Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]ccc3c2)cc(OC)c1OC
Yield: 83.6 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.54 g, 7.83 mmol), 3,4,5-trimethoxyphenylboronic acid (1.83 g, 8.61 mmol) and dichlorobis(triphenylphosphine)palladium (II) (275 mg, 0.39 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and reacted in a microwave reactor for 5 min at 150° C. EtOAc was added and the mixture was washed with water, brine, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 1.86 g (84%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 9.9 (bs, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.11 (d. J=2.1 Hz, 1H), 7.41 (t, J=2.1 Hz, 1H), 6.82 (s, 2H), 6.58 (t, J=1.5 Hz, 1H), 3.96 (s, 6H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)([O-])OC)=[N-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C@H:22]2[CH2:25][C@H:24]([CH:26]=O)[CH2:23]2)=[CH:19][CH:18]=1.CCCCCC.C(OCC)(=O)C>C1COCC1>[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C@H:22]2[CH2:25][C@H:24]([C:26]#[CH:1])[CH2:23]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(O[C@H]2C[C@H](C=O)C2)cc1
Agent: COP(=O)([O-])C=[N+]=[N-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#C[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A slurry of potassium tert-butoxide (7.85 g, 70 mmol) in THF (50 ml) was cooled to -78° C. under argon atmosphere. To this was added a solution of methyl (diazomethyl)phosphonate (J. Org. Chem. 1979, 44, 4997) (12.5 g, 70 mmol) in THF (100 ml), followed after 0.5 h by a solution of trans-3-(4-methoxyphenoxy)cyclobutanecarbaldehyde (12.1 g, 58.7 mmol) in THF (100 ml) at the same temperature. The resulting solution was stirred at -78° C. for 3 h and then maintained at room temperature for another 8 h. The reaction was quenched with water (300 ml) and the aqueous mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo to give yellow solids. Silica-gel column chromatography of the solids {SiO2, 800 g; hexane/ethyl acetate (9/1)} of the solids afforded 6.49 g (55%) of {trans-3-(4-methoxyphenoxy)cyclobutyl }ethyne as white solids: 1H NMR δ6.84-6.70 (m, 4H), 4.92-4.82 (m, 1H), 3.76 (s, 3H), 3.20-3.03 (m, 1H), 2.64-2.40 (m, 4H), 2.19 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1>>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][O:1][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
Tert-Butyl (2-hydroxyethyl)carbamate (8.88 g, 55.08 mmol) was added to a solution of NaH (55%, 55.08 mmol, washed twice with petroleum ether) in DMF (150 ml) at −10° C. and stirred for 10 mins. 2-Chloro-5-(trifluoromethyl)pyridine (10.0 g, 55.08 mmol) was added and the reaction mixture was stirred at rt for 3 days, heated to 100° C. and cooled to rt. The reaction mixture was evaporated, the residue was washed with isopropylether, and the solution was decanted from insoluble salts and concentrated. The residue was dissolved in EtOAc, washed twice with water, dried over MgSO4 and concentrated. Recrystallisation from isobutylethyl ether gave the title compound (6.2 g, 37%). 1H-NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 3.56 (br.m, 2H), 4.45 (t, 2H), 6.84 (d, 1H), 7.79 (dd, 1H), 8.44 (s, 1H.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[O:11][CH3:12].C([Li])CCC.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCOCC.CCCCCC>[CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([C:30]2([OH:33])[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COc1cc(Br)ccc1C(OC)OC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C(OC)OC
Temperature: -50 °C
Reaction time: 0.83 h

Procedure:
15.0 g of 4-bromo-2-methoxybenzaldehyde dimethyl acetal was dissolved in 150 ml of ether and the obtained solution was cooled to −50° C. Then 25.3 ml of a 1.6 M solution of n-butyllithium in hexane was dropped thereinto. 1 hour thereafter, 30 ml of a solution of 11.7 ml of 1-benzyl-4-piperidone in diethyl ether was dropped thereinto in such a manner that the bulk temperature did not exceed −35° C. After stirring at room temperature for 50 minutes, water was added thereto followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 23.82 g of a pale yellow oily substance was obtained. 13.82 g of this oily substance was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 6.31 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:32])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCc1ccccc1
Yield: 44.4 %

Procedure:
4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.023 g, 0.09 mmol) was treated with 4-chlorophenyl isocyanate (0.016 g, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 61 (0.019 g, 0.04 mmol, 42%) as a white solid. LCMS m/z (%)=511 (M+H79Br35Cl, 82), 513 (M+H81Br35Cl, 100), 515 (M+H81Br37Cl, 33). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.16 (s, 1H), 7.66 (dd, J=2.4, 8.9 Hz, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.28-7.35 (m, 5H), 7.28 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.9 Hz, 1H), 5.13 (AB quartet, J=12.0, 24.3 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:14][O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (120 g) in N,N-dimethylformamide (500 mL) was added sodium hydride (oily, 60%) (22 g) under ice-cooling, and the mixture was stirred for 30 min. To the reaction solution was added chloromethyl methyl ether (64 mL) and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic column chromatography (ethyl acetate) to give the title compound (98 g, yield 64%) as a yellow oil.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:5]=[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=[C:7]2[N:8]=1.S(OC)(O[CH3:18])(=O)=O>CO>[CH3:18][S:3][C:4]1[N:8]=[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[N:5]=1
Reactant: Sc1nc2cccccc-2n1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccccc-2n1
Temperature: 45 °C

Procedure:
First, 38 g of potassium hydroxide was dissolved in 800 ml of methanol, 100 g of 2-mercaptocycloheptimidazole was added thereto, and the mixture was stirred with heating to the inner temperature of about 45° C. Then, 131.2 g of dimethyl sulfate was added dropwise thereto and stirred with heating to the inner temperature of about 45° C. for one hour. After the solvent was distilled away to some extent under reduced pressure, 1 l of water was added and extracted with chloroform (0.5 l×2). After being dried over anhydrous sodium sulfate, the chloroform layer was evaporated under reduced pressure to 200 ml, and 1 l of hexane was added thereto to deposit crystals, which were the filtered and dried.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:12]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC.CSC>C(Cl)(Cl)Cl>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[C:15]([Br:17])[CH:14]=1
Reactant: O=C(Nc1cc(Br)cc(-c2nc3ccccc3o2)c1)OCc1ccccc1
Agent: FB(F)F
Solvent: CSC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To a solution of (3-benzoxazol-2-yl-5-bromo-phenyl)-carbamic acid benzyl ester (0.160 g, 0.38 mmol) in chloroform (5.0 mL) at room temperature was added BF3-Et2O (0.21 g, 1.5 mmol) and dimethylsulfide (0.24 g, 3.78 mmol). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed and residue was purified by preparative TLC eluting with 3:1/hexanes:ethyl acetate to give 3-benzoxazol-2-yl-5-bromo-phenylamine (0.10 g, 92%) as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1Br
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccccc3Br)CC2)nc[nH]1

Procedure:
6-[4-(2-Bromo-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-bromobenzaldehyde. Mass spectrum (ES) MH+=349.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C.[CH2:41]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH:52]1[CH2:57][CH2:58][SH:59])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C.O>[CH2:41]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH:52]1[CH2:57][CH2:58][S:59][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:29]([O-:31])=[O:30])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:50])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cc(C)cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCS
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)cc(-c2c(SCCC3CCCCN3C(=O)OCc3ccccc3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of trifluoromethanesulfonic acid 7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl ester (524 mg in 4 mL dry N,N-dimethylformamide) at 0° C. was added 0.38 mL diisopropylethylamine followed by 2-(2-mercaptoethyl)-piperidine-1-carboxylic acid benzyl ester (455 mg in 1 mL N,N-dimethylformamide) and the reaction allowed to warm to room temperature. After 1 hour, the mixture was diluted with ethyl acetate and water, and the layers separated. The organic portion was washed sequentially with water and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 7:3) gave the title compound (142 mg).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](N)=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([OH:14])=[O:1])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1(c2ccc(Cl)cc2)CC1

Procedure:
In a mixed solvent consisting of 14 ml of dioxane and 29 ml of a 1N aqueous sodium hydroxide solution was suspended 1.4 g of 1-(4-chlorophenyl)cyclopropanecarboxamide [this compound can be obtained from 1-(4-chlorophenyl)cyclopropanecarboxylic acid produced according to the method described in Chem. Ber., 119, 3694 (1986)]. To the suspension was dropwise added 4.4 g of a 12% aqueous sodium hypochlorite solution at 5°-10° C. The suspension was subjected to reaction at 20°-25° C. for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. To the thus treated organic layer was added the dioxane solution obtained in (1) above at 20°-25° C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/ethyl acetate =15/1) to obtain 0.37 g of N-[1-(4-chlorophenyl)cyclopropyl]-3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutanamide.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[C:14]([Cl:26])[CH:13]=2)[CH2:6][CH2:5]1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45](C(C2(O)CCCCC2)C(N2CCC(NC(=O)OC(C)(C)C)CC2)=O)=[CH:44][C:43]=1[Cl:72])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[ClH:26].[ClH:72].[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2([CH:16]([C:45]2[CH:46]=[CH:47][C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:43]([Cl:1])[CH:44]=2)[CH3:17])[OH:18])[CH2:6][CH2:5]1
Reactant: NC1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CC(c1ccc(OCc2ccccc2)c(Cl)c1)C1(O)CCCCC1N1CCC(N)CC1

Procedure:
In an analogous manner to Example 1, step 2 {2-(4-aminopiperidin-1-yl)-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1-[[4-(benzyloxy)-3-chlorophenyl](1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 443; HRMS: calcd for C26H35ClN2O2+H+, 443.24598; found (ESI, [M+H]+), 443.2461.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].[H-].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:18][C@@H:3]1[C@H:2]([N:1]2[CH2:2][CH2:3][NH:4][C:8]2=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1[C@H](N2CCNC2=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
(2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 610 mg, 2.46 mmol) was dissolved in 10 mL dry THF. To it was added 2-chloroethyl isocyante (210 μL, 2.46 mmol), and the mixture was stirred at RT for 2 hours. To it was added NaH (60% in mineral oil, 120 mg, 2.95 mmol) and the mixture was stirred for overnight. Another batch of NaH (120 mg, 2.95 mmol) was then added to drive the cyclization to completion in overnight. The mixture was diluted with 150 mL EtOAc and 50 mL water. The organic phase was separated, washed with water, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (354, 490 mg, 63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](SCC3C=CC=CC=3)[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[CH:32]=1.Cl[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41](OO)=O)[CH:36]=1.[S:45]([O:48]S([O-])=O)([O-])=[O:46].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:45]([CH2:41][C:37]3[CH:36]=[CH:35][CH:40]=[CH:39][CH:38]=3)(=[O:48])=[O:46])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[CH:32]=1
Reactant: O=S([O-])OS(=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccccc3)c2c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
300 mg of 6-[(2-benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was dissolved in 6 ml of dichloromethane, mixed with 468 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 48 hours at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 179 mg was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](O)=[CH:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:23])/[CH:19]=[C:20](\[NH2:22])/[CH3:21].[C:24]1([CH3:32])[C:25]([CH:30]=O)=[CH:26][CH:27]=[CH:28][CH:29]=1.C(O)C>C(O)(=O)C>[CH3:16][O:17][C:18]([C:19]1[CH:32]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:11]2[C:10](=[O:15])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C:12]=2[NH:22][C:20]=1[CH3:21])=[O:23]
Reactant: O=C1C=C(O)CN(Cc2ccccc2)C1
Reactant: COC(=O)/C=C(/C)N
Reactant: Cc1ccccc1C=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1ccccc1C

Procedure:
A mixture of 6.1 g. of 1-benzyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine, 3.6 g. of methyl-3-aminocrotonate (97%), 3.6 g. of o-tolualdehyde, 55 ml. of ethanol and 18 ml. of acetic acid was refluxed for 7 hours. The solution was evaporated to dryness in vacuo. The residue was triturated with diethyl ether and the solid was separated by filtration. Recrystallization from ethanol afforded the title compound, m.p. 201°-204° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH2:18].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([NH:19][C:20](=[O:21])[O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])=[CH:8][CH:9]=1)[CH:17]=[CH2:18]
Reactant: C=CCN=C=O
Reactant: COC(CCOc1ccc(O)cc1)OC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCNC(=O)Oc1ccc(OCCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(3,3-Dimethoxypropoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Allyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The dried solution is stirpped of solvent and unreacted isocyanate to yield the desired product O-[4-(3,3-dimethoxypropoxy)phenyl] N-allylcarbamate as the residue.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[C:34]1([C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:43]2[CH2:44][CH2:45][C:40]([OH:46])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:41][CH2:42]2)=[O:18])[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2)CCNCC1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)(c3ccccc3)CC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-phenyl-4-piperidinol, the title compound was obtained in 74% purity by HPLC. MS(ESI+): m/z=498.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([N:28]([CH3:27])[NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CNN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.0 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.35 ml of methylhydrazine and 20 ml of tetrahydrofuran was stirred at room temperature for 24 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.85 g of 3-bromo-N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31](O)=[O:32]>>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3nc4ccccc4[nH]3)CC1)O2

Procedure:
Compound 74 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1H-benzimidazole-2-carboxylic acid and conditions outlined in procedure O. M.p.=266-268° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.17 (s, 1H), 7.92 (m, 2H), 7.76 (m, 2H), 7.56 (m, 2H), 7.24-7.35 (m, 2H), 5.46 (d, 1H), 4.48 (d, 1H), 3.82 (t, 0H), 3.33 (m, 1H), 3.18 (d, 2H), 2.17 (m, 2H), 1.85-2.04 (m, 2H); LCMS=446 [M+H].