Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:40]=[N:39][C:15]3[O:16][CH2:17][CH2:18][C@@H:19]4[C@@:24]([CH3:25])([C:14]=3[CH:13]=2)[N:23]=[C:22]([NH:26]C(=O)OC(C)(C)C)[C:21]2([CH2:36][CH2:35][CH2:34]2)[S:20]4(=[O:38])=[O:37])=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>O>[NH2:26][C:22]1[C:21]2([CH2:34][CH2:35][CH2:36]2)[S:20](=[O:37])(=[O:38])[C@@H:19]2[CH2:18][CH2:17][O:16][C:15]3[N:39]=[CH:40][C:12]([NH:11][C:9](=[O:10])[C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=4)=[CH:13][C:14]=3[C@@:24]2([CH3:25])[N:23]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4ccc(C#N)cn4)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@]12N=C(N)C3(CCC3)S(=O)(=O)[C@@H]1CCOc1ncc(NC(=O)c3ccc(C#N)cn3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To tert-butyl ((4a′R,11b′R)-10′-(5-cyanopicolinamido)-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate was added TFA (0.015 ml, 0.197 mmol) and the resulting solution was stirred at rt for 15 min. The reaction mixture was poured into water and the pH was brought to >10 using sat. NaHCO3 and 5 N NaOH, then extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography using a gradient 0-3% MeOH/DCM solvent system to afford a white solid as N-((4a′R,11b′R)-2′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-10′-yl)-5-cyanopicolinamide (0.030 g, 0.064 mmol, 32.6% yield). MS m/z=466.9 (M+H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[CH:1]([NH:4][CH2:5][CH2:6][NH:7][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C

Procedure:
N-Isopropylethylenediamine (4.87 ml, 39.0 mmol) and potassium carbonate (6.37 g, 46.0 mmol) were added to a solution of 4-fluoronitrobenzene (5.0 g, 35.0 mmol) in DMF (50 ml) and the mixture was heated at 70° C. for 3 hours under a nitrogen atmosphere. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 ml) and the solution was washed with water (3×100 ml) and saturated sodium chloride (50 ml) and dried. The solvent was removed by evaporation to give the product as an orange oil which crystallised on standing (7.55 g, 95%). NMR: 1.0 (d, 6H), 1.7 (m, 1H), 2.7 (m, 3H), 3.2 (m, 1H), 6.6 (m, 2H), 7.1 (m, 1H), 8.0 (m, 2H); MS (MH+): 224.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:23])N(OC)C)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>C1COCC1.O.[Br-]>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:23])[CH2:3][CH:2]=[CH2:1])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C=CC[Mg]Br
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
Add slowly and dropwise a solution of allylmagnesium bromide (2.0 M in THF, 100.3 mL, 200.5 mmol) to a stirred solution of (S)-3-(methoxy(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (37.0 g, 143.2 mmol) in THF (296 mL) kept under nitrogen at 0° C. Allow the reaction to warm to room temperature and continue to stir for 48 hours. Add the mixture over a cold solution (0-5° C.) of sodium borohydride (5.42 g, 143 mmol) and tertabutylammonium bromide (0.74 g, 2.39 mmol) in water (74 mL) and stir for 1 hour. Separate the phases and extract the water phase with t-butylmethylether (2×). Combine the organic phases and wash with water and brine. Concentrate and purify the crude residue by silica gel column chromatography eluting with t-butylmethylether/hexanes (3/7 to 7/3) to obtain (3S)-3-(1-hydroxy-but-3-enyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-mix) (29 g, 85%). MS (m/z)=186.1 [M−55].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[Li]CCCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:17][C:10]1[O:9][C:8]2=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=1
Reactant: COc1nccc2ccoc12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nccc2cc(Cl)oc12
Temperature: -15 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A 0.13 M solution of 7-methoxyfuro[2,3-c]pyridine (250 mg, 1.7 mmol) in THF stirred at −78° C. under an atmosphere of nitrogen was treated with n-BuLi (1.6M in hexanes, 450 uL, 5.2 mmol) dropwise over 30 sec. The mixture was warmed gradually to −15° C. over a period of 7 to 10 min. After 1 h at −15° C., the mixture was cooled to −65° C. and was treated with a 0.26 M solution of hexachloroethane (473 mg, 2 mmol) in THF by dropwise addition over 3 min. After stirring at −65° C. for 15 min, the mixture was allowed to gradually warm to rt. After the mixture was allowed to stir overnight, it was quenched with water (5 mL) and extracted with EtOAc (3×15 ml). The combined organic layers were washed brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (266 mg, 87%) as an amber oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.99-4.08 (m, 3H) 7.13 (s, 1H) 7.25 (d, J=5.31 Hz, 1H) 7.95 (d, J=5.31 Hz, 1H). LCMS (M+H)+=184.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH:21]2[CH2:23][CH2:22]2)[C:18]([NH2:20])=[O:19])=[C:5]([F:24])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:24])=[CH:4][C:3]([C:1]([NH2:2])=[O:31])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH:21]1[CH2:22][CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-2-cyclopropylacetamide (38 mg, 0.110 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (18 mg). MS 364.2 (M+H); UV 219.3, 280.5, 302.6 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20]([CH2:30][CH2:31][CH3:32])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][Br:33])[CH2:26][CH2:25]2)=[C:20]([CH2:30][CH2:31][CH3:32])[CH:19]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:15])[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCNCC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CBr)CC1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
1-{6-[2-(Benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazine (27 mg, 0.0563 mmol) was dissolved in dichloromethane (1.0 mL). Under ice-cold conditions, N,N′-dimethylaniline (15 μL, 0.118 mmol) and bromoacetylbromide (5.1 μL, 0.0591 mmol) were added, and the mixture was stirred under ice-cold conditions for 20 minutes. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (25 mg (yield 78%)) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][CH2:15]Cl.[NH2:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>>[CH2:19]([CH:18]([N:17]1[C:2]2[C:11]3[CH:10]=[CH:9][C:8]([I:12])=[CH:7][C:6]=3[N:5]=[C:4]([C:13]3[C:3]([CH3:4])=[CH:2][C:11]([CH3:6])=[CH:10][C:9]=3[CH3:8])[C:3]=2[CH2:14][CH2:15]1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(N)CC
Reactant: Cc1nc2cc(I)ccc2c(Cl)c1CCCl
Product: CCC(CC)N1CCc2c(-c3c(C)cc(C)cc3C)nc3cc(I)ccc3c21

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-7-iodo-2-methylquinoline (300 mg, 0.82 mmol) in 3-aminopentane (10.0 mL) was stirred at 200° C. for eight hours in a sealed tube. The mixture was evaporated, and the residue was purified by silica gel column chromatography (10-70% ethyl acetate/hexane), to give the title compound (39 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:25]([O:27][CH:28]([O:33][CH2:34][CH3:35])[CH2:29][CH2:30][CH2:31][NH2:32])[CH3:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([O:33][CH:28]([O:27][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:35]
Reactant: CCOC(CCCN)OCC
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12)OCC

Procedure:
Stir 600 mg (1.78 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 344.7 mg (2.14 mmol) 4-aminobutyraldehyde-diethylacetal and 0.465 ml (2.67 mmol) DIEA in 5 ml DMF overnight at 80° C. After cooling, purify the mixture directly by preparative RP-HPLC (gradient acetonitrile/water). 746 mg (90.7% of theor.) of the target compound is obtained.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30]([OH:37])[CH:29]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[O:37][C:30]1[CH:31]=[CH:32][C:33]([N+:34]([O-:36])=[O:35])=[CH:28][CH:29]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 52 %

Procedure:
A 19.5 g (0.05 mole) quantity of penta-O-acetyl-β-D-mannopyranose and 13.9 g (0.10 mole) of p-nitrophenol were heated at 130° C. under reduced pressure of 20 mmHg. To the melt obtained were added 0.25 g of 12-molybdophosphoric acid and 0.05 g of zinc acetate and the mixture was reacted under reduced pressure for 30 minutes. The reaction mixture was dissolved in 100 ml of toluene and the solution was washed with 6 portions of 50 ml of 1.0M-NaoH aqueous solution and with 2 portions of 50 ml of water. After the toluene layer was evaporated to dryness under reduced pressure, the semisolid obtained was purified by silica gel column chromatography using toluene-acetone (20 : 1, v/v) as an eluent, giving 12.2 g of p-nitrophenyl 2,3,4,6-tetra-O-acetyl-β-D-mannopyranoside in a yield of 52.0%. M.p. 142° to 143° C.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]1([CH2:18][CH2:19][CH:20]2[C:24]3[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C(Cl)Cl>[C:12]1([CH2:18][CH2:19][CH:20]2[C:24]3[CH:25]=[C:26]([CH:29]=[O:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccc2c(c1)C(CCc1ccccc1)CO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)C(CCc1ccccc1)CO2
Reaction time: 12 h
Yield: 6.1 %

Procedure:
To a suspension of PCC (3.69 g, 17.10 mmol) in methylene chloride (20 ml), a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl-methanol (3.32 g, 13.16 mmol) in methylene chloride (100 ml) was added at room temperature. After stirring for 12 h, diethyl ether (300 ml) was added and the black solid precipitated was filtered and washed with diethyl ether several times. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5-9/1) affording 0.202 g of the title compound (67% yield).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][O:46][C:47]1[CH:52]=CC(N)=[CH:49][CH:48]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:49]=[CH:48][C:47]([O:46][CH3:45])=[CH:52][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: COc1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-anisidine as the aniline component. (20%, MS=500.2 (M+H))
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].CN1CCOCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)(=[O:26])=[O:25])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: C=CCNCC(C)CC=C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCC(C)CN(CC=C)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Allyl-(2-methyl-pent-4-enyl)-amine (1.0 g, 7.2 mmol) and NMM (1.7 g, 17.2 mmol) were mixed in 30 ml CH2Cl2. 2-pyridinesulphonyl chloride (1.53 g, 8.6 mmol) was added slowly to the solution while it was cooled in an ice-water bath. After addition, the reaction mixture was stirred at RT overnight. The reaction mixture was washed with 10% NaHCO3 and the brine, then was purified by column chromatography to give the title compound as a colorless oil (1.2 g ,60% yield): MS (M+H+) 281.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0–7.75(m, 2H), 7.5 (m, 1H) 5.80–5.60(m, 2H), 5.15–4.92(m, 4H), 4.00–3.90(m, 2H), 3.20–3.06(m, 2H), 2.15(m, 1H), 1.85(m, 2H), 0.89(d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 97.1 %

Procedure:
A mixture of 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), aminoguanidine hydrochloride (46 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (2 ml) was refluxed for 1 hour and 30 minutes. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dimethylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 58) (131 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[CH2:11][N:10]([C@@H](C1C=CC=CC=1)C)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClC(Cl)C>[C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[CH2:11][N:10]([C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@H]2CC=C[C@@]2(C(=O)OC(C)(C)C)C1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@]12C=CC[C@@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
[(1S,5S)-3-[(1R)-1-Phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester (370 mg, 1.18 mmol) was dissolved in dichloroethane (3 mL). Benzyloxycarbonyl chloride (1.01 g, 5.90 mmol) was added, and the mixture was stirred at 40° C. for three hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to give 385 mg of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16].C([N:22]([CH2:26][CH3:27])[CH:23]([CH3:25])C)(C)C.N1CCCC1>O1CCCC1>[N:22]1([S:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])(=[O:17])=[O:16])[CH2:23][CH2:25][CH2:27][CH2:26]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)N1CCCC1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propane-1-sulfonyl chloride (0.288 g) in dry tetrahydrofuran (5 ml) was treated with N,N-diisopropylethylamine (0.350 ml) and pyrrolidine (0.10 ml) at 22° C. under nitrogen, and the mixture was stirred at 22° C. for 1 h. After standing overnight at room temperature, the mixture was partitioned between saturated aqueous sodium bicarbonate (10 ml) and ethyl acetate (2×10 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give a white solid (0.145 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1ccco1
Product: Clc1ccc(-c2cn(-c3ccco3)cn2)cc1
Yield: 1.7 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-(4-chlorophenyl)-1H-imidazole (125 mg, 0.7 mmol) and 2-bromofuran, to prepare the desired 4-(4-chlorophenyl)-1-(furan-2-yl)-1H-imidazole (3 mg, 0.12, yield 1.7%) as a brownish solid. The HPLC purity of the final product was 95.84%. LC-MS [M+H] 245 (C13H9ClN2O+H expected 245.04). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: C(C1C=CC([C:11]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](C)=[N:16]3)=CC=1)(C)(C)C.F.F.F.C(N(CC)CC)C>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Cc1ccc2c(-c3ccc(C(C)(C)C)cc3)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.6 %

Procedure:
To a 300 mL flask was added 6.7 g of 5-(4-t-butyl-phenyl)-2-methyl-8-t-butyldimethylsiloxyquinoline and 100 ml dry THF. The mixture was stirred under nitrogen while 13.5 ml triethylamine trihydrofluoride (Aldrich) was added in 5 portions over 30 min. The reaction mixture was stirred at room temperature for 2 h and the solvents removed in vacuo. The resulting oil was purified by silica chromatography, first eluting with 15% dichloromethane in hexanes and then collecting the product by elution with 50% dichloromethane in hexanes to give 4.33 g of the desired product quinaldine 2a as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[CH2:19]([N:22]=[C:23]=[S:24])[CH:20]=[CH2:21]>C(#N)C>[CH3:17][N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:23]([NH:22][CH2:19][CH:20]=[CH2:21])=[S:24])[O:7][C:8]=2[CH:14]=1)[CH3:18]
Reactant: C=CCN=C=S
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Solvent: CC#N
Product: C=CCNC(=S)NCCSCc1cc2ccc(CN(C)C)cc2o1

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (Example 1, Step E) (2.6 g., 0.01 mole) and allyl isothiocyanate (1.1 g., 0.011 mole) in acetonitrile (15 ml.) is kept at 25°-27° C. for 16 hours. The solvent is evaporated and the residual oil chromatographed (silica gel/5% methanol in chloroform) to yield N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-(2-propenyl)thiourea.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([F:25])[O:5][C:6]1[CH:7]=[C:8]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=O)[CH:9]=[CH:10][CH:11]=1.[CH2:27](P(=O)(OCC)OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C1COCC1.C1OCCOCCOCCOCCOC1>[C:28]1([CH:27]=[C:12]([C:14]2[CH:15]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:7]=[C:6]([O:5][C:4]([F:26])([F:25])[F:3])[CH:11]=[CH:10][CH:9]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(C(=Cc2ccccc2)c2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a suspension of NaH (60% in oil, 0.24 g, 6 mmol) in dry THF (25 mL) under nitrogen was added 15-crown-5 (0.06 g). The suspension was cooled in an ice bath. Bis(3-(trifluoromethoxy)phenyl)methanone (2.10 g, 6 mmol) and diethyl benzylphosphonate (1.37 g, 6 mmol) were dissolved in THF (12 mL) and added to the suspension. The reaction mixture was stirred at ice bath temperature for 15 min, allowed to warm to rt and stirred overnight. The reaction mixture was poured into water and extracted with ether (2×). The combined ether layers were washed with 10% NaHSO3, sat. NaCl, dried over K2CO3, filtered and purified by ISCO using a gradient of 0-4% EtOAc/hexanes as eluent to give 3,3′-(2-phenylethene-1,1-diyl)bis((trifluoromethoxy)benzene) as a colorless oil (1.34 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (m, 2H), 7.2-7.1 (m, 8H), 7.04 (s, 1H), 7.0-6.97 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[C:3]=1[F:12]>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:11])[C:3]=1[F:12])[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)c(F)c(Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.4 %

Procedure:
A 250 ml round bottom flask was charged with iron powder (325 mesh) (2.6 g, 46.6 mmol), 1,3-dibromo-2-fluoro-5-nitrobenzene (2.0 g, 4.01 mmol) and acetic acid (50 ml). The flask was evacuated and back-filled with nitrogen twice, and then stirred at room temperature for 1 hour. The reaction mixture turned into very thick slurry. Acetic acid (50 ml) was added and the mixture stirred for an additional hour. The reaction mixture was poured into EtOAc. The EtOAc solution was washed with water (2×), NaHCO3+Na2CO3 solution until CO2 evolution stopped, then once with brine, then dried over MgSO4, filtered and evaporated to dryness to give 1.6 g crude 3,5-dibromo-4-fluoroaniline (1.6 g). The product was used without further purification in the next experiment.