Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
N-{3-nitro-4-(3,5-bis-trifluoromethyl-benzylamino)-phenyl}-benzenesulphonamide (8.6 g, 16.6 mmol) in 200 mL methanol are refluxed and within 0.5 h combined with a solution of Na2S2O4 (14.2 g, mmol) in 50 mL water. The mixture is refluxed until totally decolorised (this takes about 1 h). After cooling the mixture is diluted with water. About 100 mL of the methanol/water mixture are distilled off, the resulting solution is cooled, the crystals precipitated are filtered off and washed with water. The crystals are dissolved in ethyl acetate, dried and evaporated down until not quite dry. After cooling the crystals precipitated are filtered off and washed with diethylether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>>[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:30]1
Reactant: CN(C)[C@H]1CCCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=13.39 Hz, 1H) 1.83 (br. s., 2H) 2.06-2.23 (m, 1H) 2.43 (s, 3H) 2.81 (br. s., 7H) 3.04-3.25 (m, 1H) 3.35-3.42 (m, 1H) 3.54 (br. s., 1H) 4.02 (br. s., 1H) 4.44 (br. s., 1H) 7.67 (d, J=8.22 Hz, 1H) 7.74 (s, 1H) 7.78 (d, J=7.83 Hz, 1H) 8.11 (dd, J=8.59, 1.77 Hz, 1H) 8.17 (br. s., 1H) 8.42 (br. s., 1H) 8.58 (d, J=1.52 Hz, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[N:22]1([S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)N3CCc4ccccc43)cc2c2cc[nH]c12
Yield: 39.7 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 62 μL (0.55 mmol) of 2,3-dihydro-1H-indole. After purification by chromatography on silica (eluent dichloromethane/methanol 96/4) then trituration in methanol, 40 mg (20%) of 8-(2,3-dihydro-indole-1-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([O:22][CH3:23])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([O:22][CH3:23])[CH:15]=1)[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12

Procedure:
A mixture of 2.15 g (5 mmol) of 4-[(3-bromophenyl)amino]-8-methoxy-6-nitro-quinoline-3-carbonitrile, 1.95 g (37.5 mmol) of ammonium chloride, and 1.26 g (22.5 mmol) iron was stirred at reflux in 40 ml of water and 40 ml of methanol for 3 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solution was concentrated and 0.43 of dark yellow solid was collected: mass spectrum (electrospray, m/e): M+H 368.9 and 370.9.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:15])[CH2:11]C(C)=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]([OH:23])[CH:17]([OH:22])[CH2:18][CH2:19][CH2:20][CH3:21].[CH3:24][C:25]1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:6][CH:7]([C:24]1([CH3:25])[O:23][CH2:16][CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[O:22]1)[CH2:8][O:9][C:10](=[O:15])[CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Solvent: c1ccccc1
Product: C=C(C)C(=O)OC(COC(C)=O)C1(C)OCC(CCCC)O1
Yield: 77 %

Procedure:
As described in Example 1, the above compound is prepared from 2-acetoacetoxyethyl methacrylate (42.8 g) and 1,2-hexanediol (26 g) in benzene (200 ml) with p-TsOH catalysis under a water separator. Yield: 77% of theory, boiling point=130°-136° C./0.02 mbar.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:17]([O-:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])([C:2]([OH:1])([CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[CH3:20]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCNc1ccccn1
Product: CCOC(=O)C(O)(CCNc1ccccn1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 3.36 g (0.01 mole) of ethyl 2-oxo-4-(2-pyridylamino)butanoate in 6.9 g (0.05 mole) of diethyl phosphite is stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chloroform/ethanol as eluant.
Reaction SMILES: [CH3:1][C:2]12[CH:16]([CH3:17])[CH2:15][C:14](C)([OH:18])[CH:13]1[CH:12]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1.CCCCCCCCCCCC(O)CCC>>[CH3:1][C:2]12[CH:16]([CH3:17])[CH2:15][CH:14]([OH:18])[CH:13]1[CH:12]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC1CC(C)(O)C2C3CCCCCCCCC3C12C
Agent: CCCCCCCCCCCC(O)CCC
Product: CC1CC(O)C2C3CCCCCCCCC3C12C

Procedure:
1,13,15-trimethyltricyclo[10.3.0.02,11 ]pentadecane-13-ol tricyclo]9.4.0.02,10 ]pentadecane-12-ol
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[C:20]#[N:21])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.[OH-:26].[Na+].OO>O.C(O)C.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[C:20]([NH2:21])=[O:26])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C#N)c3n2)cn1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C(N)=O)c3n2)cn1
Temperature: 60 °C

Procedure:
A suspension of 2-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile (see Example 1) (40 mg, 0.24 mmol), sodium hydroxide (0.5 mL, 1M in H2O) and hydrogen peroxide (0.2 mL of a 33% solution in water) in ethanol (5 mL) was heated at 60° C. for 3 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give the title product. 1H NMR (d6-DMSO) δ 9.95 (s, 1H), 8.99 (s, 1H), 8.10-8.16 (m, 3H), 7.66 (s, 1H), 7.60 (dd, 1H), 7.54 (s, 1H), 7.37-7.40 (m, 2H), 6.95 (br s, 1H), 5.85 (s, 2H), 3.88 (s, 3H); LC-MS method B, (ES+) 349.1, RT=6.46 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:14]OC(C)(C)C>C(Cl)(Cl)Cl>[Cl:14][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OCl
Reactant: N#Cc1ccc2ccc(O)cc2c1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ccc(O)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-hydroxynaphthalene-2-carbonitrile (2.23 g) in chloroform (120 ml) was dropwise added tert-butyl hypochlorite (1.64 ml) with ice-cooling, and the mixture was stirred at room temperature for 15 min. After completion of the reaction, the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (1.88 g).
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:18])=[NH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:27][C:28]([CH3:30])=[O:29]>>[C:28]([OH:2])(=[O:29])[CH3:30].[CH2:20]([NH:19][C:17]1[NH:16][C:14]([NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15][C:28]([CH3:30])([CH3:27])[N:18]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCNC(=N)NC(=N)NCCCCCCC
Reactant: CO
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCNC1=NC(C)(C)N=C(NCCCCCCC)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.7 ml of concentrated hydrochloric acid were added to 10.0 g (27.0 mmol) of N1,N5-diheptyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure. To the residue were added 100 ml of ethanol, 60 ml of water, and 10.9 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with 10% aqueous sodium acetate, washed with water, and concentrated under reduced pressure to remove the solvent. The residue was recrystallized from methyl ethyl ketone to obtain 7.3 g of colorless crystals having a melting point of 83 to 85° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH2:7][C:8]#N.[OH-:20].[Na+].[OH2:22].Cl>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH2:7][C:8]([OH:22])=[O:20]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC#N
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A mixture of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetonitrile (8.86 g, 31 mmol), sodium hydroxide (12.5 g, 314 mmol), water (160 ml) and ethanol (160 ml) was stirred vigorously at 100° C. for 2.5 h. The reaction mixture was poured onto crushed ice and aqueous HCl and extracted three times with dichloromethane. The combined extracts were washed with water and brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9.5 g (quant.) of the title compound as light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[O:27]=[C:25]1[NH:24][C:23](=[O:28])[C:22](=[CH:21][C:20]2[CH:29]=[CH:30][C:31]([N:32]3[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][CH:3]([C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[OH:4])[CH2:34][CH2:33]3)=[C:18]([F:17])[CH:19]=2)[S:26]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3F)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) and 5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 62) according to the procedure of Example 63 as a yellow solid; mp>225° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.62–1.71 (m, 2H), 2.03–2.12 (m, 2H), 2.70–2.83 (m, 3H), 2.95 (s, 3H), 3.12–3.33 (m, 2H), 3.49–3.52 (m, 2H), 4.72–4.75 (m 1H), 5.96 (brs, 1H), 6.89 (d, J=8.1 Hz, 1H), 7.05–7.13 (m, 3H), 7.25–7.38 (m, 3H), 8.70 (brs, 1H), 9.8 (brs, 1H); MS (ES) m/z: 551.0 (MH+); HRMS for C24H27FN4O6S2 (MH+): 551.1434. Found: 551.1438.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[Cl:1][C:6]1[CH:7]=[C:8]([C:5]([CH3:11])([CH3:10])[CH3:6])[C:9]([Cl:3])=[CH:10][C:5]=1[CH3:11]
Reactant: Cc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Product: Cc1cc(Cl)c(C(C)(C)C)cc1Cl
Yield: 270.8 %

Procedure:
After adding a large excess of 2000 g of toluene and 64 g (0.48 mol) of anhydrous aluminum chloride, as a catalyst, to 284 g (1.3 mol) of 2,5-dichloro-4-t-butyltoluene obtained as stated above, the mixture was brought into reaction for 5 hours at room temperature under a vigorous agitation thereof.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@@H:20]5[CH2:25][C@@:24]([O:30][Si](CC)(CC)CC)([C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C@@:21]5([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(O[C@@]1(C(F)(F)F)C[C@H]2CCCC3C(=CC4C=NN(C5C=CC(F)=CC=5)C=4C=3)[C@]2(CN2CCCS2(=O)=O)CC1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@H:20]5[CH2:25][C@:24]([OH:30])([C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C@:21]5([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@@H:20]5[CH2:25][C@@:24]([OH:30])([C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C@@:21]5([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)O[C@]1(C(F)(F)F)CC[C@@]2(CNC(C)=O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S1(=O)CCCN1C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [F-]
Solvent: ClCCl
Product: CC(=O)NC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Product: CC(=O)NC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12

Procedure:
A solution of N-(((3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)acetamide compound with N-(43 S,4aS,12bR)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)acetamide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=TES) (195 mg, 0.32 mmol) in DCM (5 mL) was treated with TBAF (1M solution in THF, 0.32 mL, 0.32 mmol) at rt for about 30 min. The reaction was diluted with DCM (10 mL), washed with water (3×5 mL), dried over Na2SO4, filtered and concentrated to solids under reduced pressure. The residue was triturated in EtOAc (˜2 mL), filtered, rinsed with heptane and dried under vacuum to yield N-(((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)acetamide; compound with N-(((3S,4aS,12bR)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)acetamide (36, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4=Acetyl) as a white solid (125 mg, 72%); LC/MS, method 4, Rt=1.55 min, MS m/z 490 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.25 (d, J=0.7 Hz, 1H), 7.81-7.73 (m, 3H), 7.55 (s, 1H), 7.44-7.35 (m, 2H), 7.07 (t, J=5.9 Hz, 1H), 5.88 (s, 1H), 4.00-3.91 (m, 1H), 3.65-3.56 (m, 1H), 3.42-3.31 (m, 1H), 3.00-2.90 (m, 1H), 2.13-1.94 (m, 3H), 1.95-1.77 (m, 4H), 1.71-1.61 (m, 3H), 1.59 (s, 3H), 1.45-1.32 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH2:13](Br)[CH2:14][C:15]([CH3:17])=[CH2:16]>[OH-].[K+]>[OH:1][C:2]1[C:7]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[C:6]([OH:8])[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: C=C(C)CCBr
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
1-(2,4,6-trihydroxyphenyl]ethanone (2.0 mg, 11.9 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20 mL). After the mixture was cooled below 0° C., isopentenyl bromide (3.6 g, 24 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.7 g, yield 20%).
Reaction SMILES: BrCC[CH2:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8].[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=1>>[OH2:8].[N:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2([CH2:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=1.[N:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2([CH2:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2Cc1ccncc1
Reactant: NC(=O)CCCCCBr
Product: NC(=O)CCCC1(Cc2ccncc2)c2ccccc2-c2ccccc21
Product: O
Yield: 100 %

Procedure:
By substituting 4-bromobutyl acetamide and 9-(4-pyridinylmethyl)-9H-fluorene in Ex. 1, the product was obtained in 100% yield; mp 50°-52° C.
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)=[CH:7][CH:6]=1)#[N:4].OO>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)=[CH:9][CH:10]=1)(=[O:1])[NH2:4]
Reactant: Cc1[nH]n(Cc2ccc(C#N)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Product: Cc1[nH]n(Cc2ccc(C(N)=O)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
A solution of potassium hydroxide (0.24 g, 3.7 mmol) in water (10 ml) was stirred in an ice-bath for 30 minutes and 1-(4-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (0.42 g, 1.2 mmol) was added, followed by 30% hydrogen peroxide (0.6 ml, 6.1 mmol). The reaction mixture was stirred for 4 hours, warmed to room temperature and stirred for 24 hours. The reaction mixture was filtered, and the filtrate was neutralized with acetic acid to afford a white precipitate. The product was collected by filtration and washed with water, ethanol and ether. The product was recrystallized in DMF to afford 0.2 g (46%) of 1-(4-carbamoylphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a fluffy white powder, m.p. >300° C. when dried at 120° C. for 24 hours in high vacuum.
Reaction SMILES: NN[C:3](=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=CC=1Cl)[C:4]1C=CC(S(C)(=O)=O)=CC=1.[O:22]=S(Cl)Cl.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].C(N(CC)CC)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:18](=[O:22])[C:19]1[CH:4]=[CH:3][N:14]=[CH:15][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccccc1Cl
Reactant: CS(=O)(=O)c1ccc(C(=Nc2ccccc2Cl)NN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1Cl)c1ccncc1
Reaction time: 2 h

Procedure:
A mixture of isonicotinic acid 5 (1.0 g, 8.12 mmol) and SOCl2 (2.4 mL) in DCM (10 mL) was stirred for 2 hours and concentrated. The residue was dissolved in DCM (20 mL). To the solution was added 2-chlorobenzenamine (1.7 g, 8.15 mmol) and then triethylamine (1.4 mL, 10 mmol). The reaction mixture was stirred overnight at ambient temperature and ethyl acetate (50 mL) was added followed by 1N HCl (10 mL). The organic phase was washed with water and brine, dried and concentrated under reduced pressure to yield a light yellow solid. Yield: 1.5 g, 80%. N-(2-chlorophenyl)isonicotinamide 6 was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH2:35][O:36][CH2:37][C@@H:38]([NH:40][CH:41]([CH3:43])[CH3:42])[CH3:39]>>[CH3:48][O:47][C:45]1[CH:44]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[CH:46]=1)[CH2:35][O:36][CH2:37][C@@H:38]([N:40]([CH:41]([CH3:43])[CH3:42])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:39]
Reactant: COc1cc(COC[C@H](C)NC(C)C)cc(OC)c1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3cc(OC)cc(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and [(S)-2-(3,5-dimethoxy-benzyloxy)-1-methyl-ethyl]-isopropyl-amine as described for example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of 1.5 g of methyl 6-amino-pyridine-3-carboxylate in 100 ml of methylene chloride is added 3 ml of N,N-diisopropylethylamine at room temperature. To the stirred reaction mixture is slowly added a solution of 2.5 g of [1,1'-biphenyl]-2-carbonyl chloride. The reaction mixture is stirred at room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo to a solid residue. The residue is stirred with ether, filtered and dried to give 3.0 g of the desired product: M+ =332.