Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41](=[S:47])/[N:42]=[CH:43]/[N:44](C)C)[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.NOS(O)(=O)=O>CO.CCO>[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]2[S:47][N:44]=[CH:43][N:42]=2)[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)/C=N/C(=S)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of pyridine (320 mg, 4.0 mmol) in CH3OH (10 mL) was added to a mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-((E)-(dimethylamino)methylenecarbamothioyl)piperidine-1-carboxylate (1.2 g, 2.0 mmol) in EtOH (20 mL) followed by addition of (aminooxy)sulfonic acid (270 mg, 2.4 mmol). The mixture was stirred at rt for 2 hrs. The solvent was removed, and the residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (520 mg, 48%) as a yellow solid. ESI-MS (EI+, m/z): 598 [M+Na]+.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:13][C@H:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:15]2)[CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.N>ClCCl.CO>[NH2:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C@H:12]3[CH2:11][C@H:10]([CH2:9][OH:8])[CH2:13]3)[N:15]=[C:16]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][CH:29]=3)[C:17]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1
Agent: ClB(Cl)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](CO)C1
Temperature: -78 °C
Reaction time: 7 h

Procedure:
A solution of trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.244 g, 0.00051 mol) in dichloromethane (10 mL) was cooled to −78° C. and a solution of 1.0 M boron trichloride in dichloromethane (1.53 mL, 0.00153 mol) was added dropwise, keeping the temperature less than −70° C. The reaction mixture was stirred seven hours at −78° C., after which time a 8 M solution of ammonia in methanol (1.5 mL) was added . The solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (93:7). The solvent was removed in vacuo to give to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutylmethanol (0.192 g, 0.00049 mol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nccs2)CC1

Procedure:
By a similar manner to Reference Example 44, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-bromothiazole (0.59 mL, 6.5 mmol) to give the titled compound as pale yellow oily substance (189 mg, 13%)
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([O:11]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.[F:27][C:28]([F:36])([F:35])[S:29]([CH2:31][C:32](O)=[O:33])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[F:27][C:28]([F:36])([F:35])[S:29]([CH2:31][C:32]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12)=[O:33])=[O:30]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: O=C(O)CS(=O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CS(=O)C(F)(F)F)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
A solution of 0.78 g (2 mmol) of benzhydryl 7-amino-3-cephem-4-carboxylate (South African Pat. No. 71/06719), 0.35 g (2 mmol) of trifluoromethylsulfinylacetic acid and 0.4 g (2 mmol) of dicyclohexylcarbodiimide in dry tetrahydrofuran (15 ml) is stirred at room temperature overnight. The precipitate is collected and washed with tetrahydrofuran and the combined filtrate and washings are evaporated in vacuo. The residue is treated with a cold solution of trifluoroacetic acid (10 ml) and anisole (0.5 g) for 15 minutes and then concentrated in vacuo. The residue is dissolved in ethyl acetate and treated with 5 percent aqueous sodium bicarbonate. The aqueous phase is adjusted to pH 2 and the precipitated product is collected and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH3:16].[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24].O=O>N1C=CC=CC=1.CO.Cl[Cu]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:24]#[C:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CCCCC#CCO
Reactant: CCCC#CCCO
Agent: Cl[Cu]
Agent: C#CCCCCCO
Agent: O=O
Solvent: c1ccncc1
Solvent: CO
Product: OCCCCCC#CC#CCCCCCO

Procedure:
HO(CH2)5C≡CH was prepared by the KAPA-promoted isomerization of HOCH2C≡C(CH2)3CH3 (prepared according to Millar, J. G.; Oehlschlager, A. C. J. Org. Chem. 1984, 49, 2332-2338) or HO(CH2)2C≡C(CH2)2CH3 (commercially available from GFS Chemicals; Powell, Ohio). Oxidative coupling of HO(CH2)5C≡CH was carried out in a glass reaction vessel by dissolving 6.95 grams of HO(CH2)5C≡CH in pyridine/methanol (2.0 milliliters/6.2 milliliters) and adding 307 grams of CuCl followed by stirring in the presence of oxygen until all the staring material was consumed. The reaction mixture was worked up with diethyl ether and 4N HCl, the combined organic layers were dried over MgSO4, filtered and concentrated. Recrystallization of the residue from 1/1 hexanes/tert-butyl methyl ether to yield 5.35 grams of HO(CH2)5C≡C—C≡C(CH2)5OH as a pink solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH:7]1[CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH:8]1[NH2:30])([CH3:4])[CH3:3].[NH2:43][C:44]1[N:49]=[C:48]([OH:50])[C:47]([N+:51]([O-:53])=[O:52])=[C:46](Cl)[N:45]=1.C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[NH2:43][C:44]1[N:49]=[C:48]([OH:50])[C:47]([N+:51]([O-:53])=[O:52])=[C:46]([NH:30][CH:8]2[CH2:9][CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:45]=1
Reactant: CC(C)(C)[Si](OCC1CC(N)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CC(Nc2nc(N)nc(O)c2[N+](=O)[O-])C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
2-(((1,1-dimethylethyl)diphenylsilyl)oxy)-3-(((1,1- dimethylethyl)diphenyl-silyl)oxymethyl)-1-aminocyclobutane (588 mg, 0.99 mmol), the product of Step N, 189 mg (0.99 mmol) of 2-amino-6-chloro-4-hydroxy-5-nitropyrimidine (prepared as described by J. F. Constant, et al. in J. Heterocyclic Chem, 1035 (1985)) and triethylamine (220 μL, 1.50 mmol) were combined in 5 mL of anhydrous DMF. The reaction mixture was stirred in an oil bath at 50° C. under a nitrogen atmosphere for 2.5 h. Diethyl ether (200 mL) was added and the ether solution was washed with 2×50 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue (800 mg) was dissolved in methylene chloride and purified on a 1.0×45 cm silica gel column eluted @ 10 psi with 100 mL of methylene chloride, followed by 100 mL of 2% methanol in methylene chloride and finally 100 mL of 4% methanol in methylene chloride, to give 473 mg (64% yield) of the title compound; MS DCI-NH3M/Z: 748 (M+H)+ ; 1H NMR (CDCl3) δ 2.13-2.33 (m, 3H), 2.89 (s, 1H), 2.97 (s, 1H), 3.59-3.70 (m, 2H), 4.26 (t, 1H), 4.65 (m, 1H), 7.30-7.47 (m, 10H), 7.56-7.60 (m, 10H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.FC(C1C=CC(OC(F)(F)F)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(F)C>>[CH3:28][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:29][CH3:30])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:27])[C:23]([F:24])([F:25])[F:26]
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 72 in the same manner of Compound 27.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[CH3:20])=[O:6].C([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][C:9]=2[CH3:20])=[CH:3][C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-Bromo-4-methoxy-N-(2-methyl-4-morpholin-4-yl-phenyl)-benzamide (432 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (311 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (697 mg) and tetrakis(triphenylphosphine)palladium0 (127 mg) was heated to reflux for 18 h.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:13][C:14]([F:16])([F:15])[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)[OH:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
In THF (10.0 mL) was dissolved 4-(methylsulfonyl)benzaldehyde (500 mg, 2.71 mmol). To the solution were added (trifluoromethyl)trimethylsilane (0.602 mL, 4.07 mmol) and tetrabutylammonium fluoride (1.0 mol/L solution in THF, 0.136 mL, 0.136 mmol), and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1 mol/L hydrochloric acid and the mixture was stirred at room temperature for 5 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethanol (454 mg, 66% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].N1C=CC=CC=1>C(O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][N:20]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)[CH3:1]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: NOCc1cccc(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(C)=NOCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.063 g, 0.377 mmol), O-(3-fluorobenzyl)hydroxylamine hydrochloride (0.100 g, 0.569 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with water. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 95:5 petrol/ethyl acetate, to give 3′-fluoro-4′-methoxyacetophenone-O-3-fluorobenzyloxime (CP9-126) as a white solid (0.099 g, 90%), m.p. 67°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH:9](F)[F:10])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(F)(CC(F)F)C(F)(F)F>>[F:1][C:2]([F:12])([F:13])[CH:3]([C:4]([F:5])([F:6])[F:7])[CH:8]=[CH:9][F:10]
Reactant: FC(F)CC(C(F)(F)F)C(F)(F)F
Agent: FC(F)CC(F)(C(F)(F)F)C(F)(F)F
Product: FC=CC(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 3-trifluoromethyl-1,4,4,4-tetrafluoro-1-butene may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be dehydrohalogenated and then hydrogenated to from 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane. The 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane may then be dehydrohalogenated to form 3-trifluoromethyl-1,4,4,4-tetrafluoro-1-butene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CC1CCCCC1NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CCCCC1NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(2-methylcyclohexyl)-3-piperidinecarboxamide (192 mg, 0.426 mmol), EtOH (5 mL), Hunig's base (0.074 ml, 0.426 mmol), and hydrazine anhydrous (0.08 mL, 2.56 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (122 mg) as a light yellow solid. LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.68-0.98 (m, 4H), 1.14 (m, 8H), 1.66 (m, 8H), 2.25 (m, 1H), 3.30 (m, 1H), 3.36 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.56 (d, J=3.5 Hz, 1H), 7.51-7.65 (m, 1H), 7.70 (s, 1H), 7.73 (s, H), 7.94 (d, J=2.8 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH:3]([C:14]([O:16]C)=O)[CH2:2]1.[NH3:18]>CO>[CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH:3]([C:14]([NH2:18])=[O:16])[CH2:2]1
Reactant: COC(=O)C1CCc2cc3ccccc3nc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCc2cc3ccccc3nc21
Reaction time: 8 h

Procedure:
2,3-Dihydro-1H-cyclopenta[b] quinoline in ether is added to isopropylmagnesium bromide (prepared from magnesium and isopropylbromide in ether). The mixture is heated at 120° C for several hours adding toluene when necessary as the ether distilled off to maintain the contents liquid. The mixture is cooled and ether is added. The resulting solution of 2,3-dihydro-1H-cyclopenta[b]-quinoline-3-magnesium bromide is added to stirred ice-cooled ether while a stream of dry CO2 gas is bubbled through until the red colour is discharged. The resulting solid (the magnesium bromide salt of 2,3-dihydro-1H-cyclopenta[b] quinoline-3-carboxylic acid) is dried and added to methanol saturated with HCl. The solution is stirred overnight and then evaporated to dryness. The residue is dissolved in water and extracted with ether. The aqueous phase is basified with sodium carbonate, any solid filtered off and the aqueous solution is extracted with ether (3 times). The ether extracts are dried and evaporated to dryness leaving an oil which is purified by distillation under reduced pressure to give methyl 2,3-dihydro-1H-cyclopenta[b] quinoline-3-carboxylate. This ester is dissolved in methanol saturated with ammonia in a bomb and kept overnight at 80° C. The solution is then cooled and evaporated to dryness. Purification and recrystallisation of the product gives 2,3-dihydro-1H-cyclopenta [b] quinoline-3-carboxamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C=O)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34]([O:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 3-acetamidophenol (4.8 g, 32 mmol) in THF (200 mL) was cooled to 0° C. To the solution was added NaH (60% in oil, 1.3 g, 32 mol) and the mixture was warmed to rt and allowed to stir for 30 minutes. The product from Step 1 (˜8.5 g, ˜21 mmol) was added and the mixture was stirred at rt overnight then DMF (10 mL) was added and the solution was heated to 60° C. overnight. The reaction mixture was concentrated in-vacuo, then taken up in EtOAc and H2O and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude oil was purified chromatography to give the title compound (4.3 g, 39%). MS (ES+) m/e 521 [M+H]+.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1([CH2:14][NH:15][C:16](=[N:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)SC)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH2:14][NH:15][C:16](=[N:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(N=C(NCC2CCCCC2)SC)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=Nc1ccc(C(=O)O)cc1)NCC1CCCCC1
Yield: 79 %

Procedure:
This compound is obtained (yield 79%; melting point 164° C.), by saponification of N-[N-cyclohexylmethylamino(4-caraboxyphenylimino)methyl]-2-aminoethanoic acid (melting point 163° C.) in a 1N sodium hydroxide solution, whereby the former was prepared from glycine and N-cyclohexylmethyl-N'-(4-methoxycarbonylphenyl)-S-methylisothiourea according to the experimental procedure described in Example 2.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].COC1C=CC(O)=CC=1.[OH-].[Li+]>O>[C:12]([O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCC(O)CC
Agent: COc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)OC(CC)CCCCCCC

Procedure:
In the same reactor as used in Example 1, 760 kg (5 kmoles) of tricyclo[5.2.1.02,6 ]deca-8-yl alcohol and 1500 kg (15 kmoles) of methyl methacrylate were placed and well mixed with stirring. The water content of the mixture was 2500 ppm. To the mixture, 550 g of hydroquinone monomethyl ether and 3 kg of anhydrous lithium hydroxide were added to carry out the reaction. While refluxing methyl methacrylate through the distillation column, by-produced methanol was removed by distillation. The reaction was continued until almost no methanol was produced (about 7 hours). After removing unreacted methyl methacrylate by distillation under reduced pressure, the reaction mixture was cooled and filtered under pressure (2 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 975 kg of tricyclo[5.2.1.02,6 ]deca-8-yl methacrylate with the filtrating time of 5.5 hours.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1)[CH3:2]
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 33.4 %

Procedure:
A mixture of 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (Example 208, step A) (0.80 g, 3.75 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (0.928 g, 3.75 mmol) and K2CO3 (0.622 g, 4.50 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (0.551 g, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.74 (s, 1H), 4.19 (q, J=6.93 Hz, 2H), 3.19-3.28 (m, 2H), 3.06-3.14 (m, 4H), 2.87 (s, 3H), 2.52-2.79 (m, 9H), 1.80-1.92 (m, 2H), 1.46-1.67 (m, 2H), 1.33 (t, J=6.97 Hz, 3H), 1.19 (t, J=7.47 Hz, 3H).