Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>C(O)C>[OH:3][N:2]=[C:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[CH2:9][CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NO
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC1CCCC1=NO
Temperature: 25 °C
Yield: 84 %

Procedure:
Namely, to a solution of 50 ml (0.35 mol) of ethyl cyclopentanone-2-carboxylate in 130 ml of dioxane was added 3.8 ml of Triton B. Then, to the solution was added 27.1 ml (0.242 mol) of acrylonitrile in 50 ml of dioxane. The solution was stirred at room temperature for 12 hours, and extracted with ether after 100 ml of 10% hydrochloric acid was added thereto. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, 300 ml of conc. hydrochloric acid was added to the residue and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ether and 5% aqueous solution of sodium hydroxide was added to the ether layer and the mixture was stirred. An aqueous layer was made acidic with addition of 10% hydrochloric acid, and then the mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, the residue was dissolved in 150 ml of ethanol and 10 ml of conc. sulfuric acid was added thereto. The mixture was heated under reflux for 14 hours, and then ethanol was removed therefrom after cooling, and ethyl acetate was added thereto. The mixture was washed with 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 45 g (yield 70%) of ethyl 2-oxocyclopentanepropionate from hexane-ethyl acetate (4:1) eluate. In 150 ml of 80% ethanol was dissolved 5.5 g (30 mmol) of this compound. To the solution were added 4.17 g (60 mmol) of hydroxylamine hydrochloride and 2.7 g (33 mmol) of sodium acetate and the mixture was stirred at room temperature over night. After removing ethanol, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 5 g (yield 84%) of ethyl 2-hydroxyiminocyclopentanepropionate from hexane-ethyl acetate (6:1) eluate. In 15 ml of anhydrous ethanol was dissolved 4.4 g of this compound and the solution was stirred at 50° C. for 4 hours under a hydrogen pressure of 120 atm. with use of Raney nickel (W2) as a catalyst. After removing Raney nickel by filtration and removing the solvent, the resulting residue was chromatographed over silica gel to obtain 0.95 g (yield 31%) of 2-azabicyclo-[4.3.0]-nonane-3-one from ethyl acetate eluate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: Nc1cnccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cnccc12
Temperature: 16 °C
Yield: 72 %

Procedure:
A mixture of 3-amino isonicotinic acid (485 mg, 3.51 mmol) in formamide (3 mL) is heated to 16° C. for 12 h. Upon cooling, the resulting solid is filtered and washed with H2O and dried in a vacuum oven to yield 3H-pyrido[3,4-d]pyrimid-4-one (373 mg, 72%). 1H NMR (DMSO) δ 12.60 (1H, brs), 9.06 (1H, s), 8.68 (1H, d, J=5.3 Hz), 8.23 (1H, s), 7.96 (1H, d, J=5.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31](SC)[N:32]=[CH:33][C:22]=4[C:21]3=[O:36])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1.C(=O)(O)[O-].[Na+].[CH2:53]([NH2:55])[CH3:54].C1COCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N+:11]([O-:45])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:55][CH2:53][CH3:54])[N:32]=[CH:33][C:22]=4[C:21]3=[O:36])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc([N+]3([O-])CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
(S)-5-[3-(4-Tert-butoxycarbonylpiperazine-1-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.560 g, 1.097 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding 3-chloroperbenzoic acid (65%, 0.873 g, 3.29 mmol). A saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in THF (5 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ethylamine/THF solution (5.5 mL, 11.0 mmol). The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to give (S)-4-tert-butoxycarbonyl-1-[3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]piperazine-1-oxide (0.338 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3]([F:18])=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[C:10]([C:11](=[CH:19][O:20][CH2:21][CH3:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:17]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A mixture of 2.3 g (8.2 mmol) of ethyl β-(3-chloro-2,4,5-trifluorophenyl)-β-oxopropionate, 2 ml of triethyl orthoformate, and 20 ml of acetic anhydride is refluxed for 21/2 hours. The reaction mixture is cooled to room temperature and concentrated to give 2.7 g of the title compound as a red oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[F:15][C:16]1([C@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[F:15][C:16]1([C@H:19]([NH:21][C:2]2[C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:6][C:7]=2[C:8]([NH2:10])=[O:9])[CH3:20])[CH2:18][CH2:17]1
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: C[C@@H](N)C1(F)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C1(F)CC1
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 3, 20 mg, 0.102 mmol), (R)-1-(1-fluorocyclopropyl)ethanamine hydrochloride (22 mg, 0.153 mmol), and diisopropylethylamine (0.054 mL, 0.31 mmol) in NMP (0.5 mL) was heated to 120° C. for 10 min in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 4 mg (14%) of a pale yellow solid as the title compound. HPLC (condition B): retention time=3.26 min. LCMS (condition B): MH+ m/z 263.2. 1H NMR (500 MHz, MeOD) δ ppm 8.17 (1 H, s), 7.64 (1 H, dd, J=2.64, 1.53 Hz), 7.27 (1 H, dd, J=4.44, 1.39 Hz), 6.74 (1 H, dd, J=4.44, 2.77 Hz), 5.07 (1 H, br. s.), 1.37-1.56 (3 H, m), 1.01-1.37 (4 H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[NH:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.C1COCC1.CO.O[Li].O>O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[NH:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 95.6 %

Procedure:
To a stirred mixture of methyl 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate (1.4 g, 2.69 mmol), THF (10 mL), MeOH (5 mL) and H2O (2.5 mL) was added LiOH.H2O (339 mg, 8.07 mmol) then heated under reflux for 8 hrs. Concentrated and added H2O (5 mL) then acidified with 2N HCl. The solid was filtered washed with H2O and dried to give the product as a tan solid (1.3 g, 96% yield); MS (ESI) m/z=506.3
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:4][CH2:3]1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:49]CCCl>>[ClH:49].[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:14]3[O:13][CH2:12][CH2:11][C:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:3][CH2:4]4)=[O:9])=[CH:16][C:15]=3[CH:17]=2)=[CH:22][CH:23]=1
Reactant: ClCCCl
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N2CCC(N)CC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N2CCC(NC4CCOCC4)CC2)CCO3)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbonyl)piperidine (0.3 g) and tetrahydro-4H-pyran-4-one (0.083 g) dissolved in 1,2-dichloroethane (6 ml) was added under ice cooling sodium triacetoxyborohydride (0.25 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent, and the residue dissolved in ethyl acetate was mixed with 4 N hydrochloric acid/ethyl acetate (0.5 ml) to collect the precipitated powder by filtration. The powder was washed with hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbonyl)-4-((tetrahydropyran-4-yl)amino)piperidine hydrochloride (compound 77) (0.35 g) as a colorless amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=S(Cl)Cl
Product: Cc1cc(C(=O)Cl)ccc1Br

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid (5.0 g, 23.25 mmol) and thionylchloride (50 ml) was refluxed for 5 hours. After removal of thionyl chloride, the residue was dried under high vacuum and used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][S:15][C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Si:21]([CH3:43])([CH3:42])[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27](B(O)O)=[CH:26]2)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C>[C:35]([O:34][C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:42])[CH3:43])=[CH:31][CH:30]=2)[CH:26]=[C:27]1[C:10]1[C:11]2[S:15][CH:14]=[CH:13][C:12]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Yield: 61 %

Procedure:
To a solution of 3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester (200 mg, 0.57 mmol, Example 5B) and bis-(diphenylphosphinoferrocene)-dichloro palladium (complex with dichloromethane 1:1, 21 mg, 0.03 mmol) in 1,4-dioxane (5 mL) is added 5-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (335 mg, 0.86 mmol, prepared as described in Example 4-6 of International Patent Application Publication No. WO 02/32861) followed by a solution of cesium carbonate (741 mg, 2.28 mmol) in water (2 mL). The mixture is stirred at reflux for 15 minutes. Then it is diluted with ethyl acetate and washed with water and brine. The organic layer is dried over magnesium sulfate and concentrated. The residue is chromatographed through silica gel (n-heptane-ethyl acetate, 95:05 as eluant) to afford 200 mg (61%) of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanoxy)-indole-1-carboxylic acid tert-butyl ester as a white foam. LC/MS: RT=4.29 minutes, 570.1 m/e.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.FC1C=CC([CH:18]=[O:19])=C(C)C=1>Cl>[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=1[CH:18]=[O:19]
Reactant: Cc1cccc(F)c1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C=O)c(F)c1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.O>CN(C=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:20][C:37](=[O:38])[NH:22][N:21]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccnc(-c2c[nH]c3ccc(C(=O)NN)cc23)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4n[nH]c(=O)o4)cc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a solution of 3-(4-isopropylpyrimidin-2-yl)-1H-indole-5-carbohydrazide (400 mg in about 60% pure) in DMF (3 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.47 mL, 2.71 mmol) followed by CDI (242 mg, 1.49 mmol). The mixture was stirred at RT for 5 min then heated in an oil bath at 65° C. for 1 h. It was cooled to RT, treated with 5 mL of H2O and extracted with 3×20 mL of EtOAc. The combine organic solution was washed with 3 mL of brine, dried and concentrated to afford 5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (350 mg). This material was used in next step without further purification. MS (ESI, pos. ion) m/z: 322.0 (M+1).
Reaction SMILES: ClC1C=C(SCC2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](C4C=CC=CC=4OC)[CH:19]=3)[NH:14]C(C)(C)C=2)C=C(Cl)C=1.Br[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])[CH:41]=2)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=C(S)C=C(Cl)C=1>>[CH3:50][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=[C:33]2[CH2:32][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1cc(Cl)cc(Cl)c1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1cc(Cl)cc(Cl)c1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(3,5-Dichlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 33 mg of 3,5-dichlorothiophenol reacted to give 15 mg of the title compound as a foam.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][C:24]=2[Cl:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(C#N)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.50 g), 2-chloro-4-dodecylbenzonitrile (1.20 g), anhydrous aluminum chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.80 g of desired compound (refractive index: 1.5490).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCCO
Product: OCCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 3-aminopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@H:10]([CH2:19]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:21])[C@H:10]([CH2:19][Br:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CBr)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester.
Reaction SMILES: [Cl:1][C:2]([Cl:41])([Cl:40])[CH2:3][O:4][C:5]([N:7](C(OCC(Cl)(Cl)Cl)=O)[C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6].[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:40][C:2]([Cl:1])([Cl:41])[CH2:3][O:4][C:5]([NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3NC(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(4-{bis[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (1.21 g, 1.74 mmol) in THF (25 mL) was added an aqueous solution of NaOH (1.0 M, 4.0 mL, 4.0 mmol) dropwise and the reaction mixture was stirred for 1 hour. The reaction was poured into brine and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford tert-butyl 4-[4-(4-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[C:7]([O:6][C@@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[C:4]([O:3][CH2:1][CH3:2])=[O:23])([CH3:8])([CH3:12])[CH3:5]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(I)n2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reaction time: 3 h
Yield: 135.4 %

Procedure:
To a stirred solution of (S)-ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.3 g, 12.23 mmol) in CH2Cl2 (150 mL) and t-butyl acetate (105 mL) was added perchloric acid (3.15 mL, 36.7 mmol) at rt and sealed the reaction flask. After 3 h, the reaction mixture was diluted with CH2Cl2 (100 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatography on silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 8.28 mmol, 67.7% yield) as viscous oil. 700 mg of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ: 7.31 (s, 1H), 5.56 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 4.26-4.16 (m, 2H), 2.71 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.30 (s, 9H), 1.23 (t, J=7.0 Hz, 3H). LCMS (M+H)=490.0.