Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:41]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:40]=5[OH:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Temperature: 90 °C
Yield: 57.9 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (84 mg, 0.144 mmol, 1 equiv) and (2-hydroxy-5-methylphenyl)boronic acid (33 mg, 0.216 mmol, 1.5 equiv) in DMF (1.4 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (17 mg, 0.014 mmol, 0.1 equiv) and 2 M Na2CO3 (0.144 mL, 0.287 mmol, 2 equiv). The reaction was heated at 90° C. for 3 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (51 mg, 58%) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.13 (br. s., 1H), 8.08-8.01 (m, J=7.0 Hz, 1H), 7.95 (br. s., 1H), 7.62-7.56 (m, 1H), 7.51 (br. s., 1H), 7.14 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.10-5.94 (m, 2H), 5.40 (d, J=17.1 Hz, 1H), 5.03 (d, J=9.5 Hz, 1H), 3.99 (d, J=5.0 Hz, 2H), 3.90 (br. s., 1H), 3.79-3.75 (m, 1H), 3.71 (s, 3H), 3.08 (br. s., 1H), 2.79-2.70 (m, 1H), 2.56 (br. s., 3H), 2.35 (s, 3H), 2.00 (d, J=13.6 Hz, 2H), 1.88-1.77 (m, 2H), 1.34 (s, 3H), 1.26 (s, 9H); LCMS (ESI, M+1): 612.4.
Reaction SMILES: Cl[C:2]1[C:3]([C@@H:13]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:3]([C@@H:13]([N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])[CH3:14])=[N:4]2
Reactant: CSc1ccccc1B(O)O
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1nc2c(Cl)cccc2nc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet and a temperature probe was charged with DMF (2.16 L), (S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (273 g, 733 mmol) and 2-(methylthio)phenylboronic acid (136 g, 807 mmol). To the mixture, was added potassium carbonate (203 g, 147 mmol) and [1,1-bis(di-phenylphosphino)ferrocene]palladium(ii) chloride, complex with DCM (29.9 g, 36.7 mmol). The mixture was vacuum purged with N2 (2×), and heated to 100° C. The reaction was monitored by LC-MS, and deemed complete after 4 h. The reaction was cooled to rt (21° C.), and then divided into two batches. Each batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel. After phase separation, the organic layer was washed with brine (2×500 mL) and concentrated to afford the crude product. The combined batches of crude material were loaded on silica gel and purified by flash chromatography (ISCO/RediSep™) (hexane:EtOAc=10:0 to 6:4) to provide the product as a light brown solid 320 g with 98% LC purity and 95% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH3:19])[CH:6]=[CH:5]2.[N:20]1[NH:21][C:22](=[O:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:21]1[C:22](=[O:26])[CH:23]=[CH:24][CH:25]=[N:20]1)[CH:11]=[CH:10]2
Reactant: CC1CCCN1CCc1ccc2cc(Br)ccc2c1
Reactant: O=c1cccn[nH]1
Product: CC1CCCN1CCc1ccc2cc(-n3ncccc3=O)ccc2c1

Procedure:
One process for the preparation of 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one, which demonstrates activity as a histamine-3 receptor ligand, involves treating an inexpensive and readily available starting material, 6-bromo-naphthalen-2-ol, to afford 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one. Briefly, the process involves providing 6-bromo-naphthalen-2-ol. Preparing the triflate, or trifluoromethansulfonic acid ester, of 6-bromo-naphthalen-2-ol (2) with trifluoromethanesulfonic anhydride or another suitable trifluoromethanesulfonic reagent. The resulting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester (2) is converted to 2-bromo-6-vinyl-naphthalene (3) via a Pd-catalyzed Suzuki cross-coupling reaction. The 2-bromo-6-vinyl-naphthalene is reacted with a 2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine (4). Compound (4) is reacted with 2H-pyridazin-3-one to provide the desired 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one (5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:24][C:19]2[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OCC1CCN(c2ccncc2)CC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-yl-methoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].[CH3:37][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:37])=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reaction time: 0.33 h
Yield: 59 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (260 mg, 0.5 mmol) was initially charged in THF (10 ml) at −78° C., and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (0.6 ml; 1.2 eq.) was added. After 20 min of stirring, iodomethane (355 mg; 5 eq.) was added, and the mixture was stirred with gradual warming from −78° C. to RT for 16 h. The reaction mixture was then concentrated, and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 55:45). This gave the title compound as a solid (157 mg, 59% of theory).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCOCC.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:42][C:43]([C:44]([OH:46])=[O:45])([F:48])[F:47]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Reaction time: 1 h

Procedure:
46.1 g of BOC-Leu-Ser-Thr-OBzl are dissolved in 92.5 ml of 90% strength trifluoroacetic acid and left for 1 hour at 20° C. Thereafter dry ether (925 ml) is added whilst stirring, and the mixture is stirred for one hour at 0° C. and left to stand overnight at -10° C. The resulting precipitate is filtered off, washed three times with dry ether and dried in vacuo over sodium hydroxide. Melting point 168°-171° C.; Rf7 = 0.80 (on silica gel).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:25][C:26]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)cc1Oc1ccc(F)cc1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1)c1ccccc1
Yield: 91.1 %

Procedure:
Following the procedure in Example 7, Step C, 5-bromo-3-(4-fluorophenoxy)pyridin-2-amine (800 mg, 2.83 mmol) and benzoyl isothiocyanate (0.457 mL, 3.39 mmol) afforded 1-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg, 91.2% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH:16]=CC2C=CC=CC=2)[NH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:26]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][OH:26])[NH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1C=Cc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Temperature: -78 °C

Procedure:
In a mixture of 80 ml of methanol and 16 ml of dichloromethane is dissolved 0.8 g of (3S,4R)-3-benzyloxycarbonylamino-4-styryl-2-azetidinone obtained in Example 33 and, with cooling at -78° C., ozone gas is bubbled into the solution for 30 minutes. Thereafter, the excess ozone is purged with nitrogen and 0.19 g of sodium borohydride is added, followed by warming the solution to about 0° C. and stirring with ice-cooling for 30 minutes. To the mixture is added 0.3 g of acetic acid and the resulting mixture is concentrated under reduced pressure. To the residue are added ethyl acetate and water, and the ethyl acetate layer is separated. The aqueous layer is extracted with ethyl acetate and the combined ethyl acetate layer is washed with aqueous sodium chloride, dried over mangesium sulfate and concentrated under reduced pressure. The residue is crystallized from diethyl ether and the crystals are collected by filtration to give 0.5 g of (3S,4S)-3-benzyloxycarbonylamino-4-hydroxymethyl-2-azetidinone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.C(O)(=O)C.[CH:22](N)=[NH:23]>COCCO>[CH3:13][O:12][C:6]1[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=[C:2]2[C:7]=1[C:8](=[O:9])[N:23]=[CH:22][NH:1]2
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OC)c(OC)c1OC
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1cc2[nH]cnc(=O)c2c(OC)c1OC
Yield: 35.6 %

Procedure:
A solution of methyl 6-amino-2,3,4-tris(methyloxy)benzoate (2.87 g, 11.90 mmol) and formamidine acetate (3.72 g, 35.7 mmol) in 2-methoxyethanol (25 mL) was stirred at 125° C. for 2 hrs before being concentrated. The residue was suspended in water and the solid was collected by filtration, washed with water, and dried under vacuum (45° C.) to give 5,6,7-tris(methyloxy)-4(1H)-quinazolinone (1 g, 34%) as a light brown solid. MS (m/z) 237.1 (M+H+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl.CCOCC>[CH2:12]([CH:13]1[O:9][CH2:14]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CC2CO2)cc1
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A solution of m-chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mL of methylene chloride was added (at ambient temperature) dropwise to a solution of allyl benzene (10 g, 85 mmol) in 200 mL of methylene chloride. After the reaction mixture was stirred for 5 h with a mechanical stirrer, 5 additional grams of m-CPBA were added and the reaction mixture stirred for another 2 h. The reaction mixture was then diluted with 200 mL of ether, washed with 2×100 mL of aqueous sodium bisulfite solution, 100 mL of aqueous sodium bicarbonate solution and 100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by bulb-to-bulb distillation (60° C., 0.1 mm) to give 8.5 g (77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [Cl-].[C:2]([C:5]1([NH3+:8])[CH2:7][CH2:6]1)([OH:4])=[O:3].C(N(CC)CC)C.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>CO>[F:16][C:17]([F:24])([F:23])[C:18]([NH:8][C:5]1([C:2]([OH:4])=[O:3])[CH2:7][CH2:6]1)=[O:19]
Reactant: [NH3+]C1(C(=O)O)CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Carboxycyclopropanaminium chloride (0.980 g, 7.124 mmol) was suspended in methanol (14 mL) and triethylamine (1.514 g, 14.960 mmol) was subsequently added. To this suspension was then added ethyl trifluoroacetate (1.113 g, 7.836 mmol) and allowed to stir at 25° C. After 16 hours, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried with sodium sulfate, filtered and concentrated under reduced pressure to produce the title compound as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.76 (s, 1H), 9.94 (s, 1H), 1.38-1.44 (m, 2H), 1.08-1.14 (m, 2H).
Reaction SMILES: N(OS(=O)(=O)O)=[O:2].[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18](N)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.ClCCl>[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18]([OH:2])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=NOS(=O)(=O)O
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(N)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of 1.81 g (12.81 mmol) nitrosylsulfuric acid in 1.5 ml water at 0° C. under nitrogen, was added dropwise a suspension of 463 mg (1.423 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzamide in 2.9 ml dichloromethane. The reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was poured over ice and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude solid was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>100% in 15 minutes) to provide 431 mg (y: 64.9% yield) of the title compound as a white solid. MS (m/e): 325.1 (M−H)
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:16]([CH3:18])=[CH2:17])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3].[CH3:19]I.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:16]([CH3:18])=[CH2:17])=[CH:8][C@H:9]2[CH2:14][O:15][CH3:19])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2COC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a solution of (2S,5R)-6-(allyloxy)-2-(hydroxymethyl)-4-(prop-1-en-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 58, 0.289 g, 1.15 mmol) in DMF (10 mL) at 0° C. was added methyl iodide (0.435 mL, 6.93 mmol) followed by sodium hydride (60% in mineral oil) (0.051 g, 1.27 mmol). The reaction was stirred for 1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the desired product as a pale yellow oil (233 mg, 76%).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C:34]#[N:35].Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:35][CH2:34][C:33]#[N:32])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: N#CCN
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NCC#N
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.008 mol) of product of Example 103, 1.72 g (0.017 mol) of triethylamine and 0.79 g (0.008 mol) of aminoacetonitrile hydrochloride in 30 ml of DMF was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature and poured into 3.7% HCl. This solution was extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4) . The dry ether phase was concentrated in vacuo to 2.56 g of a brown semi-solid oil. The crude product was recrystallized in hexane/ethyl acetate to 0.9 g (28) of product as a beige solid; mp 87°-89° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:32].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[C:11]([Br:32])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)ccn2CCN1Cc1ccc(Cl)c(Cl)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 62.3 %

Procedure:
To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (3.8 g) obtained in Example 1, Step 3 in chloroform (90 ml)-methanol (60 ml) was added phenyltrimethylammonium tribromide (5.0 g) and the mixture was stirred at room temperature for 13 hr. An aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The combined extract was washed with brine and purified as it was by silica gel column chromatography (chloroform-methanol=19:1–10:1) to give 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (2.44 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Fc1ccc(C(OCCN2CCCC2)c2ccc(F)cc2)cc1
Yield: 47.7 %

Procedure:
1-[Bis(4-fluorophenyl)methoxy]-2-chloroethane (3) (0.92 g, 3.3 mmol) was added to acetonitrile (50 ml) containing potassium carbonate (1.1 g, 8.0 mmol). This was followed by the addition of pyrrolidine (0.51 g, 7.2 mmol). The resulting mixture was then heated to reflux for 72 hours under an atmosphere of nitrogen. At the end of this time, the solution was added to ether (75 ml), washed with water (50 ml) and brine (50 ml). This was then dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give a clear light yellow oil. The oil was chromatographed on silica gel and eluted with 3:1 ethyl acetate/methanol to afford the desired product (4) (500 mg, 48%) as a clear light yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C=O.[C:15](OCC)(=O)C.Cl>C(O)(C)C>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:9](=[O:11])(=[O:10])[NH:12][CH2:15]1
Reactant: CCOC(C)=O
Reactant: CNc1ccncc1S(N)(=O)=O
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: CN1CNS(=O)(=O)c2cnccc21

Procedure:
A mixture of 1 g of 4-methylaminopyridine-3- sulfonamide (Preparation 6) and 1 g of paraformaldehyde (excess) in 10 cm3 of isopropanol to which 4 cm3 of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 10 hours. After this lapse of time, the solvent is removed under partial vacuum (rotary evaporator) and the residue is redissolved in methanol. A possible insoluble material is filtered and the filtrate, to which 2 volumes of diethyl ether have been added, is left to precipitate the title compound in the form of crystals. The crystals are collected on a filter, washed with diethyl ether and dried. Yd. : 60-65% M.p. (hydrochloride): 291-294° C.