Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[N:4][CH:3]=1.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1)([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.[Cl-].[Na+].O>[C:11]([C:10]1[C:5]2[N:6]([C:2]([C:21]3[CH:20]=[C:19]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[CH:18]=[C:17]([O:16][CH:13]([CH3:15])[CH3:14])[CH:22]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1cccn2c(I)cnc12
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(C#N)cccn23)c1
Temperature: 110 °C
Yield: 32.1 %

Procedure:
To a mixture of 3-iodoimidazo[1,2-a]pyridine-8-carbonitrile (100 mg, 373 μmol), 1-(3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (90 mg, 224 μmol), PdCl2(dppf)-CH2Cl2Adduct (30.5 mg, 37.3 μmol) in Dioxane (3 ml), was added 2M Na2CO3 (0.559 ml, 1119 μmol). The vial was degassed for 5 minutes then capped and heated to 110° C. for 30 minutes in microwave. After cooling to ambient temperature reaction was partioned between EtOAc and brine, separated and organics washed with brinex2. Combined organics were dried directly on to silica and purified via flash chromatography (0-100% Hex/EtOAc; 12 g column). Recovered the title compound (30 mg, 71.9 μmol, 32.1% yield) as a brown solid. MS (ES+) C20H18F3N5O2 requires: 417. Found: 418 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH3:22][O-:23].[Na+].CO>O1CCCC1>[CH3:22][O:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Yield: 50 %

Procedure:
4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.00 g, 3.39 mmol) and 28% sodium methoxide in methanol (9.69 g, 50.2 mmol) were added to a mixture of methanol (30 mL) and tetrahydrofuran (30 mL), and the solution was heated under reflux for 2.5 hours. After the solution was cooled to room temperature, the solvents were evaporated under reduced pressure. The residue was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (0.73 g, 50% yield).
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.O>[Pd].C(O)C.C(O)(=O)C>[CH2:15]([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC(O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCc1cccc(O)c1
Yield: 387.5 %

Procedure:
A mixture of 3.0 grams (0.008 mole) of 1-(3-(phenylmethoxy)phenyl]undecanol and 0.5 gram (catalyst) of 10% palladium on charcoal and 50 mL of acetic acid in 50 mL of ethanol was hydrogenated using a Parr hydrogenator. Upon the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered and concentrated under reduced pressure to a residual oil. NMR analysis of the oil indicated that the phenol portion of the molecule was completely unprotected, and the benzylic hydroxyl was about 70% removed. The oil was then mixed with. 16.5 grams (0.047 mole) of 1-[3-(phenylmethoxy)phenyl]undecanol, 2.0 grams of 10% palladium on charcoal, 10 mL of water, and 50 mL of ethanol in 130 mL of acetic acid. The mixture was then hydrogenated as previously described, using the Parr hydrogenator. The reaction mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 9:1 petroleum ether and diethyl ether and 8:2 petroleum ether and diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.7 grams of 3-undecylphenol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([O:7][CH:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H][H]>[Pd].CO>[CH:1]1([O:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(OC2C=CCCC2)CC1
Agent: [Pd]
Solvent: CO
Product: C1CCC(OC2CCNCC2)CC1
Yield: 109.6 %

Procedure:
A solution of 4-(2-cyclohexenyloxy)-N-(benzyloxycarbonyl)piperidine (3.80 g), and 10% palladium on carbon (50% wet) (1.0 g) in methanol (40 ml) was hydrogenated under an atmospheric pressure of hydrogen at ambient temperature for 6 hours. The catalyst was filtered off, and the filtrate was evaporated in vacua and dried in vacuo to give 4-(cyclohexyloxy)piperidine (2.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[S:22][CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=4)=[CH:18][C:17]=3[CH:30]=1)[N:7]=[C:6]2[C:31]([OH:33])=[O:32].S(=O)(=O)(O)O.[CH3:39]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[S:22][CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=4)=[CH:18][C:17]=3[CH:30]=1)[N:7]=[C:6]2[C:31]([O:33][CH3:39])=[O:32]
Reactant: COc1ccc2c(c1)c(C(=O)O)nn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylic acid (3.0 g) and concentrated sulfuric acid (0.3 ml) in methanol (30 ml) was stirred under reflux for 6 hours. After being cooled to room temperature and stored for overnight, the precipitate was collected by filtration and washed with isopropyletyl ether to give methyl 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylate.
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1.N1C=CC=CC=1.[O:20]=[O+][O-].NC(N)=S>C(Cl)Cl.CO>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][C:2](=[O:20])[CH3:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: C=C(C)Cc1ccc2c(c1)CCO2
Reactant: O=[O+][O-]
Agent: NC(N)=S
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 5-(2-methylallyl)-2,3-dihydrobenzofuran (58 grams, 0.333 mole) and pyridine (27 ml) in methylene chloride (450 ml) and methanol (150 ml) was cooled in a dry ice/acetone bath and a stream of ozone passed through for 1.0 hour. Thiourea (18 grams, 0.24 mole) was added and the mixture was warmed to room temperature. The resultant precipitate was filtered and the mother liquor evaporated to give an oil which was distilled under reduced pressure to give 1-(2,3-dihydrobenzofuran-5-yl)propan-2-one (32 grams, 54%), bp. 110° C. @ 120 mT.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:51]1[CH2:56][CH2:55][O:54][CH2:53][CH:52]1[C:57]1[C:65]2[S:64][C:63]([NH2:66])=[N:62][C:61]=2[C:60]([O:67][CH3:68])=[CH:59][CH:58]=1>C1COCC1.C(Cl)(Cl)Cl>[O:51]1[CH2:56][CH2:55][O:54][CH2:53][CH:52]1[C:57]1[C:65]2[S:64][C:63]([NH:66][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][N:17]=[C:9]([CH2:8][O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)=[N:62][C:61]=2[C:60]([O:67][CH3:68])=[CH:59][CH:58]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(COC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COC4CCOCC4)c3)nc12

Procedure:
From 2-(tetrahydro-pyran-4-yloxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+84.9° (c=1.05, CHCl3), ES-MS m/e (%): 486 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C[N:22]([CH2:27][CH2:28][C:29]1[CH:34]=CC=[CH:31][N:30]=1)[CH:23]1[CH2:26][NH:25][CH2:24]1.O=[C:36]1CN(C(OC(C)(C)C)=O)C1>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:25]2[CH2:24][CH:23]([N:22]3[CH2:27][CH2:28][CH:29]([N:30]([CH3:31])[CH3:36])[CH2:34]3)[CH2:26]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CN(CCc1ccccn1)C1CNC1
Product: CN(C)C1CCN(C2CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)C1

Procedure:
The title compound was prepared by reacting 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid with N-methyl-N-(2-(pyridin-2-yl)ethyl)azetidin-3-amine. The azetidine intermediate was prepared using procedures similar to those described in Abdel-Magid, et. al., Tetrahedron Letters 1990, 31(39), 5595 starting with tert-butyl 3-oxoazetidine-1-carboxylate, which itself was prepared as described in Example 3. The title compound: 1H NMR (400 MHz, d6-DMSO): 8.56 (s, 1H), 7.58 (m, 1H), 7.38 (d, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 6.67 (m, 1H), 4.16 (m, 1H), 3.97 (m, 2H), 3.77 (m, 1H), 3.26 (br s, 4H), 2.63 (m, 1H), 2.42 (br s, 6H), 1.99 (br s, 1H), 1.74 (br s, 1H). MS (EI) for C22H24F3IN4O: 545 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(O)(C)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Agent: CS(=O)(=O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 33 h

Procedure:
To a 3 L 3 Neck RB equipped with overhead stirrer was charged 2-Fluoro-6-methyl-benzonitrile (191.8 g., 1419 mmol) and MsOH (563 mL, 8516 mmol). NBS (265 g., 1490 mmol) was added portionwise to this stirred solution over 30 minutes, and the mixture was stirred at 50° C. for 33 hours. By this time, HPLC shows the reaction to be mostly complete, so the reaction was poured into 1 L of ice (exotherm noted), diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organics washed 2× with 1N NaOH and with water. The aqueous cuts were observed to be significantly enriched with impurities. The organics were dried over MgSO4, concentrated, then stored in a −10° C. freezer overnight. Precipitate formed over this time, and was filtered and washed with 5% EtOAc/Hexanes. A second crop of precipitate was combined with the first crop to provide 3-bromo-6-fluoro-2-methyl-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.C([CH:20]([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])C.[O:27]1CC[CH2:29][CH2:28]1>>[CH2:28]([O:27][C:24]([C:20]1[C:21](=[O:22])[NH:1][C:2]2[N:3]=[C:4]([N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:25])[CH3:29]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: CN(c1ccccc1)c1ncc(C#N)c(N)n1
Product: CCOC(=O)c1c(N)c2cnc(N(C)c3ccccc3)nc2[nH]c1=O
Reaction time: 0.08 h

Procedure:
To 10 g. (0.044 moles) of 4-amino-2-(methylphenylamino)-5-pyrimidine-carbonitrile in 200 ml. of tetrahydrofuran was added 6.7 g. (0.044 moles) of ethyl malonyl chloride and then this mixture was heated at reflux for 2 hours. The reaction was then filtered and the filtercake rinsed with tetrahydrofuran. The filtrate was evaporated to dryness on a rotary evaporator. The viscous liquid residue was treated with 50 ml. of 20% NaOH and heated to boiling for 5 minutes. The resulting solid was removed by filtration. This solid was slurried in water, acidified with acetic acid and filtered. The crude product was recrystallized from 95% ethanol to give 1.05 g. of solid with m.p. 297° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:33])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(C2OC(Br)=CC=2)=O)[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:33])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluorobenzoic acid (330 mg, 1.5 mmol) was coupled to aniline (99)(290 mg, 1.5 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(OC)c(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 4-methoxy-3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].Cl.[F:9][C:10]([F:14])([F:13])[CH2:11]N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:5]([O:4][C:2](=[N:7][CH2:11][C:10]([F:14])([F:13])[F:9])[CH3:3])[CH3:6]
Reactant: NCC(F)(F)F
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(C)=NCC(F)(F)F
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Ethyl acetimidate hydrochloride (1.23 g, 9.95 mmol) and 2,2,2-trifluoroethylamine hydrochloride (1.35 g, 9.95 mmol) were dissolved in CH2Cl2 (32 mL)/H2O (3.2 mL). K2CO3 (0.69 g, 4.98 mmol) was added and stirred for 30 minutes. The two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layer was dried with Na2SO4 and concentrated to give 1.48 g of N-(2,2,2-Trifluoro-ethyl)-acetimidic acid ethyl ester as a light yellow liquid in 87% yield.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][NH:2]2.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].CCOCC>C(COC)OC>[CH2:12]([N:2]1[CH2:3][CH2:4][CH:5]2[CH2:9][CH:1]1[CH2:8][CH2:7][CH2:6]2)[CH:11]=[CH2:10]
Reactant: C1CC2CCNC(C1)C2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: C=CCN1CCC2CCCC1C2
Yield: 50.7 %

Procedure:
To a solution (6.5 ml) of 2-azabicyclo[3.3.1]nonane (100 mg, 0.62 mmol) in dimethoxyethane were added allylbromide (105 mg, 0.87 mmol) and potassium carbonate (94 mg, 0.68 mmol) and the mixture was heated at reflux temperature for 3.5 hours. Ether (10 ml) was added to the reaction mixture, followed by filtration and removal of the solvent, and the residue was purified with silica gel column chromatography (chloroform-methanol-triethylamine=100:9:1), to obtain 2-allyl-2-azabicyclo[3.3.1]nonane (52 mg, 51%) as a colorless oily substance.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([CH3:1])[C@@H:3]1[C:8]([OH:10])=[O:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H]1CCCN[C@H]1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(+/−)-Cis-3-methylpiperidine-2-carboxylic acid (10.4 g, 72.9 mmol) in 1,4-dioxane (200 mL) and 1 N NaOH (218 mL, 219 mmol) was treated with CBzCl (15.4 mL, 109 mmol) and stirred for 18 h. The mixture concentrated and the resulting solid was suspended in EtOAc (200 mL) and the mixture was filtered. The solids were washed with EtOAc (3 50 mL) and the solution was dried over MgSO4. The solution was concentrated to afford (+/−)-cis-1-(benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid, which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[Cl:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:13]
Reactant: O=C=NCCCCl
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1C(=O)NCCCCl
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of 17.1 g (201 mmol) of 2-oxopyrrolidine and 20 g (167 mmol) of chloropropyl isocyanate was heated with stirring at 95°-105° C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting product obtained from the eluate with toluene - ethyl acetate (20/-10/1 v/v) was washed with ether - n-hexane and then collected by filtration, whereby 27.87 g of the objective compound 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) melting at 57.0°-58.0° C. was obtained as crystals. Yield:81.0%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:27])([F:26])[S:24]Cl>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[C:11]([S:24][C:23]([F:27])([F:26])[F:22])[NH:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)SCl
Reactant: COc1ccc(-c2cc[nH]c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
Following the procedure of Example 1, reaction of 2,3-bis(4-methoxyphenyl)pyrrole with trifluoromethanesulfenyl chloride gave 4,5-bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole as a white solid, m.p. 114°-115°.
Reaction SMILES: [C:1]([C:3](=[N:7][O:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].O1CCCC1.[H-].[Na+].[CH3:17][O:18][CH2:19][N:20]=[C:21]=[O:22]>C(O)(=O)C>[C:1]([C:3](=[N:7][O:8][CH3:9])[C:4]([NH:6][C:21](=[O:22])[NH:20][CH2:19][O:18][CH3:17])=[O:5])#[N:2]
Reactant: CON=C(C#N)C(N)=O
Reactant: COCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCNC(=O)NC(=O)C(C#N)=NOC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2.70 g. of 2-cyano-2-methoxyiminoacetamide in 10 ml. of tetrahydrofuran was added 1.20 g. of a 55% suspension of sodium hydride in mineral oil in portions with stirring. After stirring for 15 minutes, 2.40 g. of methoxymethylisocyanate was added dropwise. The mixture was stirred at 50°C. for 3 minutes to ensure completion of the reaction. The mixture was then cooled in an ice bath, and a solution of 1.9 ml. of acetic acid in 120 ml. of ice water was added rapidly with stirring. After stirring for another 25 minutes, 2-cyano-2-methoxyimino-N-methoxymethylcarbamoylacetamide was collected on a filter, washed with water and ether, and dried. The product weighed 2.7 g. and melted at 163.5°-165°C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17]C)=[O:15])[CH2:7][CH2:8][CH3:9])=[C:4]([CH:21]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>COC(=O)OC.O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:21][C:4]=2[CH:3]=1
Reactant: CCCN(CCCCC(=O)OCC)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: O
Solvent: CO
Product: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)ccc21
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a solution of ethyl 5-(4-bromo-2-formyl-N-propylanilino)pentanoate (5.0 g) in dimethylcarbonate (100 ml) was added a methanol solution of 28% sodium methoxide (3.5 g), and the mixture was heated at 50° C. for 2 hours under a nitrogen atmosphere. After cooling to 0° C. and neutralization with 1N hydrochloric acid, to the solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain yellow oil of methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (3.5 g).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.O>CS(C)=O>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: C=C(c1cc(F)ccc1O)n1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(c1cc(F)ccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 55 °C
Reaction time: 0.83 h
Yield: 68 %

Procedure:
85% Potassium hydroxide powder (36.0 g, 0.545 mole) was suspended in dimethyl sulfoxide (500 g) and stirred at 55° C. for 50 minutes. After cooling to 25° C., 1-[1-(2-hydroxy-5-fluorophenyl)vinyl]-1H-imidazole (90.0 g, 0.441 mole) was added and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichlorobenzyl chloride (94.5 g, 0.483 mole) was added dropwise over 1 hour and the mixture was stirred for 2 hours. Water (680 ml) was added dropwise over 25 minutes to the reaction mixture with stirring and then stirring was continued for additional 1 hour. The precipitated crystals were filtered off and washed with water (135 ml×5) and n-hexane (135 ml×3). The resulting crude crystals were recrystallized from n-hexane/ethyl acetate to obtain the title compound (109 g, 68.1%), m.p. 118°-120° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:15]([Cl:14])[C:20]=2[N+:21]([O-:23])=[O:22])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1

Procedure:
A solution of 1-[1,1-dimethylethoxycarbonyl]piperazine (1.88 g) in dichloromethane (30 ml) is added drop by drop over 1.5 hr to a solution of 4,6-dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.32 g) in dichloromethane (170 ml) at 78°. After stirring an additional hr at -78°, the reaction is diluted with aqueous sodium bicarbonate (10%). The phases are separated, the organic phase is concentrated to a liquid which solidified on standing at 20°-25°. The solid is dissolved in chloroform and flash chromatographed on silica gel eluting with methanol/chloroform (1/99), pooling and concentrating the appropriate fractions gives the title compound, Anal. Calc for C13H18N5ClO4 ; MW=343.77: C,45.42; H,5.28; N,20.37; Cl,10.31. Found: C,45.52; H,5.40; N,20.34; Cl,10.36.