CH:29][CH:28]=1>>[CH3:22][C:2]([CH3:1])([CH3:21])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:29]([CH3:30])=[CH2:28])[CH3:9]
Reactant: CN(CC=CC#CC(C)(C)C)Cc1cccc(C(C)(C)O)c1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C(C)c1ccccc1CN(C)C/C=C/C#CC(C)(C)C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
A mixture of pyridine (10 ml), Compound 37 (940 mg; 3.1 mmol), and thionyl chloride (1.12 g; 9.4 mmol) was stirred for 15 minutes while being cooled with ice, and then stirred for 15 minutes at room temperature. Subsequently, unreacted pyridine and thionyl chloride were evaporated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added thereto. The mixture was extracted with ether twice (70 ml and 50 ml), and the combined organic layer was washed with saturated brine, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 360 mg of the target compound (yield: 40.8%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([NH:31][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:21])=[CH:22][CH:23]=1
Reactant: CCCCS(N)(=O)=O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in dichloromethane (5 mL) was added butane-1-sulfonic acid amide (44.2 mg, 0.32 mmol), N,N-dicyclohexylcarbodiimide (67.1 mg, 322 mmol) and 4-dimethylaminopyridine (40.1 mg, 0.32 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then filtered and the filtrate was concentrated and purified by chromatography (SiO2, heptane:ethyl acetate 100:0 to 0:100) to give the title compound (17 mg, 12%) as a white solid. MS: m/e=428.1 [M−H]−.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:12]([NH:16][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[CH2:13][CH2:14][CH3:15]
Reactant: OC(CCI)c1ccccc1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNCCC(O)c1ccccc1

Procedure:
(Compound 15) (12.5 g) was treated with butylamine (40 ml) in THF (75 ml) at RT for 4 h. The mixture evaporated and the residue extracted with OH- /ether. The ether phase washed with H2O and saturated NaCl-solution, dried (MgSO4) and evaporated giving 6.2 g of 3-butylamino-1-phenyl-1-propanol (compound 16). Identified by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Agent: C[Si](C)(C)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A stirred solution of (3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.0 g, 2.28 mmol) in dry dichloromethane (30.0 ml) under nitrogen at 5° C. was treated with triethylamine (0.52 ml, 3.77 mmol) followed by chlorotrimethylsilane (0.32 ml, 2.52 mmol) dropwise. The resulting suspension was stirred at room temperature for 20 min, treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.52 mmol) and stirred at room temperature until the reaction was judged to be complete from TLC inspection (˜30 min). The solvent was removed by evaporation, the residue was taken up in ethyl acetate (200 ml), washed with 2M aqueous sodium hydroxide (3×100 ml), brine (100 ml) and 2M aqueous hydrochloric acid (2×100 ml). Evaporation of the dried organic extracts (Na2SO4) gave a yellow/brown oil. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a yellow oil (0.80 g, 80%). [α]D26 −157 (c=0.014 gml−1, CHCl3); νmax (thin film)/cm−1 3418.5 (br. OH), 3064.5, 3033.5, 2935.5, 2879.0, 1593.5, 1570.5; δH (270 MHz) 2.35 (2H, m, 2×2-H); 3.50 (2H, m, 2×1-H); 5.13 (2H, q, CH2Ph, 2J=11.1 Hz); 6.6 (m, 2H, 3-H, indole 3-H); 6.72 (1H, dd, indole 6-H, Jo=7.6 Hz, Jm=0.7 Hz); 6.90 (1H, dd, indole 4-H, Jo=8.3 Hz, Jm=0.8 Hz); 7.00 (2H, m, indole 5-H, 5′-H); 7.15 (1H, d, indole 2-H, 3J2,3=3.0 Hz); 7.19-7.40 (8H, m, 8ArH). δC (67.8 MHz) 38.4 (2-C); 56.4 (3-C); 59.3 (1-C); 70.7 (PhCH2); 103.2 (indole 3-C); 104.3 (indole 6-C); 114.3 (indole 4-C); 120.1 (indole 5-C); 122.5 (3′-C); 125.0 (indole 2-C); 131.8 (1′-C); 136.4 (benzyl ipso-C); 144.9 (indole 7a-C); 146.5(indole 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][N:15]([C:19]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=4)[CH2:24][NH:25]C(=O)OC(C)(C)C)=[O:20])[CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[ClH:36]>C(OCC)(=O)C>[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][N:15]([C:19]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=4)[CH2:24][NH2:25])=[O:20])[CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)N2CCOc3nccc(-c4ccc(F)cc4)c3C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(C(=O)N2CCOc3nccc(-c4ccc(F)cc4)c3C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-{[6-(4-fluorophenyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl]carbonyl}benzylcarbamate (0.32 g) obtained in Example 72C was added a 4N solution (10 ml) of hydrochloric acid in ethyl acetate, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was dissolved in a small amount of isopropanol. Ethyl acetate was added and the resulting crystals were collected by filtration to give the title compound (0.25 g) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]2[C:17]([CH3:18])=[CH:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[OH:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]2[C:17]([CH3:18])=[CH:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12
Reactant: COC(=O)c1nn2c(C)cn(C)c(=O)c2c1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nn2c(C)cn(C)c(=O)c2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5,7-dimethyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (62 mg, 0.189 mmol) in CHCl3 was added TFA (200 μL), and the reaction was stirred at room temperature for 2 hours. Following treatment with additional TFA (200 μL), the reaction was heated to 50° C. overnight. The solvent was removed in vacuo, and the resulting residue was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 6.44 (s, 1H), 4.03 (s, 3H), 3.48 (s, 3H), 2.44 (s, 3H); ES MS (M+Na)=260.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 8.5 g of 4-hydroxybenzophenone in 75 ml of dry pyridine 6.75 ml of isobutyric chloride was added at 0°~10° C. The reaction mixture was allowed to stand at 25° C. for 2 h, poured into ice water. The precipitate was collected by suction and recrystallized from ethanol; M.P.~69°-69.5° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:34][CH3:35])[CH2:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OCC)(=O)C>CCCC(C)C>[CH:28]1([N:27]([CH2:26][CH:25]([O:34][CH3:35])[O:24][CH3:23])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[C:9]([C:7]3[N:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)[CH:10]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Reactant: COC(CNC1CCCCC1)OC
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cn(C(C)C)nn2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (230 mg) was prepared from 3-(3-(1-isopropyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoic acid [Example 12, Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 4, Step v) and the elution gradient to 0 to 100% ethyl acetate in isohexane. MS [M+H-MeOH]+=441 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.71-7.61 (m, 2H), 7.32 and 7.31 (2×t, J=7.7 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 4.87 (septet, J=6.7 Hz, 1H), 4.51 and 4.36 (2×t, J=5.4 Hz, 1H), 4.03-3.94 and 3.69-3.60 (2×m, 1H), 3.76-3.66 (m, 4H), 3.34 and 3.25 (2×d, J=5.3 Hz, 2H), 3.34 (s, 3H), 3.31 (s, 3H), 2.91-2.85 (m, 2H), 2.68-2.61 (m, 2H), 1.79-1.01 (m, 10H), 1.61 (d, J=6.8 Hz, 6H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:39]=[CH:38][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C.C(OCC)(=O)C>CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:38][CH:39]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A mixture of tert-butyl 4-[(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenoxy)methyl]piperidine-1-carboxylate obtained in Example 37 (1.5 g), 4 M hydrochloric acid-ethyl acetate solution (20 mL), ethyl acetate (100 mL), and methanol (100 mL) was stirred at room temperature for 16 h. The solvent was evaporated. 1 M sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (1.1 g, 90%) as crystals.