Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2F)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 111 mg (83%) of a white solid. MS (ISP) 429.6 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[N:7]([CH2:20][C:21]([O:23]CC)=O)[N:6]=1>CO>[NH2:4][C:5]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[N:7]([CH2:20][C:21]([N:2]([CH3:3])[CH3:1])=[O:23])[N:6]=1
Reactant: CNC
Reactant: CCOC(=O)Cn1nc(N)c2cc3cc(OC)ccc3nc21
Solvent: CO
Product: COc1ccc2nc3c(cc2c1)c(N)nn3CC(=O)N(C)C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a saturated solution of dimethylamine in 250 ml methanol at 0° C. was added 4.5 g ethyl 3-amino-6-methoxy-1H-pyrazolo[3,4-b]quinolin-1-acetate (Example 20), and the mixture was stirred at 0° C. for one hour, at room temperature for 48 hours and at reflux for two hours. The reaction mixture was cooled to room temperature and the solid product was collected by filtration and chromatographed on silica gel using 95% chloroform/2.5% isopropyl alcohol/2.5% isopropylamine amine as eluant. The appropriate fractions were combined and evaporated to give 2.0 g 3-amino-6-methoxy-N,N-dimethyl-1H-pyrazolo[3,4-b]quinolin-1-acetamide, orange solid, m.p. 251°-253° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[C:1]([C:3]1[CH:4]=[C:5]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Product: CCOC(=O)C(=CN(C)C)c1cccc(C#N)c1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(3-cyanophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.1 Hz, 3 H) 2.67 (s, 6H) 4.00 (q, J=7.1 Hz, 2 H) 7.42-7.45 (m, 1 H) 7.45-7.50 (m, 1 H) 7.53-7.55 (m, 1 H) 7.57 (s, 1 H) 7.64 (dt, J=7.1, 1.7 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1([C:13]2[S:17][C:16]([S:18]([CH2:21][N+:22]([O-:24])=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=2)OCC(C)(C)C[O:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(O)C>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]([C:13]1[S:17][C:16]([S:18]([CH2:21][N+:22]([O-:24])=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1)=[O:6]
Reactant: CC1(C)COC(c2ccc(S(=O)(=O)C[N+](=O)[O-])s2)(C(C)(C)C)OC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccc(S(=O)(=O)C[N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 53.3 %

Procedure:
A mixture of 2-t-butyl-5,5-dimethyl-2-[2-(nitromethylsulphonyl)thien-5-yl]-1,3-dioxane (A) (1.47 g), trifluoroacetic acid (15 ml), and water (1.5 ml) was stirred for 45 minutes at 60° C. The reaction mixture was poured into water (50 ml), and extracted with ether (2×50 ml). The combined ether extracts were washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water (3×20 ml), and then dried (MgSO4). The solvent was removed by evaporation to give 2-(2,2-dimethylpropionyl)-5-(nitromethylsulphonyl)thiophene as a white solid (0.605 g, 54% yield), m.p. 98°-99° C. (after recrystallisation from aqueous ethanol); MMR (250 MHz): 1.42(s, 9H), 5.72(s, 2H), 7.78(d, 1H), 7.82(d, 1H); m/e (electron impact) 292 (M+H)+ ; microanalysis, found: C,41.3, H.4.5, N,4.7%; C10H13NO5S2 requires: C,41.2, H,4.5, N,4.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:19][CH:20]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid (5) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (45 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-chlorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 18 mg (15%). 1H-NMR: 8.64-8.61 (m, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.87 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.19-7.14 (m, 2H), 3.19 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8](C(O)=O)=[CH:7][C:6]=1[CH3:15])(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:23])C=CC=CC=1.C1C=CC=CC=1.C([N:41]([CH2:44]C)CC)C>>[C:1]([O:4][C:5]1[C:6]([CH3:15])=[CH:7][C:8]([N:41]=[C:44]=[O:23])=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)cc(N=C=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-acetoxy-3,5-dimethylbenzoic acid (270 mg), diphenylphosphoryl azide (DPPA, 430 mg) and benzene (6 ml) was added dropwise triethylamine (0.18 ml) and the mixture was stirred at room temperature for 30 minutes and then at reflux for 40 minutes to obtain a solution of 4-acetoxy-3,5-dimethylphenylisocyanate. To the solution was added 5-amino-2-ethyl-4-(2-methoxyphenyl)-thieno[2,3-b]pyridine (284 mg) and the mixture was heated under reflux for 5 hours. The mixture was washed with water and dried over MgSO4 and the solvent was distilled off. To the residue was added ethanol to obtain N-(4-acetoxy-3,5-dimethylphenyl)-N'-[2-ethyl-4-(2-methoxyphenyl)thieno[2,3-b]pyridin-5-yl]urea (350 mg, 71.6%) as crystals. The crystals were recrystallized from ethanol to obtain colorless needles, mp: 217°-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:14](=[O:16])[CH3:15])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
A mixture of 3,5-dinitroaniline (12.8 g.) and acetic anhydride (64 ml.) was stirred during the dropwise addition of concentrated sulphuric acid (1.0 ml.). The temperature of the reaction mixture rose to about 45°C., and afer a few minutes colourless crystals were deposited. Afer 1 hour the reaction mixture was diluted with diethyl ether (200 ml.) and the crystalline solid was filtered off. Recrystallisation from a mixture of ethanol and water (2:1 by volume) gave 3',5'-dinitroacetanilide (11.5 g.) in the form of colourless plates, m.p. 191°-193°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.[ClH:37]>C(Cl)Cl.CO.O1CCOCC1>[ClH:37].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([C@H:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[OH:36])[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCNC[C@H]3O)cc1OCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108 %

Procedure:
To a solution of racemic-cis-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (92 mg, 0.186 mmol) in DCM (0.5 mL) and methanol (0.3 mL) was added slowly a solution of hydrogen chloride in dioxane (4M, 0.8 mL). The mixture was stirred at room temperature for 2 h 20 min, then concentrated in vacuo. The resultant residue was triturated twice with ether and dried under vacuum to give racemic-cis-4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (86 mg, 108%). LCMS RT=1.93, [M+H]+=395.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:11]([C:14]1[CH:25]=[C:18]2[C:19](OC(=O)[NH:23][C:17]2=[CH:16][CH:15]=1)=[O:20])([O-:13])=[O:12]>>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:25][C:18]=1[C:19]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:20]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Reactant: NOCc1ccccc1
Agent: Cl
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)NOCc1ccccc1
Yield: 71 %

Procedure:
In the same manner as Example 35(a), O-benzylhydroxylamine hydrochloride (0.52 g, 3.25 mmol) reacted with 5-nitro-isatoic anhydride (0.52 g, 2.5 mmol) to give 2-amino-5-nitro-N-benzyloxylbenzamide as a yellow solid (0.51 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+:10]([C:13]1[CH:14]=[CH:15][C:16](O)=[N:17][CH:18]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.07 g, 8.48 mmol), 5-nitro-pyridin-2-ol (1.34 g, 8.48 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMA (10 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 13A (1.01 g, 48%).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:12][C:11]1[C:2]([NH:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[CH:15]=2)(=[O:21])=[O:22])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cccc(S(N)(=O)=O)c1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 170 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A suspension of 2,3-dichloroquinoxaline (500 mg; 2.5 mmol; 1 eq), 3-methylbenzene sulfonamide (430.1 mg, 2.5 mmol, 1 eq.), dry K2CO3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5 ml) is heated up at 170° C. in the microwave for 30 min under normal absorption. The solvent is evaporated to dryness. Water (20 ml) is added then AcOH until acidic pH. The residual suspension is left at 4° C. for 1 h and the precipitate formed is filtered off, washed with water until neutral, then ACN and dried under vacuum at 40° C. overnight, to afford 548.3 mg (65%) of the title compound. 1H NMR (DMSO-d6) δ 11.53 (brs, 1H), 7.99 (m, 2H), 7.87 (t, J=8.6 Hz, 2H), 7.77 (dt, J=1.5, 7.5 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.56-7.43 (m, 2H), 2.42 (s, 3H). HPLC (max plot) 99%; Rt 3.70 min. LC/MS: (ES+): 334.2, (ES−): 332.2.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([OH:39])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C1COCC1.O>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:37])[CH3:38])=[CH:34][C:33]([O:39][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(OS(C)(=O)=O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Triethylamine (30 mg, 0.3 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (50 mg, 0.1 mmol) in THF (1 ml), then methanesulfonyl chloride (34 mg, 0.3 mmol) was dropped thereinto with ice cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:methanol=19:1) to provide 47 mg (yield 82%) of the desired compound as colorless needles.
Reaction SMILES: Cl.C(OC([O:7][CH:8]([CH:16]1[CH2:21][CH2:20][C:19]([N:27]([CH3:29])[CH3:28])([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C)C.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:29][N:27]([CH3:28])[C:19]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:17][CH:16]([CH:8]([OH:7])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccs2)(N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1(c2cccs2)CCC(C(O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 M hydrochloric acid (20 ml) was added to a solution of {4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-thiophen-2-yl-cyclohexyl}dimethylamine (1.10 g, 2.73 mmol) in tetrahydrofuran (20 ml) and the reaction mixture was stirred at room temperature overnight. It was then rendered alkaline with 4 M sodium hydroxide solution and extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (956 mg) was purified by flash chromatography with cyclohexane/ethyl acetate (3:2) and then methanol. The two product fractions obtained in this way were each taken up in diethyl ether, and 2 M hydrochloric acid (20 ml) was added. The phases were separated. The acid aqueous phases were extracted with diethyl ether (3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxide solution. The aqueous phases were extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36].O>C1COCC1>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:11](=[C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]1=[O:1])[O:12][CH2:13]2)=[O:22])[CH3:36]
Reactant: CCN(CC)CCN
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(C(=O)O)ccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A mixture of 1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-carboxylic acid (100 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in THF (10 ml) was stirred at room temperature for 16 hours. N,N-diethylethylenediamine (0.25 ml, 1.76 mmol) was added. The mixture was stirred for 15 minutes and poured into water (100 ml). The precipitates were filtered, washed with water and dried under vacuum to give the title compound as a yellow powder (99 mg, 74%).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1)OC(=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C

Procedure:
Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10% Pd—C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield). Crystals formed in the freezer, then at room temperature over several days. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40-1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49-2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
Reaction SMILES: [C:1]([N:5]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.I[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>C(OCC)(=O)C.CO.O1CCCC1>[C:1]([N:5]1[C:17]([CH2:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:39][CH2:40]2)=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc2c(n1)c(=O)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCc2c3c(nn2C(C)(C)C)c(=O)[nH]c2ccccc23)CC1
Temperature: -78 °C
Yield: 6.1 %

Procedure:
To a round-bottomed flask containing 2-tert-butyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (1.5 g, 6.2 mmol) was added tetrahydrofuran (20 mL) followed by N,N,N′,N′-tetramethylethylenediamine (3.6 g, 31.1 mmol). The reaction was stirred under nitrogen in an ice bath. To this suspension n-butyllithium (2.5 M in hexanes, 7.47 mL, 18.67 mmol) was added dropwise. The reaction mixture was cooled to −78° C. in an acetone-dry ice bath and tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (2.3 g, 6.84 mmol) was added to the reaction. The reaction was warmed to ambient temperature over 30 minutes and stirred at that temperature for another 2 hours. Methanol was carefully added to quench the reaction and the solvent was evaporated to afford a dark oil. The oil was taken up in ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was separated, dried (magnesium sulfate), filtered, and evaporated to afford a dark oil. The product was purified twice by automated flash chromatography (Combiflash Separation System, eluted with a gradient of 0-5% methanol in dichloromethane with 1% ammonium hydroxide) to provide tert-butyl 4-[2-(2-tert-butyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-ethyl]-piperidine-1-carboxylate as a gray solid (0.17 g), mp 223-225° C.; MS (ESI) m/z 453 (M+H).
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.C1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]CN1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH2:19]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:18][N:16]1[CH2:15][C:4]1[C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[NH:2][N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCN(Cc1n[nH]c3c1CCc1ccccc1-3)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.40 g), 1,2,3,4-tetrahydroisoquinoline (0.20 cm3) and diisopropylethylamine (0.28 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 24 hours, then stirred at room temperature for 48 hours. The mixture was poured into water (30 cm3) and extracted with ethyl acetate (2×20 cm3). The organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% ethanol-ethyl acetate, gave a yellow oil that crystallised on standing. The material was recystallised from ethyl acetate-hexane to give the title compound (0.111 g; 33%) as white needles, m.p. 180°-182° C. (from EtOAc-hexane); Found: C, 79.7; H, 6.7; N, 13.1. C21H21N3 requires C, 80.0; H, 6.7; N, 13.3%. δH (360 MHz; CDCl3) 2.72-2.80 (4H, m, 2 x --CH2 --), 2.90-2.98 (4H, m, 2 x --CH2 --), 3.70 (2H, s, --CH2N), 3.73 (2H, s, --CH2N), 6.99 (1H, d, J5.8, 1 of ArH), 7.10-7.28 (6H, m, 6 of ArH) and 7.79 (1H, d, J 7.3, 1 of ArH); m/z (CI+ ; NH3) 316 (MH+ ; 100%).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccc(O)cc1

Procedure:
A solution of 101 g of allylbicylo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 54.5 g of 4-aminophenol in 155 g of toluene is heated to boiling point, and the water formed during imidation is separated in a Hahn stillhead.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(Cl)c1ccc(CBr)cc1
Reaction time: 0.5 h

Procedure:
p-Bromomethyl benzoic acid (10.5 g., 0.05 moles) is charged to a round-bottom flask equipped with a magnetic stirrer. Thionyl chloride (50 ml.) is added thereto and the mixture heated under reflux with stirring. After approximately 10 minutes the solid material is dissolved. The heating under reflux is continued for an additional 30 minutes, the clear solution stoppered and cooled in a dry atmosphere. The excess thionyl chloride is removed using a rotary evaporator to yield p-bromomethyl benzoyl chloride (m.p. 56°-58°). This product is not further purified but utilized in the next stage of the reaction.