Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Cl:14][C:15]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.ClC1C=CC=C(F)C=1C=O.N1CCCC1>>[Cl:14][C:15]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:16]=1[CH:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]1[N:1]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=1
Reactant: Fc1cccc(Cl)c1C=[N+]1CCCC1
Reactant: Nc1ccccc1-n1cccc1
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Solvent: C1CCNC1
Product: Nc1ccccc1-n1cccc1C(c1c(F)cccc1Cl)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and 1-(2-chloro-6-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 2-chloro-6-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].CCN(CC)CC.[CH2:25]([CH:32]1[C:40]2[C:35](=[CH:36][C:37]([F:42])=[C:38]([OH:41])[CH:39]=2)[CH2:34][CH:33]1[NH:43][C:44](=[O:48])[O:45][CH2:46][CH3:47])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:1][C:2]([F:17])([S:13]([O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][C:37]=1[F:42])[CH2:34][CH:33]([NH:43][C:44]([O:45][CH2:46][CH3:47])=[O:48])[CH:32]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)NC1Cc2cc(F)c(O)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2cc(F)c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
Perfluorobutanesulfonyl fluoride (0.392 ml, 2.004 mmol) and Et3N (0.419 ml, 3.01 mmol) in abs. dichloromethane (10 ml) was added dropwise to the intermediate ethyl 1-benzyl-5-fluoro-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (330 mg, 1.002 mmol), dissolved in dichloromethane and stirred at room temperature over night. Evaporated and purified by flash silica gel chromatography on 12 g SiO2-cartridge using dichloromethane to afford 3-benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a yellow product. M=389 mg (63%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([O-])=O>CO.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncc2)cc1N
Temperature: 25 °C
Reaction time: 42 h

Procedure:
4-(3,4-Dinitro-phenoxy)-pyridine (1.36 g, 5.21 mmol) was dissolved in 20 mL MeOH and 40 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.35 g). The reaction was vigorously stirred for 42 h at RT under 1 atm of H2 gas. The reaction was filtered through a Celite® plug. The solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Na+]>CN(C)C=O.O>[CH2:19]([O:11][C:1](=[O:12])[C:2]1[CH:10]=[CH:9][C:7]([O:8][CH2:1][C:2]2[CH:10]=[CH:9][CH:7]=[CH:4][CH:3]=2)=[C:4]([O:5][CH3:6])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 52.6 g (313 mmol) of commercially available vanillic acid in 250 ml of dimethylformamide was slowly added 129.8 g (939 mmol) of potassium carbonate under ice-cooling, and 78.2 ml (657 mmol) of benzyl bromide was slowly added thereto, followed by overnight stirring in an atmosphere of argon at room temperature. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried to give 104.2 g (96%) of 4-benzyloxy-3-methoxybenzoic acid benzyl ester.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:14][Li]>C(OCC)C>[OH:3][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:14])[CH3:1]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: [Li]C
Solvent: CCOCC
Product: CC(C)(O)c1cccc2ccccc12

Procedure:
A 10 ml (65.8 mmole) quantity of 1-acetonaphthone was dissolved in 150 ml of diethyl ether in a 500 ml, two neck, round bottom flask equipped with a pressure equalizing dropping finnel and fitted with a rubber septum and a protected reflux condenser. A 138 ml (98 mmole) quantity of 1.4 M methyllithium in ether (Aldrich) was transferred to the fiumel by use of a cannula and nitrogen pressure. This was slowly added to the stirred ketone over a 20 minute period. A light green color indicated an excess of methyllithium. This was refluxed for an additional hour and the reaction was carefully quenched with water. The ether layer was made acidic using HCl, neutralized with NaHCO3, dried using MgSO4, and filtered. After the solvent was removed, the crude product was recrystallized from benzene, filtered and washed with cold pentane to yield white, fibrous crystals (>98%), m.p. 81-86° C. 1H NMR (acetone-d6): (=9.01 (m, 1 H, aromatic), 7.95 (m, 1 H, aromatic), 7.82 (d, J=10.6, 1 H, aromatic), 7.68 (d, J=10.3, 1 H, aromatic), 7.50 (m, 3 H, aromatic), 4.30 (s, 1 H, --OH), 1.84 (s, 6 H, --CH3).
Reaction SMILES: [CH3:1][NH:2][NH2:3].CO[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:18])[C:8](=[O:19])[N:7]=1>CO>[CH3:1][NH:2][NH:3][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:18])[C:8](=[O:19])[N:7]=1
Reactant: CNN
Reactant: COc1nc(-c2ccccc2)n(C)c(=O)n1
Solvent: CO
Product: CNNc1nc(-c2ccccc2)n(C)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.71 ml of methylhydrazine dissolved in 30 ml of methanol are added to a stirred solution of 4-methoxy-1-methyl-6-phenyl-1,2-dihydro-1,3,5-triazin-2-one in 100 ml of methanol. The mixture is stirred for one hour at RT and then refluxed for four hours. The reaction mixture is concentrated and the triazinone precipitated from ethyl acetate and hexane, filtered, washed with ether, and dried to yield 1.95 g of the desired product.
Reaction SMILES: C([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N:17]([CH3:27])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:20])=[O:19])[CH:16]=1)[NH:13][C:12]([C:28]1[S:29][CH:30]([CH:33](OC)OC)[CH2:31][N:32]=1)=[CH:11]2)(=O)C(C)(C)C.O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].F[C:50](F)(F)[C:51](O)=O>>[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N:17]([CH3:27])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:19])=[O:20])[CH:16]=1)[NH:13][C:12]([C:28]1[S:29][CH:30]([CH2:33][N:13]3[CH2:51][CH2:50][S:29][CH2:28][CH2:12]3)[CH2:31][N:32]=1)=[CH:11]2
Reactant: O=C(O)C(F)(F)F
Reactant: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of 2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-5-yl pivalate (273 mg) in trifluoroacetic acid (2 mL) were added water (4 mL) and concentrated sulfuric acid (2 mL), and the mixture was stirred at 80° C. for 5 hr, basified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure. To a tetrahydrofuran solution (5 mL) of the residue were added thiomorpholine (0.041 mL) and sodium triacetoxyborohydride (215 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction solution, and the organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:2) to give the title compound (145 mg, yield 85%) as a colorless amorphous powder. MS: 504 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:12][C@H:13]([N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH2:14][O:15]CC1C=CC=CC=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:12][C@H:13]([N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH2:14][OH:15])[CH2:8][CH:9]([F:10])[F:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COCc1ccccc1)CN(CC(F)F)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H](CO)CN(CC(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of [(S)-3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (2.42 g, 5.28 mmol) in MeOH (20 mL) and AcOH (2.0 mL) was added Pd/C (10%, 1.0 g). The reaction mixture was transferred to an autoclave and charged with hydrogen (50 psi). The mixture was stirred RT for 20 h and filtered. The filtrated was concentrated and the residue was purified on silica gel using a mixture of EtOAc and hexanes to give [(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-hydroxy-propyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butylester (1.81 g, 93%). LRMS (M+Na+) m/z 391.2.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(C#N)cc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1ccc(C#N)cc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoate (737 mg, 1.61 mmol) obtained from Example 5-(3), anisole (1.0 g, 9.2 mmol), and trifluoroacetic acid (5 ml) were reacted, and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above, oxalyl chloride (1.27 g, 10 mmol), and N,N-dimethylformamide (15 μl) were reacted, and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoyl chloride as a crude product.
Reaction SMILES: [CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N+:13]([O-:39])=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A solution of tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (0.113 g, 0.270 mmol) in anhydrous DCM (2.5 mL) was cooled to 0° C. and mCPBA (0.080 g, 0.33 mmol, 4×0.020 g) was added portion-wise. After 15 min., the reaction mixture was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched by the addition of a solution of Na2S2O3 (0.051 g, 0.32 mmol) in water (1 mL) followed by 4 M aq. NaOH (1 mL). The layers were separated and the organic fraction was concentrated and purified by flash column chromatography (20 g silica gel column, eluting with 0-30% MeOH/EtOAc) to afford the sub-title compound (0.050 g, 43%). LCMS (ESI) m/z calc. for C21H31N4O6 435.2 [M+H]+. found 435.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccc(Br)c2)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.1 %

Procedure:
To a solution of 2-amino-5-methyl-benzenesulfonamide (Example 45a) (6.0 g, 32.3 mmol) in pyridine (20 mL), 3-bromobenzenesulphonyl chloride (8.24 g, 32.3 mmol) was added portionwise at 0° C. The reaction was stirred at RT for 10 h. The pyridine was removed in vacuo at 35° C. and the residue was dissolved in ethyl acetate. The organic phase was washed with aqueous 1N HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) as eluent to give the title compound (8 g, 63%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>O1CCOCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(-n3ccc4c(OCc5ccccc5)cccc43)cc2)cc1
Temperature: 100 °C
Yield: 16 %

Procedure:
4-[(phenylmethyl)oxy]-1H-indole (504 mg, 2.26 mmoL), 4-bromophenyl phenylmethyl ether (580 mg, 1.88 mmoL), K3PO4 (998 mg, 4.7 mmoL) and L-Proline (43.3 mg, 0.376 mmoL) were dissolved in 1,4-Dioxane (4 mL) in a microwave vial and degassed by sonication under a flow of argon. To this was added CuI (18 mg, 0.094 mmoL) and the solution was heated to 100° C. in the microwave reactor. After 5 hours a second portion of CuI (48 mg, 0.252 mmoL) and L-Proline (40 mg, 0.347 mmoL) were added and the mixture heated for 2 more hours. The reaction mixture was filtered through a pad of celite and concentrated. The residue was partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (2×50 mL) then water (50 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D24), (143 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CCN[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CCN)CCOc1cccnc1[N+](=O)[O-]
Reactant: CCN(CCNC(=O)OC(C)(C)C)CCOc1cccnc1F
Product: CCN(CCNC(=O)OC(C)(C)C)CCOc1cccnc1[N+](=O)[O-]
Yield: 64 %

Procedure:
This compound was prepared, starting from compound 59 (500 mg, 1.97 mmol), according to the procedure developed for compound 64. Reaction time at room temperature: 18 h to give compound 65 (444 mg, 1.25 mmol) as a yellow oil. Yield 64%; IR (CCl4) ν 1172, 1289, 1367, 1500, 1549, 1716, 2977 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 1.36 (s, 9H), 2.60 (m, 4H), 2.89 (t, 2H, J=5.6 Hz), 3.13 (q, 2H, J=5.9 Hz), 4.13 (t, 2H, J=5.6 Hz), 7.51 (m, 2H), 8.05 (dd, 1H, J=2.4, 3.4 Hz); ESI-MS m/z 355.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:10]([C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC=Cc1ccccc1
Reactant: Cc1ccc(O)c(O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: Cc1cc(O)c(O)cc1CC=Cc1ccccc1
Yield: 49.6 %

Procedure:
A mixture of 1,2-dihydroxy-5-methylbenzene (124 g.) and cinnamyl alcohol (134 g.) in 2% aqueous citric acid (1.5 l.) containing ascorbic acid (10.0 g.) was boiled at reflux for 20 hours. After cooling, an oily layer separated and was collected and distilled to give 4-cinnamyl-5-methyl-1,2-dihydroxybenzene (119 g.) as a colorless oil, b.p. 205°-230° at 1.0 mm Hg. The oil was crystallized from a benzene/low-boiling petroleum ether (1/1) mixture to give colorless needles, m.p. 85°. Found: C, 79.9; H, 6.68. Calculated for C16H16O2 : C, 80.0; H, 6.71. The 100 MHz nuclear magnetic resonance (nmr) spectrum of this compound in deuterated chloroform exhibited a singlet (3 protons) at δ 2.07, a doublet (2 protons) at δ 3.37 (J = coupling constant = 5.0 Hz), a singlet (2 protons) at δ 5.02, a multiplet (2 protons) at δ 6.23-6.31, a singlet (1 proton) at δ 6.65, a singlet (1 proton) at δ 6.68, and a multiplet (5 protons) at δ 7.10-7.38.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=[CH:5][CH:6]([CH3:8])[CH3:7].[CH3:18][NH:19][C:20]([NH2:22])=[O:21].C[O-].[Mg+2].C[O-].CO>>[Cl:16][C:11]1[CH:10]=[C:9]([C:4](=[CH:5][CH:6]([CH3:7])[CH3:8])[C:3]([NH:22][C:20]([NH:19][CH3:18])=[O:21])=[O:17])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: COC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
The isomeric mixture of 2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoic acid methyl ester [749.0 mg, 2.74 mmol, (E):(Z)=3.5:1] and methyl urea (812.6 mg, 10.97 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 16 mL, 10.97 mmol). The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded impure 1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (280.2 mg) as a white solid. A second flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/diethyl ether) again afforded impure 1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (114.6 mg) as a white solid. Recrystallization from hexanes/ethyl acetate afford pure (E)-1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (24.7 mg, 3%) as a white solid: mp 177-178° C.; FAB-HRMS m/e calcd for C14H16Cl2N2O2 (M+H)+315.0667, found 315.0652.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][CH:27]=[CH:28][C:29](Cl)=[O:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:29](=[O:30])[CH:28]=[CH:27][CH3:26])=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Reactant: CC=CC(=O)Cl
Product: CC=CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 77.3 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochlQride (0.60 g, 1.702 mmol) and 3-methyl-acryloyl chloride (0.163 mL, 1.702 mmol) and following the procedure outlined in Example 512, but-2-enoic acid{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl]amide (0.553 g, 1.315 mmol) was obtained. Yield=77%. 100% purity at 254 nM; LCMS (APCI): 421.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.01 (d, J=8.53 Hz, 1H), 7.51 (t, J=8.01 Hz, 1H), 7.38 (t, J=8.01 Hz, 1H), 7.29 (d, J=8.01 Hz, 1H), 7.04 (s, 1H), 6.99 (d, J=8.01 Hz, 1H), 6.70 (dq, J=6.86 Hz, J=15.27 Hz, 1H), 6.15 (d, J=15.32 Hz, 1H), 3.44–3.35 (m, 4H), 3.29 (s, H2O), 2.72-s.58 (m, 6H), 2.57–2.49 (m, 2H), 2.11 (s, 3H), 1.80 (d, J=6.89 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:5]([C:6]([NH2:24])=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2]>FC(F)(F)C(O)=O.C(#N)C.[Pt](=O)=O>[CH:18]1([CH2:17][CH2:16][C:15]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]3[C:14]=2[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]3[NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCc1ccccc1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCn1nc2c(N)nc3c(c2c1CCC1CCCCC1)CCCC3
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 53.8 %

Procedure:
A mixture of 2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 41, 575 mg, 1.81 mmol) and platinum (IV) oxide (290 mg) in trifluoroacetic acid (8 mL) was shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 22.5 hours on a Parr apparatus. The reaction mixture was filtered through a poly(tetrafluoroethylene) membrane to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution using 0-30% CMA in chloroform) and the appropriate fractions were concentrated to yield a solid that was slurried in hot acetonitrile. The mixture was allowed to cool to ambient temperature with stirring, then 318 mg of 1-(2-cyclohexylethyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine was isolated as a white powder, mp 177.0-179.0° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:18]([O:17][C:15]([N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH2:9][CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of crude 3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-tert-butyl ester 7-methyl ester (2.7 g, 9.2 mmol) in methanol (30 ml) was treated with 3N NaOH (10 ml, 30 mmol, 3.3 equiv.) and stirred at room temperature for 5 h. The methanol was evaporated and the residual slurry was treated with 3N HCl (10 ml). The white precipitate was filtered, washing with water, and dried under high vacuum to afford 3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-tert-butyl ester as a white solid, 2.5 g (97%). MS (ISP): m/e=276.1 (M−H); δH (300 MHz; CDCl3) 8.40 (0.25H, s), 8.33 (0.75H, s), 7.70 (0.25H, d), 7.64 (0.75H, d), 7.14 (1H, m), 3.75 (2H, m), 2.82 (2H, m), 1.94 (2H, m), 1.54 (9H, s).