Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:46][C:47]1[CH:51]=[CH:50][N:49]([CH2:52][C:53]([CH3:56])([OH:55])[CH3:54])[N:48]=1>ClCCl>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][N:49]1[CH:50]=[CH:51][C:47]([NH:46][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:2]=3[Cl:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:48]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A solution of (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (200 mg, 0.57 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96 mg, 0.62 mmol) and 1-hydroxybenzotriazole (80 mg, 0.60 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 105 mg, 0.68 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-Chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (198 mg, 71%) as an off-white solid: LR-ES-MS m/z calculated for C24H31ClN4O5 [M]− 490, observed [M+H]+ 491; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.43 (br. s., 1H), 1.48-1.65 (m, 1H), 1.68-1.84 (m, 1H), 3.89 (br. s., 2H), 3.90 (s, 3H), 4.19 (d, J=18.6 Hz, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.68 (s, 1H), 4.80 (s, 1H), 4.89 (dd, J=10.9, 4.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.09 (dd, J=8.5, 1.3 Hz, 1H), 7.13 (dd, J=8.5, 1.3 Hz, 1H), 7.41 (t, J=8.5 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: N#N.Br[C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[S:15]1[C:19]([C:4]2[C:5]([O:13][CH3:14])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=2)[CH:9]=[O:10])=[CH:18][C:17]2[CH:5]=[CH:4][CH:11]=[CH:8][C:16]1=2
Reactant: COc1cc(O)c(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(O)c(C=O)cc1-c1cc2ccccc2s1
Yield: 170.1 %

Procedure:
Ex-62B: A stream of N2 was bubbled through a solution of 5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A in 30 mL of ethylene glycol dimethyl ether for 15 min. Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was added along with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10 mL of Na2CO3 (2M aqueous solution). The resulting mixture was stirred under reflux overnight. The solvent was removed by rotary evaporation and the residue was treated with saturated NaHCO3 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, and filtered to remove drying agent. Solvent was removed by rotary evaporation. Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1) gave 1.04 g of the desired 5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde.
Reaction SMILES: C([O:4][C@H:5]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]([NH:8][C:9]1[C:10]([O:21][CH3:22])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C@H:5]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]([NH:8][C:9]1[C:10]([O:21][CH3:22])=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:14]=1)=[O:7]
Reactant: COc1ncc(-c2ccncc2)cc1NC(=O)[C@@H](Cc1ccccc1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ncc(-c2ccncc2)cc1NC(=O)[C@H](O)Cc1ccccc1
Reaction time: 1 h
Yield: 76.2 %

Procedure:
The mixture (R)-1-(2-methoxy-5-(pyridin-4-yl)pyridin-3-ylamino)-1-oxo-3-phenylpropan-2-yl acetate 11.1.E (1500 mg, 3832 μmol) was dissolved in 22 mL MeOH. Potassium carbonate (1059 mg, 7664 μmol) was added to the mix. The reaction was stirred for 1 hour. LC/MS showed the product and trace starting material. Filtered, concentrated and worked up between DCM and water to afford 1.4 g of crude mix. Used DCM to rinse and filtered. The solids are purer by TLC. 1.02 g of 11.1.F was obtained.
Reaction SMILES: C(N)CC1C=CC=CC=1.C1(CO[C:18]2[CH:27]=[CH:26][C:25]3[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][CH:18]=1
Reactant: O=C1CCCc2nc(OCc3ccccc3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of phenethylamine (5.0 g), 5,6,7,8-tetrahydro-2-(phenylmethoxy)-5-oxoquinoline (10.0 g), and a catalytic amount of para-toluenesulfonic acid (206 mg) was heated under reflux in toluene (200 ml) with azeotropic removal of water for 36 hrs. The solution was cooled and washed with water. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Sodium borohydride (1.4 g) was added to a solution of the residue and ethyl alcohol (125 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to afford 12.5 g (92%) of 5,6,7,8-tetrahydro-5-(2-phenethylamino)-2-phenylmethoxy)quinoline.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15](F)=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH2:30](N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.O>CN1CCCC1=O>[CH:37]1([S:40]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NS(=O)(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were added triethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204 mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and recrystallized from hexane/ethyl acetate to give the title compound (74 mg, 16%) as a white powder.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:11][C:6]2(OCC[O:7]2)[CH2:5][C@@H:4]1[C:12]1[N:16]2[C:17]3[CH:23]=[CH:22][N:21]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:18]=3[N:19]=[CH:20][C:15]2=[N:14][N:13]=1)[CH3:2].Cl>C1COCC1>[CH2:1]([CH:3]1[CH:4]([C:12]2[N:16]3[C:17]4[CH:23]=[CH:22][N:21]([S:24]([C:27]5[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=5)(=[O:26])=[O:25])[C:18]=4[N:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:5][C:6](=[O:7])[CH2:11]1)[CH3:2]
Reactant: CC[C@@H]1CC2(C[C@@H]1c1nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n13)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A round bottom flask was charged with 1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (3.56 g, 7.61 mmol) and THF (20 mL). To the solution was added aqueous HCl (6N, 3.81 mL, 22.8 mmol) and the mixture was stirred at rt for about 2 h. The solvent was removed under reduced pressure and DCM (75 mL) and water (50 mL) were added. The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone as a brown foam (2.99 g, 93%): LC/MS (Table 1, Method c) Rt=1.40 min; MS m/z: 424 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[OH:21])=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Brc1ccncc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-bromopyridine (0.78 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2.0 Min tetrahydrofuran, 2.5 mL, 5.0 mmol) via syringe under nitrogen at room temperature. The reaction mixture was stirred for one hour. To the reaction mixture was then added bis(4-fluorophenyl)methanone (0.98 g, 4.5 mmol) dissolved in tetrahydrofuran (7 mL) via syringe. The reaction mixture was stirred overnight, quenched with a saturated aqueous solution of ammonium chloride (10 mL), and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave bis(4-fluorophenyl)(pyridin-4-yl)methanol on (0.73 g, 2.45 mmol).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[C:34]([NH:41][CH2:42][C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[NH:41][CH2:42][C:43]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[C:6]([C:4](=[O:5])[N:3]([CH3:33])[CH3:2])[N:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[C:9]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: Cl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1

Procedure:
By repeating procedures described in Example 88, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol), N-BOC-glycine (56 mg, 0.318 mmol) gave a crude product which is purified by SiO2 chromatography, eluting with 0-7% methanol/dichloromethane to give (2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:31])[O:27][C@@H:28]([CH2:29][OH:30])[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:32]=2)[C:13](=[O:33])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:31])[O:27][C@@H:28]([CH2:29][O:30][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:32]=2)[C:13](=[O:33])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CO)OC(=O)N32)C(=O)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OC[C@@H]1OC(=O)N2c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4=O)cc3OC[C@@H]12
Yield: 82.5 %

Procedure:
Using compound 4-((3R,3 aS)-3-(hydroxymethyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-3-oxopiperazin-1-carboxylic acid benzyl ester (0.946 g, 2.088 mmol), methylsulfonyl chloride (0.359 g, 3.13 mmol), and TEA (0.422 g, 4.18 mmol) as starting materials, preparation following the method as described in Example 1 (c) afforded white solid 0.916 g, yield: 82.52%.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[C:16]([F:28])[CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH:12]=2)=[CH:15][C:16]=1[F:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Yield: 77.9 %

Procedure:
Dissolve tert-butyl N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-2-fluoro-phenyl]carbamate (12.14 g, 31.28 mmol) in DCM (280 mL), add trifluoroacetic acid (35 mL). Stir the reaction at room temperature for 5 hrs. Remove the volatiles under reduced pressure. Add EtOAc (300 mL), washed with saturated NaHCO3 solution (300 mL×2), and brine (300 mL×2). Dry the organic layer with anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (7 g, 78.4%). MS: (M+1): 288.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([NH:16][C:15]2[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=2)=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1scc(Br)c1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1scc(Br)c1O
Yield: 82.4 %

Procedure:
Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:41]O>>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:41])=[O:34])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 62 %

Procedure:
The title compound (1.03 g, 62%) was prepared from 3,4,5-triphenyl-lH-pyrazole-1-decanoic acid (1.60 g) by esterification in methanol using a catalytic amount of conc. sulfuric acid. MS(CI): m/e =481 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][N:27]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][CH2:15][CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:14]([C:13]1[N:27]([OH:26])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH3:16]
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1O
Product: CCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-(4-chloroquinolin-3-yl)butyramide (20.0 g, 80.4 mmol) and O-benzylhydroxylamine hydrochloride (16.0 g, 0.100 mol) in ethanol (150 mL) was heated at reflux overnight and allowed to cool to room temperature. A precipitate was present, and the mixture was cooled to approximately 0° C. The precipitate was collected by filtration and purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent) to provide 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinoline and 2-propyl-1H-imidazo[4,5-c]quinolin-1-ol.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[C:8]([O:14][CH3:15])[CH:7]=[CH:6]2)[CH3:2].C[O:17][CH:18](Cl)Cl.[OH2:21]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([O:14][CH3:15])[C:7]([OH:21])=[C:6]2[CH:18]=[O:17])=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(Cl)Cl
Reactant: O
Reactant: CCc1ccc2c(O)c(OC)ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc2cc(OC)c(O)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.3 g of 6-ethyl-2-methoxy-1-naphthol was dissolved in 25 ml of dichloromethane and cooled to 0° C. 3.65 ml of titanium tetrachloride and 2.4 ml of dichloromethyl methyl ether were added successively at that temperature and stirred for 10 min. After the reaction was over, water was added and the solution was extracted with ethyl acetate. After washing the extract with an aqueous saturated solution of sodium chloride, it was dried over anhydrous magnesium sulfate. When the solvent was distilled off and deposited crystals were washed with isopropyl ether, 2.5 g of the above-captioned compound was obtained as brown crystals.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]([S:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:7].Cl>O1CCCC1.CO.O>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][S:8][CH:6]([CH3:7])[C:5]([OH:35])=[O:4])[CH:15]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1)C(=O)O
Temperature: 25 °C

Procedure:
2N Sodium hydroxide solution (0.33 mL, 0.66 mmol) was added dropwise to a stirred solution of methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (5 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound has a white solid (86 mg, 89%); Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (DMSO-d6): □ 8.19 (2H, m, Ar—H), 8.02 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.75 (4H, m, Ar—H), 7.29-7.41 (5H, m, Ar—H), 3.96 (2H, s, PhCH2S), 3.36 (1H, q, J=7 Hz, SCHMe), 1.36 (3H, d, J=7 Hz, CHMe); ESI-LCMS e/z calcd for C28H22O3S 438.54, found 439 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[C:20](OCC)(=O)[CH:21]=[O:22].O.Cl>[Na].CO>[NH2:17][C:15]1[C:14]2[N:18]=[CH:20][C:21](=[O:22])[NH:19][C:13]=2[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product of step (c) (100 mg) was dissolved in a solution of sodium (0.05 g) in methanol (5 ml). This was left to stir for 15 min at room temperature, then ethyl glyoxalate (134 μl) was added to the mixture which was left to stir for 12 hr at room temperature. Water (5 ml) was added, then concentrated hydrochloric acid was slowly added to acidify the solution to ˜pH5 whereupon a solid precipitated which was isolated by filtration and dried over P2O5 at 50° C. to yield a pale yellow solid (44.5 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])C.[OH-].[K+].C(O)(=O)C.O>C(O)C>[CH:23]1[CH2:24][CH2:25][CH:20]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:18]([CH3:19])[C:17]3=2)[CH2:21][CH:22]=1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4CC=CCC4)cc3c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)O)ncc2[nH]c3ccc(C4CC=CCC4)cc3c12
Yield: 94.2 %

Procedure:
440 mg (1.31 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated under reflux for one hour in 20 ml of ethanol with 3.25 ml of 1N potassium hydroxide solution. After neutralizing with acetic acid and addition of 10 ml of water, the precipitated product is suctioned off, washed with water, and dried under vacuum over potassium hydroxide, thus obtaining 378 mg (94% of theory) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid, mp 284°-285° C.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([C@@H:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: N[C@@H](Cc1ccccc1)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N[C@@H](Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 91 %

Procedure:
The title compound was prepared in a yield of 91% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (S)-1,2-diphenylethylamine.