Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].ClCCl>CCCCCC>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.60 g, 2.70 mmol), SOC2 (0.96 mL, 13.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.77 g, 3.50 mmol). After normal workup, the pure objective compound (0.98 g, 82%) was obtained as white solid by recrystallization (dichloromethane:n-hexane=1:3): m.p 122° C.; 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.2 Hz, 3H, CH3), 3.65-3.84 (m, 4H, CO2CH3 & CH), 7.55 (dd, J=8.8, 2.2 Hz, 1H, ArH), 7.84 (d, J=2.2 Hz, 1H, ArH), 8.44 (d, J=2.0 Hz, 1H, ArH), 9.51 (br s, 1H, NH).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccsc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Under an argon atmosphere, a suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (656 mg), 3-thiopheneboronic acid (511 mg), dichloro[bis(triphenylphosphine)]palladium (70 mg) and sodium carbonate (636 mg) in 1,2-dimethoxyethane (10 mL)-water (3 mL) was stirred at 100° C. for 2 hr. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a colorless oil (yield 549 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH:18]([CH:21]=O)[CH:19]=O>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:21]=[C:18]([Cl:17])[CH:19]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(Cl)C=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2nn3cc(Cl)cnc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2 g; 8.92 mmol; 1 eq.) and 2-chloromalonaldehyde (1.04 g; 9.81 mmol; 1.1 eq.) in AcOH was stirred at room temperature for 18 hours then diluted with water (30 mL). The precipitate was filtered off and purified by column chromatography (DCM/EA, from 95/5 to 80/20) to afford the title compound (1.24 g, 47%) as a white solid. 1H NMR (DMSO-d6) δ 9.57 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H), 4.63-4.57 (m, 4H), 1.47 (s, 9H). HPLC (max plot) 99.1%; Rt 3.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15]O)=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:15][C:4]1[C:3]([O:2][CH3:1])=[N:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=1
Reactant: COc1nc(-c2ccccc2)cnc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1nc(-c2ccccc2)cnc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-methoxy-5-phenyl-pyrazin-2-yl)-methanol (60 mg, 0.28 mmol) in DCM (5 mL) is added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 65 mg of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine as an oil.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:8]([NH2:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CCOC(C)=O.[OH-].[Na+].C1CCCCC1>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:6][C:7]=1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 51c (45.3 mg, 0.197 mmol) in EtOAc (1 mL) and aqueous NaOH (1 M, 0.49 mL) was added 2,2,2-trichloroethyl chloroformate (0.0326 mL, 0.237 mmol) and the resulting mixture stirred at RT for 45 min. The layers were separated and the aqueous extracted with EtOAc (2 mL). The combined organics were washed with brine (2 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange-red gum. FCC, using 0-50% EtOAc in cyclohexane, gave the title compound as a pale orange film (44.1 mg, 55%). LCMS (Method 3): Rt 2.87 min, m/z 404, 406 [MH+].
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1I)=[O:4].[OH-].[K+].O.[CH3:29][S:30]SC>N1C=CC=CC=1.[Cu]>[F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:30][CH3:29])=[O:4]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(I)n2c1
Reactant: CSSC
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CSc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Temperature: 104 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
The 2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo[1,2-a]pyridine (1.00 g, 2.17 mmol) was dissolved in 20 ml of pyridine (predried over KOH and then molecular sieve 3A , 0.04% H2O) under argon atmosphere. Copper bronze (207 mg, 3.25 mmol) was added. To the golden suspension in brown solution was added methyldisulfide (160 μl, 2.17 mmol) via syringe. The reaction mixture was heated for 1 hour at 104° C. then 68 hours at 100° C. The evolution of the reaction was followed by NMR (in each case, a sample was taken, hydrolized and washed with ammonia/NH4Cl (1:9) before checking by NMR). When the reaction was complete, the reaction mixture was diluted in 3 L of EtOAc and stirred for 15 minutes. Two liters of NH4OH/NH4Cl 1:9 were added and the mixture was strongly stirred for 30 minutes in a 10 L funnel. The layers were separated and 2 L of NH4OH/NH4Cl (1:9) were added to the organic layer. The mixture was again stirred for 30 minutes and then left without stirring for 5 to 10 minutes. The layers were separated and the organic layer was washed with brine. The organic layers were removed in vacuo and the resulting brown solid was subjected to a vary rapid column chromatography (MeOH/CH2Cl2, 2:98) to give 670 mg (81%) of a yellow solid. NMR
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([CH:20]=[CH2:21])[CH:10]=1)(C)(C)C.C(N(CC)CC)C.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:6](=[O:22])[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[C:11]([CH:20]=[CH2:21])[CH:10]=2)=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)NCc2ccc(Cl)cc2)ccc1NS(C)(=O)=O
Yield: 14.9 %

Procedure:
As described in scheme 12, (4-methanesulfonylamino-3-vinylbenzyl)carbamic acid t-butylester (50 mg, 0.153 mmol) and triethylamine (0.1 ml) and 4-chlorobenzylamine (26 mg) were stirred for one night in the presence of acetonitrile solvent. The solvent was removed from the reaction mixture and purified by column chromatography to yield the purposed compound (9 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][C:36]3[CH:35]=[C:34]([F:33])[CH:41]=[C:40]([F:42])[CH:39]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (50 mg, 0.11 mmol) in 1,2-dichloroethane (1.0 mL) was added 3,5-difluorobenzaldehyde (0.014 mL, 0.12 mmol) and sodiumtriacetoxyborohydride (31 mg, 0.14 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 2-{5-[1-(3,5-difluoro-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C32H34F5NO2 (M+H) 560.61, Found 560.3 (methyl ester) and Calcd for C33H36F5NO2 (M+H) 574.64, Found 574.2 (ethyl ester).
Reaction SMILES: [CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7](OC)[O:8]C)/[CH3:2].CC(C)=O>O>[CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7]=[O:8])/[CH3:2]
Reactant: C=CC(Br)=N/C(=C\C)C(=O)CCC(OC)OC
Solvent: O
Solvent: CC(C)=O
Product: C=CC(Br)=N/C(=C\C)C(=O)CCC=O
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]acrylimidoyl bromide (7.0 g, 28.9 mmol) in a solution of acetone (30 mL) and water (1.5 mL) at room temperature, is added Amberlyse-15 (20 g). After mechanical shacking for 3 hr at room temperature, the reaction mixture is filtered. The resin beads were washed with acetone (contain 10% of Et3N). The combined organic layers were concentrated and purified by chromatography (Hexane/EtOAc:70/30) to yield N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (5.18 g, 88.1%) as light yellow liquid. M/Z=421, 243.9 [M+1]
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:53])([F:52])[C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:13][N:14]([CH3:44])[C:15]([N:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH3:43])=[O:16]>C(Cl)Cl>[F:53][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:47]=1)[CH2:13][N:14]([CH3:44])[C:15]([N:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH2:19][C@@H:18]1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH3:43])=[O:16]
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCN(C(=O)OC(C)(C)C)CC2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCNCC2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
TFA (1 mL) was added to a solution of intermediate 15b (155 mg) in anhydrous DCM (5 mL). The solution was stirred at r.t. for 3 hours, then it was concentrated in vacuo. The residue was diluted in a saturated potassium carbonate solution (10 mL) and extracted with DCM (2×20 mL) and AcOEt (20 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (104 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(C)cccc4Cl)cc3)c2cc1OC
Yield: 74 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2-chloro-6-methylphenyl isocyanate (0.1 ml) was added, and the admixture was refluxed with heat for 17 minutes. The separated crystals were filtered and then washed with toluene to obtain 61 mg of the title compound (yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]N(C)CCN(C)C.C([Li])(C)(C)C.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran (40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C. The mixture was stirred at −78° C. for 40 minutes. To the resulting mixture was added iodomethane (5.07 mL) dropwise and the mixture was stirred at −78° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (40 mL×3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flask chromotography (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[CH3:7].[F:9][C:10]1[CH:15]=[C:14](F)[N:13]=[CH:12][N:11]=1>>[F:9][C:10]1[CH:15]=[C:14]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[N:3]=[C:4]2[CH3:8])[N:13]=[CH:12][N:11]=1
Reactant: Fc1cc(F)ncn1
Reactant: Cc1nc(I)c(C)[nH]1
Product: Cc1nc(I)c(C)n1-c1cc(F)ncn1

Procedure:
The title compound, white cristalline solid, MS: m/e=340.2, 342.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-iodo-2,5-dimethyl-1H-imidazole and 4,6-difluoropyrimidine.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CO.O>[C:30]([S:32][C@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:33])[CH3:31]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)S[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of 0.7 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 10 ml of methanol is added a solution of 0.25 g of potassium thioacetate in 2 ml of water. The mixture is stirred for 30 minutes at 55°-60° C. Methanol is distilled off under reduced pressure. To the residue is added ethyl acetate, followed by washing with water, drying and concentration under reduced pressure. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.195 g of (3R,4R)-4-acetylthio-3-tritylamino-2-oxoazetidine
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:13]2[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]4[C:20]=3[C:15](=[CH:16][CH:17]=[CH:18]4)[N:14]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CC(C)=O>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[N:3]1([CH2:8]/[CH:9]=[CH:10]\[CH2:11][NH:12][C:13]2[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]4[C:20]=3[C:15](=[CH:16][CH:17]=[CH:18]4)[N:14]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: C(=CCn1ccnc1)CNC1=Nc2cccc3cccc1c23
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Product: C(=C\Cn1ccnc1)\CNC1=Nc2cccc3cccc1c23
Temperature: 25 °C

Procedure:
The free base of the product of Example 10 was dissolved in acetone and added to a boiling solution of two equivalents of fumaric acid in acid. After cooling to room temperature, the bright yellow precipitate of the desired product was collected and dried. It melted at 111° C.-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH:9]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(c1ccc(F)cc1)C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2ccccc12
Yield: 31.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (100 mg, 0.21 mmol) in ethanol (2 ml) was added 8N aqueous sodium hydroxide solution (130 ml) and the mixture was heated under reflux for 4 hrs. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from diisopropyl ether-hexane gave (1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (29.6 mg, 31%).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44]>C(Cl)Cl.CO>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCN(CC(=O)N(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine trihydrochloride (10 mg, 0.03 mmol) in methylene chloride (1.0 mL), potassium carbonate (18 mg, 0.13 mmol) was added, followed by 2-chloro-N,N-dimethylacetamide (2.7 μL, 0.026 mmol) and the mixture was stirred for 5 min. The mixture was then heated at 60° C. overnight. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound, (3.7 mg, 30%). LCMS calc. for C27H32N7O3 (M+H)+: m/z=502.2. found: 502.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[C:5]([N+:25]([O-:27])=[O:26])[CH:4]=1.Cl.[NH2:29]O>N1C=CC=CC=1>[CH2:20]([C:19]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:25]([O-:27])=[O:26])=[C:15]([CH2:16][CH3:17])[O:18][N:29]=1)[CH3:21]
Reactant: NO
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1[N+](=O)[O-])C(=O)CC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1CCCCCCOc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
3,5-Diethyl-4-[6-(4-methoxy-2-nitrophenoxy)hexyl]isoxazole [I; Ar is 2-O2N-4-CH3OC6H3, Y is O(CH2)6, R is C2H5 ] was prepared from 10.0 g. of 4-[6-(4-methoxy-2-nitrophenoxy)hexyl]-3,5-heptanedione and 2.0 g. of hydroxylamine hydrochloride in 40 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a yellow oil, b.p. 200°-205° C. (0.02 mm.); yield 7.5 g.; MIC=3 μg/ml (herpes 2).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1cccc(F)c1
Yield: 60 %

Procedure:
Reduction 3-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (60% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.50 (3H, s, OCH3), 4.04 (2H, s, NCH2), 5.75 (1H, broad s, NH), 6.95-7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 130-131° C. (dec.). Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.10; H, 5.73; N, 7.38.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>CC(C)=O>[O:21]=[C:17]([CH3:16])[CH2:18][C:19]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:2]1[CH3:1])=[O:20]
Reactant: C=C1CC(=O)O1
Reactant: Cc1nc2cnccc2n1CCCCO
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCCCCn1c(C)nc2cnccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a stirred solution of 2-methyl-1-(4-hydroxybutyl)imidazo[4,5-c]pyridine (0.5 g) in acetone (10 ml) at room temperature was added, dropwise, freshly distilled diketene (0.2 g). The solution was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was chromatographed on silica gel eluting with a methylene chloride-ethyl acetate mixture and the fractions containing the product were evaporated under vacuum to leave the title compound, (0.51 g).