Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Br[CH2:43][CH2:44]Cl.P(=O)(O)(O)O.[K]>C(#N)C>[N:1]1([C@:2]23[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:35])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:44][CH2:43]1
Reactant: ClCCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 100.3 %

Procedure:
To a sealable vial was added ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.2 g, 0.356 mmol), 1-bromo-2-chloroethane (0.295 mL, 3.56 mmol) and phosphoric acid, potassium salt (0.378 g, 1.780 mmol). The mixture was diluted with acetonitrile (5 mL), was flushed with nitrogen, then sealed and heated to 120° C. After 24 h of heating, the mixture was cooled to rt. The reaction mixture was filtered to remove solids, then the solids were washed with dichloromethane and the filtrate was concentrated under reduced pressure to give the title compound (0.21 g, 0.357 mmol, 100% yield) as an off-white solid. LCMS: m/e 588.7 (M+H)+, 2.21 min (method 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([C:19](=[O:33])[NH:20][C@@H:21]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:15]2[C:10](=[C:11]([F:34])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:35])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH-].[K+].I[CH2:47][CH2:48][CH2:49][F:50]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:1]([O:5][C:6](=[O:36])[N:7]([N:8]1[C:17]([CH3:18])=[C:16]([C:19](=[O:33])[NH:20][C@@H:21]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:15]2[C:10](=[C:11]([F:34])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:35])[CH2:47][CH2:48][CH2:49][F:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: FCCCI
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1N(CCCF)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 135.6 %

Procedure:
To (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (0.5000 g, 1.005 mmol; prepared as described in example 8) and tetra-N-butylammonium bromide (0.340 g, 1.05 mmol) in toluene (10 mL, 90 mmol) was added potassium hydroxide (84.6 mg, 1.51 mmol) (powdered). The reaction was stirred at 50° C. for 10 minutes. 1-Iodo-3-fluoropropane (0.525 g, 2.79 mmol) was added and the reaction mixture was stirred for 1 hour at 50° C. The temperature was raised to 80° C. and the reaction mixture was stirred for another for 2 hours. The reaction mixture was cooled to room temperature and washed with 50 ml of water, dried over MgSO4 and was concentrated in vacuo to give 0.76 g (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester as an oil. The Boc-protection group was removed analogously to the method described in example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[S:8][C:9](C(O)=O)=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].N1C2C(=CC=CC=2)N=CC=1.Cl>[Cu].CCOCC>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Cu]
Agent: Cl
Agent: c1ccc2nccnc2c1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2sccc2c1
Temperature: 190 °C
Reaction time: 0.67 h
Yield: 67.4 %

Procedure:
Copper (8.18 g, 0.129 mol) was added to a mechanically stirred slurry of 5-nitrobenzo[b]thiophene-2-carboxylic acid (28.73 g, 0.129 mol) and quinoxaline (160 mL). The thick mixture was heated to 190° C. Upon heating, stirring became easier, and at around 170° C. gas evolution was observed. Gas evolution ceased after 40 min and the reaction mixture was allowed to cool to r.t. overnight. The mixture was then poured over crushed ice and acidified with concentrated hydrochloric acid. The resulting brown suspension was warmed with diethyl ether (4×400 mL). The ether layers were combined, washed with 2 N aqueous hydrochloric acid (300 mL), water (300 mL) and brine (300 mL), and then separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude yellow solid (26 g) was recrystallized from hot acetone (175 mL) to yield 5-nitrobenzo[b]thiophene (15.58 g, 68%) as pale yellow crystals. 1H NMR δ (d6-DMSO, 400 MHz) 7.63 (d, J=5.5 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 8.08 (dd, J=9, 2 Hz, 1H), 8.20 (d, J=9 Hz, 1H), 8.75 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:34])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:25])=[O:34])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCS(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.80 mmol) and chloroform (14 mL). Solid 3-chloroperbenzoic acid (0.69 g, 3.09 mmol) was added portion wise over 5 minutes and the reaction was stirred at ambient temperature for 20 minutes at which time the starting material was completely consumed. The solution was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford an off-white solid which was shown by 1H-NMR to be the 3-chlorobenzoic acid salt of the desired product. The solid was stirred in water and then made basic (pH 10) by addition of solid sodium carbonate. The resulting free base was collected by filtration to provide a white solid which was recrystallized from acetonitrile to give 2-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.07 mmol) as a white powder, m.p. 119-121° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:24]=[CH:23][C:22]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:19]=4)[C:14](=O)[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:37].P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[Cl:37][C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:13]=1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:24]=[CH:23]3)=[CH:19][C:18]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2
Reactant: O=C(CCN1CCCC1)Nc1ccc2c(=O)c3cc(NC(=O)CCN4CCCC4)ccc3[nH]c2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCN1CCCC1)Nc1ccc2c(Cl)c3cc(NC(=O)CCN4CCCC4)ccc3nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A suspension of 2,6-bis(3-pyrrolidinopropionamido)acridone AR-ACO-10 (2.0 g, 4.2 mmol) in CHCl3 (40 mL) was treated with phosphorus pentachloride (0.9 g, 4.2 mmol), followed by cautious addition of phosphorus oxychloride (50 mL). This suspension was stirred at room temp. for 30 min and brought to a gentle reflux over 1 hr. Gentle reflux was maintained for 26 hr. The reaction mixture was cooled to rt then slowly dropped onto ice (˜600 mL) over 10 min. The aqueous mixture was made basic to pH 7/8 with ammonia whilst maintaining a temp. <25° C. The aqueous layer was extracted with CHCl3 (5×200 mL). The organic extracts were combined, washed with brine (200 mL), dried (Na2SO4) and concentrated. The resulting solid was tritrated with diethyl ether (30 mL) to give the desired product (1.3 g, 62%) as a light brown solid.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]CC)=O)=[N:5][C:4]([C:12]([O:14]CC)=O)=[N:3][C:2]=1[C:17]([O:19]CC)=O.[CH3:22][O:23][N:24]1[C:29]([CH3:31])([CH3:30])[CH2:28][CH:27]([NH:32][CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:41][CH3:42])[C:35]([CH3:44])([CH3:43])[CH2:34]2)[CH2:26][C:25]1([CH3:46])[CH3:45]>>[CH3:42][O:41][N:36]1[C:37]([CH3:40])([CH3:39])[CH2:38][CH:33]([N:32]([CH:27]2[CH2:28][C:29]([CH3:31])([CH3:30])[N:24]([O:23][CH3:22])[C:25]([CH3:46])([CH3:45])[CH2:26]2)[C:17]([C:2]2[N:1]=[C:6]([C:7]([N:32]([CH:27]3[CH2:28][C:29]([CH3:31])([CH3:30])[N:24]([O:23][CH3:22])[C:25]([CH3:46])([CH3:45])[CH2:26]3)[CH:33]3[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:41][CH3:42])[C:35]([CH3:44])([CH3:43])[CH2:34]3)=[O:9])[N:5]=[C:4]([C:12]([N:32]([CH:33]3[CH2:34][C:35]([CH3:44])([CH3:43])[N:36]([O:41][CH3:42])[C:37]([CH3:40])([CH3:39])[CH2:38]3)[CH:27]3[CH2:26][C:25]([CH3:46])([CH3:45])[N:24]([O:23][CH3:22])[C:29]([CH3:30])([CH3:31])[CH2:28]3)=[O:14])[N:3]=2)=[O:19])[CH2:34][C:35]1([CH3:44])[CH3:43]
Reactant: CON1C(C)(C)CC(NC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Product: CON1C(C)(C)CC(N(C(=O)c2nc(C(=O)N(C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)nc(C(=O)N(C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)C2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and bis(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)amine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8].Cl>C(O)C.[Pd].O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nccs2)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)Nc2nccs2)c1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a suspension of 1-(thiazol-2-ylaminosulphonyl )-3-nitrobenzene (0.5 g, 1.8 mmol) in ethanol (50 ml) was added 10% palladium on carbon. (0.25 g, 50% (w/w)) in water (2 ml) and 5M hydrochloric acid (1 ml, 5 mmol). The mixture was hydrogenated at 45 psi for 3 h. The catalyst was filtered off and washed with ethanol. The solvents were evaporated in vacuo and the residue chromatographed on silica gel using 10% methanol in dichloromethane as the eluant to afford the product (0.34 g, 76%) as a pale yellow solid. mp 187°-190° C. 1H NMR (360 MHz, D6 -DMSO) δ 5.49 (2H, brs), 6.66-6.73 (1H, m), 6.80 (1H, d, J=4.6 Hz), 6.85-6.90 (1H, m), 6.98-7.02 (1H, m), 7.11 (1H, dd, J=7.9 and 7.9 Hz), 7.22 (1H, d, J=4.7 Hz), 12.59 (1H, brs).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu].CN(C=O)C>[C:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(N(c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)c2cccc3ccccc23)cc1
Temperature: 200 °C
Yield: 55.8 %

Procedure:
To 32.4 g (148 mmol) of N-phenyl-1-naphthylamine were added 25.1 g (61.5 mmol) of 4,4′-diiodobiphenyl, 2.14 g of polyethylene glycol (PEG-6000 (a trade name) manufactured by Wako Junyaku K.K.), 17.1 g (0.124 mol) of potassium carbonate and 15.7 g (247 mmol) of copper (powder) were added, and heated to 200° C. The reaction was traced by high-performance liquid chromatography. Heating was continued under stirring until the peaks of raw materials and intermediates were disappeared (for 12 hours). After the completion of the reaction, water and DMF are added, and the resulting mixture is dispersed, filtrated, and washed with water. The resulting crystal is purified by silica gel chromatography to afford 20.2 g (yield: 55.9%) of N,N′-di(l-naphthyl)-N,N′-diphenyl-4,4′-diaminobiphenyl represented by the formula:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][N:12](CC2C=CC(OC)=CC=2OC)[CH2:11][N:10]([C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])[CH:29]=2)[C:9]1=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH2:1]([N:8]1[CH2:13][NH:12][CH2:11][N:10]([C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])[CH:29]=2)[C:9]1=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CN(Cc3ccccc3)C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2CNCN(Cc3ccccc3)C2=O)cn1
Yield: 57.6 %

Procedure:
1-benzyl-5-(2,4-dimethoxybenzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinan-2-one (example 9-6a) (44 mg, 0.09 mmol), anisole (9 mg, 0.09 mmol), and 50% trifluoroacetic acid/dichloromethane solution (1 mL) in dichloromethane (1 mL) were stirred at room temperature for 2 hours. The reaction was concentrated, quenched with saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (2×, 50 mL) and washed with brine (50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and, concentrated. Purification by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) afforded 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinan-2-one (19 mg, 62%) as a white solid. LC/MS; [M+H] calculated for C19H22N6O2; expected 367.18. Found 367.20. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 5.84 μM.
Reaction SMILES: BrC1SC2C(O)=C(C(=O)CCC=O)C(=O)N(C)C=2C=1.[O:20]1CCC[O:22][CH:21]1[CH2:26][CH2:27][C:28]([C:30]1[C:35](=[O:36])[N:34]([CH3:37])[C:33]2[CH:38]=[C:39]([Br:41])[S:40][C:32]=2[C:31]=1[OH:42])=[O:29]>C(O)(=O)C>[Br:41][C:39]1[S:40][C:32]2[C:31]([OH:42])=[C:30]([C:28](=[O:29])[CH2:27][CH2:26][C:21]([OH:22])=[O:20])[C:35](=[O:36])[N:34]([CH3:37])[C:33]=2[CH:38]=1
Reactant: Cn1c(=O)c(C(=O)CCC2OCCCO2)c(O)c2sc(Br)cc21
Agent: Cn1c(=O)c(C(=O)CCC=O)c(O)c2sc(Br)cc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2sc(Br)cc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-(2-Bromo-7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl)-4-oxobutanal. To 6-(3-(1,3-dioxan-2-yl)propanoyl)-2-bromo-7-hydroxy-4-methylthieno[3,2-b]pyridin-5(4H)-one (155 mg, 385 μmol) was added 80% aqueous acetic acid (7.7 mL), and the resulting mixture was stirred for 2 hours at 100° C. The reaction product precipitated on addition of water, and was filtered and then dried in a vacuum oven to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=2)[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
Triethylamine (1.55 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under water. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (4.8 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.96 (s, 6H), 4.84 (s, 2H), 6.9 (d, 1H), 7.26 (m, 3H), 7.5-7.7 (m, 3H), 7.8-8.1 (m, 4H), 9.97 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−H− 420.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.BrC1C=CC([C:25](OC)=[O:26])=C(CBr)C=1.Cl.NC(COC)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:17][O:26][CH3:25])[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COCC(N)C(=O)OC
Agent: Cl
Product: COC[C@@H](C(=O)OC)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 383 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 2-amino-3-methoxypropanoate hydrochloride.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([OH:40])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([O:40][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](O)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Yield: 84.8 %

Procedure:
A solution of p-toluenesulphonyl chloride (650 mg, 3.4 mmol) in pyridine (10 ml) was added dropwise to a mixture of the 20,20-Ethylenedioxypregna-5,14-diene-3β,12β-diol 12-acetate (22) (1.3 g, 3.1 mmol) in pyridine (15 ml) at 0° C. The reaction mixture was left stirring at room temperature for 24 hours after which water was added to the reaction mixture. The solution was extracted with ethyl acetate (2×50 ml), the ethyl acetate layer was washed citric acid (5×50 ml), saturated sodium bicarbonate solution (100 ml), saturated sodium chloride solution (100 ml) and water (100 ml) The ethyl acetate was dried (MgSO4), filtered, and evaporated and purified by flash column chromatography using hexane-ethyl acetate (8:2 v/v) as the eluant to give the β-O-tosyl steroid (26), (1.5 g, 84%), as a yellow oil, (Found M 570.271, C32H42O7S requires: M 570.273).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)SC2CCCCC2)cc1OC
Yield: 66.3 %

Procedure:
The procedure of Example 3 is repeated using 2.7 g of α-(5-chloropentyl)-α-(cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile and 2.53 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.5 g of the desired product as a light yellow oil.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]2[CH:17]=[CH:18][N:19]=[C:13]2[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-].[K+].Cl>CO>[N:19]1[CH:18]=[CH:17][N:14]2[CH:15]=[CH:16][C:11]([C:9]([OH:10])=[O:8])=[CH:12][C:13]=12
Reactant: O=C(OCc1ccccc1)c1ccn2ccnc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2ccnc2c1
Yield: 97.3 %

Procedure:
A solution of 0.16 g (0.634 mmol) of benzyl-imidazo[1,2-a]pyridine-7-carboxylate and 1.5 mL of a 1M aqueous solution of KOH (1.6 mmol) in 4 mL of CH3OH was stirred at rt for 2 h. The reaction mixture was made acidic with 1N HCl and partitioned between water and CH2Cl2. The organic fraction was dried over MgSO4 filtered and the filtrate was concentrated to give 0.1 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][C:25]2[C:33]3[N:32]=[CH:31][N:30]([CH2:34][C:35]4[C:43]5[C:38](=[N:39][C:40]([NH:44]CC6C=CC(OC)=CC=6)=[CH:41][CH:42]=5)[N:37](CC5C=CC(OC)=CC=5)[N:36]=4)[C:29]=3[CH:28]=[CH:27][C:26]=2[Cl:63])[CH:23]=1)[C:19]#[N:20]>FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:44][C:40]1[N:39]=[C:38]2[NH:37][N:36]=[C:35]([CH2:34][N:30]3[C:29]4[CH:28]=[CH:27][C:26]([Cl:63])=[C:25]([O:24][C:22]5[CH:21]=[C:18]([CH:17]=[C:16]([Cl:15])[CH:23]=5)[C:19]#[N:20])[C:33]=4[N:32]=[CH:31]3)[C:43]2=[CH:42][CH:41]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4cnc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2ncn3Cc2n[nH]c3nc(N)ccc23)c1

Procedure:
A solution of 3-chloro-5-{[5-chloro-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)-1H-benzimidazol-4-yl]oxy}benzonitrile bis(trifluoroacetate) (39 mg, 0.042 mmol) in trifluoroacetic acid (2 mL) was heated to 70° C. for 4 hours. After this time, the solvent was removed in vacuo and the residue was purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the desired compound.