Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.ClCCl.[OH:15][CH2:16][C:17]1[O:22][C:21]([CH3:24])([CH3:23])[O:20][C:19](=[O:25])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH:16]([C:17]1[O:22][C:21]([CH3:24])([CH3:23])[O:20][C:19](=[O:25])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:15]
Reactant: CC1(C)OC(=O)C(c2ccccc2)=C(CO)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)OC(=O)C(c2ccccc2)=C(C=O)O1
Reaction time: 5 h
Yield: 62 %

Procedure:
Pyridinium chlorochromate (1.29 g) was suspended into dichloromethane (8 ml), then a dichloromethane suspension (3 ml) of 6-hydroxymethyl-2,2-dimethyl-5-phenyl-2H,4H-1,3-dioxin-4-one (Compound No. 236, 0.70 g) was added thereto at room temperature. After stirring for 5 hours, a large amount of ether was added and extracted by decantation. The organic layer was dried with magnesium sulfate, the solvent was removed by evaporation, and the crude product was purified by silica gel chromatography to afford the captioned compound (0.43 g, yield 67%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:12](=O)[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:12](=[S:33])[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)COCc2ccccc2)c1
Temperature: 120 °C
Yield: 137.2 %

Procedure:
To the solution of 3-(2-Benzyloxy-acetylamino)-4-chloro-benzoic acid methyl ester (1.70 g, 5.10 mmol) in 20 ml of toluene was added Lawesson's reagent (1.03 g, 2.50 mmol) and the reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.20 g, 67%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(OC(C)C)(C)C.[F:12][C:13]([F:40])([S:36](F)(=[O:38])=[O:37])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].Cl>O>[CH2:1]([NH:4][S:36]([C:13]([F:12])([F:40])[C:14]([F:34])([F:35])[C:15]([F:32])([F:33])[C:16]([F:30])([F:31])[C:17]([F:28])([F:29])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])(=[O:38])=[O:37])[CH:2]=[CH2:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCN
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O
Product: C=CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Allyl amine (45.0 milliliters, 3.0 molar equivalent) and isopropyl ether (200.0 milliliters) were charged into a 3-neck 500-milliliter round bottom flask equipped with a Claisen joint adapter, dropping funnel and overhead mechanical stirrer at room temperature under a nitrogen blanket. The Claisen joint adapter was attached to a Thermowatch® thermometer adapter and water cooled condenser (to the nitrogen inlet). The mixture was warmed to 25° C. with stirring. Perfluoro-1-octanesulfonyl fluoride (100.0 grams, 1.0 molar equivalent, Aldrich Chemical Co.) was added by the dropping funnel over 1.5 hours. The reaction mixture was maintained at about 25° C. by immersing the reaction flask in a room temperature water bath. After the addition was completed, the reaction mixture was heated for 2 hours at 30° C., followed by 2 hours at 40° C. Upon cooling to 30° C. using a water bath, 120 milliliters of a 9% aqueous hydrochloric acid solution was added over 15 minutes while maintaining the temperature at 25° C. After separation of the layers in a separatory funnel, the organic layer was washed with an aqueous 4.5% hydrochloric acid 4.0% ferrous sulfate solution. The organic phase was isolated and evaporated in vacuo, further dried under vacuum (0.1 millimeters Hg) in a water bath at 70° C. for 0.5 hours to give a red pasty solid. The crude reaction product was subjected to high vacuum distillation to give a slightly yellow solid (boiling point 98° C.) (0.1 millimeters Hg)(85.62 grams, 80% purified yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>C(#N)C>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:15])=[O:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ncccc1Br
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1Br

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]-3-bromopyridine (from the dihydrobromide, 3.0 g) and 1-nitro-2,2-bis-methylthioethylene (1.21 g) in acetonitrile (30 ml) was set aside at room temperature for 3 days. The product was chromatographed on a column of silica gel with elution by ethyl acetate, to give 1-nitro-2-methylthio-2-[2-((3-bromo-2-pyridyl)methylthio)ethylamino]ethylene (1.2 g), m.p. 79°-80° (from ethanol-ether).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:16]=1.O>CN(C)C=O>[CH:20]([C:17]1[N:16]=[C:15]([CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[O:19][N:18]=1)([CH3:22])[CH3:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)c1noc(CCl)n1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C

Procedure:
To a solution of potassium phthalimide (72 g, 0.39 mol) in dry N,N-dimethylformamide (300 mL) was added 5-(chloromethyl)-3-isopropyl-1,2,4-oxadiazole (50 g, 0.31 mol) gradually with stirring. The reaction mixture was maintained at ambient temperature for 2 h and then poured into cold water (1.2 L). The resulting yellow precipitate was collected by filtration, washed with water, and dried in the air to yield the title compound.
Reaction SMILES: [Si]([O:8][C@H:9]([C@@H:18]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C@H:9]([C@@H:18]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](CN2CCCNC2=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCNC2=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.035 g of tert-butyl {1(S)-[1(S)-(tert-butyldimethylsilanyloxy)-2-(2-oxotetrahydropyrimidin-1-yl)ethyl]-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate in 0.65 ml of tetrahydrofuran is admixed with 0.064 ml of 1M tetrabutylammonium fluoride (in tetrahydrofuran) and stirred at room temperature over 18 hours. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.36 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.44 (gradient I).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([CH:4]([CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[C:3]([OH:26])=[O:2])[C:13](=[O:25])[CH:14]=1
Reactant: COC(=O)C(CC(C)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid methyl ester (614 mg, 1.56 mmol) dissolved in tetrahydrofuran (10 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (131 mg, 3.13 mmol) in water (10 mL). The mixture was then stirred for 2 h at 25° C. After such time, the mixture was treated with a 1N aqueous hydrochloric acid solution until pH=2 and extracted with ethyl acetate (3×20 mL). The organics were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid (575 mg, 98%) as a yellow-orange solid.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[C:26][CH2:27][OH:28])[N:23]=2)[N:18]=[CH:17][C:16]=1[C:29](OCC)=[O:30]>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:29]([C:16]2[CH:17]=[N:18][C:19]3[C:24]([C:15]=2[OH:14])=[N:23][C:22]([C:25]#[C:26][CH2:27][OH:28])=[CH:21][CH:20]=3)=[O:30])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(C#CCO)nc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)nc2c1O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2 M in toluene, 42 μL) is added dropwise to a room temperature solution of 4-chlorobenzylamine (17 μL) in CH2Cl2 (1 mL) under nitrogen. The solution is stirred for 5 minutes before the addition in one portion of ethyl 4-hydroxy-6-(3-hydroxy-1-propynyl)[1,5]naphthyridine-3-carboxylate (Preparation 2, 19 mg). The reaction is stirred at room temperature for 3.5 h. The reaction mixture is partitioned with dil. aq. HCl (2 mL) and extracted with CH2Cl2 (2×2 mL). After drying over MgSO4, the extracts are concentrated under vacuum. The crude residue is flash chromatographed (silica, 10% methanol/CH2Cl2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH2:18][CH3:19])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:26])=[O:14])=[C:11]([CH2:18][CH3:19])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCc1c(C(=O)O)ccc(OCc2ccccc2)c1C
Agent: O=S(=O)(O)O
Product: CCc1c(C(=O)OC)ccc(OCc2ccccc2)c1C
Temperature: 67 °C

Procedure:
19.7 g of 4-benzyloxy-2-ethyl-3-methylbenzoic acid (D1) are dissolved in 200 ml of methanol. 5.0 ml of H2SO4 (95-98%, extra pure) are subsequently added. The reaction solution is heated under reflux at 67° C. for 18 h overnight and subsequently evaporated to ⅓ of the volume in vacuo, and 200 ml of water are added. The mixture is then extracted twice with 200 ml of ethyl acetate each time. The combined organic phases are subsequently washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo, giving 17.5 g of the title compound as a colourless oil; MS: 285.2 (MH+); TLC: Rf=0.72 (cyclohexane/methyl tert-butyl ether 1:1 parts by volume).
Reaction SMILES: B(Cl)(Cl)Cl.CSC.[N:8]1([C:12]2[S:13][C@H:14]3[CH2:20][C@H:19]([CH2:21][O:22]CC4C=CC=CC=4)[C@@H:18]([O:30]CC4C=CC=CC=4)[C@H:17]([O:38]CC4C=CC=CC=4)[C@H:15]3[N:16]=2)[CH2:11][CH2:10][CH2:9]1>>[N:8]1([C:12]2[S:13][C@H:14]3[CH2:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([OH:30])[C@H:17]([OH:38])[C@H:15]3[N:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc(COC[C@H]2C[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Solvent: CSC
Product: OC[C@H]1C[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Yield: 48.3 %

Procedure:
This compound was prepared by boron trichloride-methyl sulfide de-benzylation via a procedure as described above in Example 4, Step 3 from (3aR,4R,5R,6R,7aS)-2-(Azetidin-1-yl)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole (0.220 g, 0.417 mmol). Purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/CH2Cl2, 1:4), afforded the title compound as an off-white solid (0.052 g, 48%). 1H NMR (400 MHz, CD3OD) δ 4.37-4.33 (m, 1H), 4.08-3.98 (m, 4H), 3.80-3.75 (m, 2H), 3.62 (dd, J=6.3, 10.8 Hz, 1H), 3.40 (t, J=9.1, 1H), 3.32 (t, J=9.8 Hz, 1H), 2.35 (quint, J=7.6, 2H), 2.22-2.17 (m, 1H), 1.96-1.89 (m, 1H), 1.78-1.70 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 167.63, 78.24, 76.76, 74.30, 64.03, 55.10, 53.30, 40.73, 26.99, 17.58; MS, m/z=281 (M+23).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([OH:22])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61]>C(Cl)Cl>[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:20]([C:3]1[N:4]([CH2:17][CH2:18][CH3:19])[C:5](=[O:16])[C:6]2[C:11]([C:2]=1[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[CH:7]=2)=[O:22]
Reactant: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
A solution of 360 mg (1.1 mmol) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid in DCM (20 ml) was cooled to 0° C. and 870 mg (2.3 mmol) HATU and 0.8 ml (4.6 mmol) DIPEA were added. After stirring at 0° C. for 10 min, 0.2 ml (1.7 mmol) 3-fluoro-benzylamine was added and the RS was stirred at RT for 1 h. The mixture was then diluted with DCM (40 ml) and the organic layer was separated, washed with a sat. aq. NaHCO3-sol. (25 ml), a sat. aq. NH4Cl-sol. (20 ml), water (20 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by CC (acetone/hexan 1:9) to yield 120 mg (0.3 mmol, 25%) N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide (example 2). [M+H]+ 421.1.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C[O-].[Na+].[Cl-].[NH4+:24].[C:25]([OH:28])(=[O:27])[CH3:26]>CO>[C:25]([OH:28])(=[O:27])[CH3:26].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[NH:24])[NH2:15])[N:6]=1
Reactant: [NH4+]
Reactant: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nc(Cc2ccccc2F)n2ncccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
584 mg (2.315 mmol) of the compound prepared in Example 6A were added to 125 mg (2.315 mmol) of sodium methoxide in methanol (10 ml), and the mixture was stirred at 20° C. for 16 hours. 148 mg (2.778 mmol) of ammonium chloride and acetic acid (0.517 ml) were then added, and the mixture was heated at reflux for 8 h. The mixture was then concentrated to dryness, the residue was taken up in water and ethyl acetate and 1 N aqueous sodium hydroxide solution was added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated and then dried under high vacuum. This gave 543 mg of the target compound (71% of theory).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl.CCOCC>O1CCCC1.C([Li])CCC>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:38]([NH:37][C:28]2[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])=[O:39])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred room temperature solution of 3-dodecyl-5-(phenylmethyl)isoxazole (38.3 g, 0.117 mol) in tetrahydrofuran (600 mL) was cooled to -78° C. under nitrogen. To the resulting precipitate was added dropwise a 2.01M solution (58 mL, 0.12 mol) in n-butyl lithium in hexanes over 10 minutes. The mixture was stirred for 1.25 hours before a solution of 2,4,6-trimethoxyphenyl isocyanate (24.43 g, 0.1168 mol) in tetrahydrofuran (350 mL) was added dropwise over 30 minutes. The mixture was stirred for 45 minutes then quenched with a dropwise addition of 1M HCl (235 mL, 0.235 mol) followed by ether (500 mL). The mixture was allowed to warm to room temperature. The organic layer was washed with 0.2M HCl , water, saturated sodium bicarbonate, and saturated sodium chloride, dried (MgSO4), and rotoevaporated to a solid. The material was recrystallized twice from diisopropyl ether and chromatographed on silica gel (830 g, 230- 400 mesh) using petroleum ether-ethyl acetate (2:1, 20×900 mL) to give a white solid; yield 40.7 g (65%), mp 106°-107° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[N:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[N:7]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: N#Cc1cccc(COc2cncc(Cl)n2)c1
Reactant: C1CNCCN1
Solvent: CCO
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
A mixture of 3-(6-chloro-pyrazin-2-yloxymethyl)-benzonitrile I-3a (3.53 g, 14.4 mmol) and piperazine (12.4 g, 143.70 mmol) in ethanol (144 mL) was stirred under reflux for 48 h. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate (300 mL). The ethyl acetate solution was washed with H2O (4×125 mL), brine (125 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was chromatographed over Silica Gel (40 g) using 5% methanol/methylene chloride with 1% NH4OH as the eluant to give 3.03 g of the desired product (I-3b) as a white solid.
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:10]2[N:15]3[CH2:16][CH2:17][C@@H:12]([C@@H:13]([C:18](N)=[O:19])[CH2:14]3)[C@@H:11]2[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C1C=C(C=O)C(OC)=CC=1)(=O)=[O:43]>Cl>[ClH:1].[ClH:1].[C:35]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:10]2[N:15]3[CH2:16][CH2:17][C@@H:12]([C@@H:13]([C:18]([OH:43])=[O:19])[CH2:14]3)[C@@H:11]2[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(S(C)(=O)=O)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(N)=O)[C@H]1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(S(C)(=O)=O)cc1C=O
Agent: Cl
Product: COc1ccc(S(C)(=O)=O)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(=O)O)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.6 %

Procedure:
A solution of (3R,4S,5S,6S)-6-Diphenylmethyl-5-(-2-methoxy-5-methylsulfonyl-benzylamino)-1-azabicyclo[2.2.2]octane-3-carboxamidedihydrochloride (the compound of Example 1, 400 mg) in conc. HCl (10 ml) was warmed up to 90° C. and stirred for 15 hr. After cooling down to room temperature, the mixture was evaporated in vacuo. The residue was recrystallized from EtOAc-MeOH to give a titled compound (268.2 mg, 55.6%) as a white crystalline.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Br)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[S:6].[CH3:14][NH2:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[S:6])[NH:15][CH3:14]
Reactant: CN
Reactant: CC1(C)CN1P(=S)(Br)N1CC1(C)C
Solvent: C1CCOC1
Product: CNP(=S)(N1CC1(C)C)N1CC1(C)C
Reaction time: 8 h
Yield: 65 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)thiophosphinic bromide in about 170 milliliters of THF, prepared in accordance with Example 1, is saturated with an excess of gaseous methylamine, kept overnight at 4° C., filtered, concentrated on a rotary evaporator at room temperature, and vacuum distilled to provide about 65% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N methylthiophosphinic amide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Br:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:17][CH2:16][Br:15])=[CH:11][CH:12]=1
Reactant: BrCCBr
Reactant: COC(=O)CCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 16.8 %

Procedure:
4-(4-hydroxyphenyl)butanoic acid methyl ester (2) (2.6 g) from the previous step was dissolved in N,N′-dimethylformamide (30 mL), 1,2-dibromoethane (12.6 g) and potassium carbonate (3.7 g) were added, and stirred at 80° C. for two days. The reaction solution was poured into water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=8:1) to give the above-identified compound (676 mg, yield 17%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:20]([F:19])[CH:21]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Product: O=C(NCc1cc(F)cc(C(F)(F)F)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)benzyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.37 mmol of 3-fluoro-5-trifluoromethyl-benzylamine. LC/MS [6.51 min; 534 (M+1)]