Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][O:16][C:14]([C@@H:9]1[CH2:10][C@@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a solution of methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (4.68 g, 19.1 mmol) in DCM (47 mL) at RT was added DIPEA (3.66 mL, 21.0 mmol) and 4-dimethylaminopyridine (233 mg, 1.91 mmol) followed by p-toluenesulfonyl chloride (3.82 g, 20.1 mmol). The reaction mixture was stirred at RT overnight, washed with 1N HCl (2 mL), saturated sodium bicarbonate (2 mL), and brine (2 mL), dried over sodium sulfate, filtered and concentrated to give a yellowish oil, which was purified by silica gel chromatography (80 g silica, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate (1.74 g, 23% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[C:16]1([C:3]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:34])[F:22])=[CH:26][CH:27]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(OC(F)(F)F)cc3)nc2c1
Yield: 47.9 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-(trifluoromethoxy)phenylboronic acid (89.6 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 57 mg (47%) of 2-phenyl-3-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CCOCC>O.ClCCl.[Fe]>[NH2:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:20]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccn2nc(SCc3ccccc3)nc12
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1cccn2nc(SCc3ccccc3)nc12
Reaction time: 6 h
Yield: 68 %

Procedure:
2-Benzylthio-8-nitro[1,2,4]triazolo[1,5-a]pyridine (174.0 g, 0.61 mol), iron filings (204.2 g., 3.65 mol) and acetic acid (2 L) were combined and heated with stirring at 70°-80° C. for 6 hours. The reaction mixture was cooled and diluted with water and dichloromethane. The resulting mixture was filtered through Celite®, the liquid phases in the filtrate were separated, and the aqueous layer was extracted with a little more dichloromethane. The organic phase and extract were combined and washed several times with water and then with dilute aqueous sodium hydroxide. The resulting organic solution was concentrated by evaporation under reduced pressure and the residue obtained was mixed with ether. The insoluble solids were collected by filtration and dried to obtain 106.3 g of the title compound as a brown powder melting at 116°-117° C. An additional 14.2 g of lower purity product was isolated from the ether filtrate (77 percent of theory total yield). This reduction was also carried out with iron powder and calcium chloride in aqueous ethanol and with stannous chloride in hydrochloric acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:35])=[C:23]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:42]>>[ClH:42].[ClH:42].[ClH:42].[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[C:23]1[C:22]([NH2:35])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ccc5ccccc5c4)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(6-amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15.2 mg, 0.0324 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) was added HCl (4.0 M solution in 1,4-dioxane; 1.0 mL, 4.0 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately a white solid precipitated. The solid was filtered off, washed with MTBE, and dried in vacuo overnight to give the title compound as off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=14.7 (very brs, 1H), 9.32-9.17 (brm, 1H), 9.17-9.02 (brm, 1H), 8.43 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.12 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 8.08 (s, 1H), 8.06-8.00 (mc, 2H), 7.75 (brs, 2H), 7.66-7.59 (m, 3H), 4.53-4.45 (mc, 1H), 3.36 (brd, J=13.0 Hz, 2H), 3.08 (brq, J=11.2 Hz, 2H), 2.27-2.08 (m, 4H). MS(ES+): m/z=370.19 (37) [MH+], 287.12 (100) [MH+-piperidine]. HPLC: tR=1.88 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:11][CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Bromo-2-fluorobenzaldehyde (5.1 g) in tetrahydrofuran (50 mL) was added 1M tetrahydrofuran solution of ethylmagnesium bromide (41 mL) at 0° C., and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride under ice-cooling, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (3.78 g) as a colorless liquid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2([CH2:27][C:10]3=[C:11]([C:24](=[O:26])[CH3:25])[C:12]4[C:17]([CH:18]=[C:9]3[CH2:8]2)=[C:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:14][CH:13]=4)[CH2:4][O:3]1.Cl>C1COCC1>[OH:3][CH2:4][C:5]1([CH2:6][OH:7])[CH2:8][C:9]2=[CH:18][C:17]3[C:12]([C:11]([C:24](=[O:26])[CH3:25])=[C:10]2[CH2:27]1)=[CH:13][CH:14]=[CH:15][C:16]=3[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)c1c2c(cc3c(N4CCCC4)cccc13)CC1(COC(C)(C)OC1)C2
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1c2c(cc3c(N4CCCC4)cccc13)CC(CO)(CO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
An oven-dried 50 mL one-necked round-bottomed flask was charged with compound 6d (0.013 g, 0.034 mmol) and THF (10 mL). HCl (3 mL of a 1 N aqueous solution) was added and the mixture was stirred at rt for 1 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwise addition of sat'd aq NaHCO3. The layers were separated and the aqueous phase was extracted with ether (3×15 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure to provide 0.006 g of the title compound as a yellow solid in 52% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8](=O)[NH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:14]>>[C:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cnc(=O)[nH]c1
Product: CC(C)(C)c1cnc(Cl)nc1

Procedure:
200 mL POCl3 and 14 g (0.09 mol) 5-tert-butylpyrimidin-2(1H)-one are heated in a sealed glass ampoule for 3 h at 160° C. The mixture is cooled and the excess
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[C:24](O)(=[O:35])[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:24]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)=[O:35])[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)c3ccc4ccccc4n3)C1)c1cccc(Cl)c21
Yield: 78 %

Procedure:
To a dry roundbottom flask is add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), quinaldic acid (23 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol), 1-hydroxy-7-azabenzotriazole (18 mg, 0.13 mmol), 4-dimethylamino-pyridine (1 mg, 0.01 mmol), and dimethylformamide (3 mL). Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform, wash with 1N sodium thiosulfate, saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/ chloroform) to give 40.6 mg of the title compound as a white solid, 77% yield. 1H NMR: consistent with structure. MS (ion spray) 466 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][S:24]([NH2:27])(=[O:26])=[O:25].CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:27][S:24]([CH2:23][CH2:22][C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)CCc1cccs1
Reactant: Clc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(CCc1cccs1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Yield: 68.7 %

Procedure:
A solution of 4,6-dichloro-5-(4-chlorophenyl)pyrimidine (848 mg), 2-thiophen-2-yl-ethanesulfonic acid amide potassium salt (1.5 g, Referential Example 14) and Hunig's base (1 ml) in DMSO (20 ml) was stirred at rt for 24 h before it was diluted with water (200 ml) and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate was collected, washed with water and diethyl ether and dried to give 2-thiophen-2-yl-ethanesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) as a beige powder. LC-MS: tR=5.01 min, [M+1]+=413.49, [M−1]−=411.93.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].C(=O)(O)[O-].[Na+].[K+].[Br-]>C(O)C.O.[Pd]>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(OCc1ccccc1)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21

Procedure:
Benzyl clavulanate (840 mgs) in ethanol (30 ml) and water (5 ml) was hydrogenated over 10% Pd/C (267 mgs) and sodium bicarbonate (244 mgs) for 25 minutes at room temperature and atmospheric pressure. The catalyst was filtered, washed with water and ethanol and the combined filtrates were evaporated in vacuo. The product crystallised from a water-acetone mixture was microneedles (565 mgs). Recrystallisation from water-acetone gave needles which, after drying over P2O5 in vacuo for 24 hours gave the following analysis: C 41.01, 40.86; H 3.77, 3.64; N 5.68, 5.51; i.r.(KBr disc) 1785, 1700, 1620 cm-1 ; Nmr (D2O) 3.06 (d,1,J=18.5 Hz), 3.57 (dd,1,J1 =18.5 Hz, J2 =2.5 Hz), 4.15 (d,2,J=8 Hz), 5.3 (HOD), 4.9(m), 5.71 (d,1,J=2.5 Hz).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([NH:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:2]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[N:43]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)CCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)CCN(Cc1ccccc1)C(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 25.7 %

Procedure:
To a solution of N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 7.2 mmole) in dichloromethane (20 mL) was added TFFH (1.91 g, 7.2 mmole). The mixture was cooled to 0° C. and N′-benzyl-N,N-dimethylethylenediamine (2.57 g, 14.4 mmole) was added to the reaction. The reaction was allowed to warm to room temperature and stirred for 6 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 1d (0.81 g, 26%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][OH:13])[C:6](=[O:14])[CH:5]=1)[CH3:2].CCN(CC)CC.[CH3:22][N:23]1C(=O)O[C:26](=[O:27])[C:25]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:24]12.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:13][CH2:12][CH2:11][CH2:10][CH:7]1[CH2:8][CH2:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]1=[O:14])=[O:27]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC1=CC(=O)C(CCCO)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1=CC(=O)C(CCCOC(=O)c2ccccc2NC)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Alcohol 3 (180 mg, 0.89 mmol), NEt3 (0.56 mL) and catalytic DMAP were added to a solution of N-methylisatoic anhydride (220 mg, 0.89 mmol) in dry DMF (2.0 mL) at rt. After stirring overnight, the solution was warmed to 65° C. for 3 h. After cooling to rt, water was added and this mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by flash column chromatography to afford 87.0 mg (45% yield) of 4 as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, m), 7.33 (1H, m), 6.56 (2H, m), 5.27 (1H, s), 4.22 (2H, t, J=5.2 Hz), 3.85 (2H, q, J=7.0 Hz), 2.86 (3H, s), 2.39 (2H, t, J=5.3 Hz), 2.04-1.41 (7H, m), 1.31 (3H, t, J=7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 201.1, 176.8, 168.7, 151.7, 134.7, 131.7, 115.0, 111.3, 110.6, 102.5, 101.9, 64.7, 64.5, 64.3, 44.9, 30.0, 28.2, 26.6, 26.5, 26.4, 14.3; ESI MS m/z 354 (M++Na+).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2[O:8][CH2:9][C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[CH:12]([C:13]([NH:15][C:16]3[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH:25]([CH3:27])[CH3:26])=[O:14])[C:6]=2[CH:5]=1)(O)=[O:2].ClC(OCC)=O.[BH4-].[Na+].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[OH:2][CH2:1][C:4]1[CH:33]=[CH:32][C:7]2[O:8][CH2:9][C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[CH:12]([C:13]([NH:15][C:16]3[C:17]([CH:25]([CH3:26])[CH3:27])=[CH:18][CH:19]=[CH:20][C:21]=3[CH:22]([CH3:24])[CH3:23])=[O:14])[C:6]=2[CH:5]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After 1.33 g of 2-ocarboxy-6,11-dihydro-N-(2,6-diisopropylphenyl)dibenz[b,e]oxepin-11-carboxamide (Compound 25) obtained in Example 25 was dissolved in 10 ml of tetrahydrofuran, 1.0 ml of triethylamine and 0.39 g of ethyl chloroformate were added to the solution under ice cooling. The mixture was stirred at room temperature for 12 hours. Then 0.57 g of sodium borohydride was slowly added to the reaction mixture under ice cooling. After stirring at room temperature for 6 hours, saturated aqueous sodium chloride solution was added and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (2:1)]. The crude crystal was recrystallized from ethyl acetate-hexane to obtain 1.08 g of Compound 26 as white needles.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[CH:14]1([C:19](O)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:19]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:20]
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (0.6 g, 2.72 mmol) in methanol (50 ml) was added cyclopentane carboxylic acid (0.310 g, 2.72 mmol). The reaction mixture was cooled to 0° C. and then 1-ethyl-3(3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl) (0.78 g, 4.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water. The solid was filtered and washed thoroughly with water followed by diethyl ether. The product obtained was dried under high vacuum. The crude product (0.40 g) was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:17](O)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[C:18]([C:19]3[C:20]([C:25]([F:27])([F:28])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2=NOC(O)C2c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nocc2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Reaction time: 0.17 h

Procedure:
3-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)-4,5-dihydroisoxazol-5-ol (2.06 g, 5 mmol) was heated in 20 mL of ethyl acetate to 70° C. To the resulting slurry was added trifluoroacetic acid (0.74 g, 6.5 mmol) dropwise. After 10 minutes, the reaction was evaporated to dryness and the residue was recrystallised from isopropanol to give 3-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)isoxazole, 1.224 g (62%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[C:57]([O:61][C:62]([N:64]1[CH2:67][CH:66]([CH2:68][NH2:69])[CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58].[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[C:57]([O:61][C:62]([N:64]1[CH2:67][CH:66]([CH2:68][NH:69][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NCC2CN(C(=O)OC(C)(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of 0.097 g (0.15 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0634 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 3 mL of dichloromethane, 0.13 mL of triethylamine was added followed by 0.0317 g (0.17 mmole) of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester. After 1 hour, 4 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 100:0-0:100) to give 0.0714 g of 3-{[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (I-91).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18](O)[C@H:17](O)[CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9](O)=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(Cl)(=O)C1C=CC=NC=1>N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][CH2:18]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Agent: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: C[C@@]12CCC[C@H]1[C@@H]1CCc3ccccc3[C@H]1CC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
In a 100 cc flask, protected from light and humidity, 5.76g (0.02 Mole) of estriol are dissolved in 60 cc of anhydrous pyridine; 9.87g (0.07 mole) of nicotinoyl chloride are added and the whole shaken at 60° C for 6 hours. After cooling, the reaction mixture is poured into a liter of ice water and shaken for 15 minutes. The precipitate is dried and washed with water until neutral. Yield: 95%. The precipitate can also be extracted with chloroform or ether.