Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.[Cu]>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:19][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Yield: 69 %

Procedure:
A solution of 29.0 g (0.106 mol) of (±)-1-(p-hydroxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in 530 ml of freshly distilled pyridine was refluxed with stirring under nitrogen with 12.88 ml of bromobenzene, 51.5 g of copper (granular) and 22.55 g of potassium carbonate for 14 days. The reaction mixture after cooling was diluted with ether 1 1. and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in ether (300 ml). The ether solution was washed with 4N aqueous sodium hydroxide (200 ml) then with water and dried. Removal of the solvent under reduced pressure gave 25.8 g (69%) of crude (±)-1(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm Hq).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[NH4+].[Cl-]>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][N:11]([C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CNCc1cccc(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of the amine from Step D (754 mg, 1.93 mmol) and triethylamine (0.403 mL, 2.89 mmol) in 5 mL of dichloromethane at 0° C. was added benzylchloroformate (0.303 mL, 2.12 mmol). After 2 hours, the solution was poured into EtOAc and sat NH4Cl solution, and the organic layer was washed with sat. NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (30-40% EtOAc/hexane) to obtain the titled compound (360 mg) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:32])[C@H:26]([OH:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]1.CCOC(C)=O.[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[OH:31][C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:39]#[N:40])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:6]=2)[CH2:24][CH2:23]1)=[O:32]
Reactant: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(Br)cc23)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(C#N)cc23)CC1
Yield: 75 %

Procedure:
(R)-1-(4-(6-Bromo-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (188 mg, 0.38 mmol), Zn(CN)2 (44 mg, 0.38 mmol), and Pd(Ph3)4 (6.5 mg, 0.0112 mmol) were dissolved in DMF (4 mL) and the reaction mixture was heated in a microwave synthesizer at 200° C. for 15 minutes EtOAc (50 mL) was added and the mixture was washed twice with H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-40% EtOAc in CH2Cl2:hexanes (1:1) gave 4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile (127 mg, 75%). LC/MS: m/z 446 (M+H)+ at 3.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=1.5 Hz, 1H), 8.46 (dd, J=8.4, 1.8 Hz, 1H), 8.15 (dd, J=8.7, 1.7 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.45-7.41 (m, 1H), 6.99-6.95 (m, 2H), 4.94 (d, J=7.0 Hz, 1H), 4.39-4.36 (m, 1H), 4.14-4.04 (m, 4H), 3.89-3.67 (m, 4H), 1.82-1.76 (m, 1H), 1.47-1.37 (m, 2H), 0.93-0.91 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][CH2:29][CH2:28][C:27]1=[O:37]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:26][C:27](=[O:37])[CH2:28][CH2:29]1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C1CCNc2ccccc2N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC(=O)Nc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (800 mg) and catalytic amount of N,N-dimethylformamide in dichloromethane (8 ml) was added oxalyl chloride (0.7 ml) at 0° C. and the solution was stirred at ambient temperature for 30 minutes followed by the removal of solvents to give a crude acid chloride. To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (658 mg) and triethylamine (821 mg) in dichloromethane (4 ml) was added a solution of the above acid chloride in dichloromethane (4 ml) at ambient temperature and the mixture was stirred at ambient temperature for 1 hour. The resultant mixture was filtered and the solid was washed with water and diethyl ether to give 5-(3-methoxy-4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.29 g) as a colorless prisms.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl>C(O)C>[CH2:3]([S:13][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][S:13][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCS
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCSCCNCCSCCCCCCCCCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaOH (3 g, 75 mmol) and decanethiol (15.5 ml, 75 mmol) in ethanol (75 ml) was added to a solution of bis(2-chloroethyl)amine hydrochloride (4.4 g, 25 mmol) in ethanol (50 ml) at 0° C. The solution was stirred for 2 hours at 0° C. and then for another 16 h at room temperature. After filtering, the filtrate was evaporated to dryness. The residue was taken up with dry ether and filtered again. After evaporation of the solvent under vacuum, the product remained as a colourless semi-solid. Yield: 9.4 g (90%). 1H-NMR (CDCl3) δ 0.87 (6H, t, CH3), 1.25-1.4 (28H, m, SC2H4C7H14CH3), 1.56 (4H, qn, SCH2CH2C8H17), 1.88 (1H, s, NH), 2.52 (4H, qt, SHCH2C9H19), 2.69 (4H, t, SCH2CH2NH), 2.82 (4H, t, NCH2).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:35]([S:44][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCS
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Product: CCCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1

Procedure:
Using the procedure of Example 4 with 30 g of 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and 17.6 g of nonyl mercaptan, the title compound is prepared.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39](O)=[O:40])[S:38][C:34]=2[CH:33]=1>O.CN(C=O)C>[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:40])[S:38][C:34]=2[CH:33]=1
Reactant: COCOc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCOC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methoxyethylamine (0.082 mL), EDCI (181 mg), HOBt (128 mg), 6-((2,4-dichlorobenzyl)oxy)-3-(methoxymethoxy)-1-benzothiophene-2-carboxylic acid (260 mg) and DMF (5 mL) was stirred at room temperature for 18 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with 1N HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (205 mg). The obtained crystals were recrystallized from EtOAc-hexane.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC#N>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: N#Cc1ccc2c(c1)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
7-Cyano-1,2,3,4-tetrahydroisoquinoline (7 g; 44.25 mmol; 1 eq.) and K2CO3 (7.34 g; 53.1 mmol; 1.2 eq) were suspended in CH3CN (280 mL). tert-Butyl 3-bromopropionate (7.77 mL; 46.46 mmol; 1.05 eq.) was added. The reaction mixture was heated to 70° C. for 24 hours. As the reaction was not complete, tert-butyl 3-bromopropionate (3.70 mL; 22.12 mmol; 0.50 eq.) and K2CO3 (3.06 g; 22.12 mmol; 0.5 eq) were added and the mixture was stirred at 70° C. for additional 48 hours. Solvents were removed under vacuum and the solid residue was partitioned between NaHCO3 sat (100 mL) and EtOAc (200 mL). The organic layer was then washed with brine and dried over magnesium to give the title compound as a yellow oil (11.9 g; 93.9%). It was used in the next step without further purification. 1H NMR: (DMSO-d6, 400 MHz) δ 7.57-7.54 (m, 2H), 7.32-7.29 (m, 1H), 3.59 (s, 2H), 2.87-2.83 (t, J=5.94 Hz, 2H), 2.74-2.66 (m, 4H), 2.46-2.42 (t, J=7.01 Hz, 2H), 1.39 (s, 9H). HPLC/MS: 287.1 (M+H)+. HPLC (Method A) Rt 2.37 min (Purity: 96.4%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=C=O.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34]>>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][C:10]([C@@H:9]1[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]1[C:6]([NH:17][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:7])=[O:12]
Reactant: NCc1ccco1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1cccc(N=C=O)c1
Product: C=C1C[C@@H](C(=O)NCc2ccco2)N(C(=O)Nc2cccc(OC)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 1-isocyanato-3-methoxybenzene, and 2-furylmethylamine the title compound was obtained in 95% purity by LC/MS. MS(ESI+): m/z=356.0.
Reaction SMILES: NN.[C:3]([O:7][C:8](=[O:37])[NH:9][C@H:10]([CH2:25][N:26]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])([CH3:5])[CH3:4].C(OCC)C>C1COCC1.C(O)C>[C:3]([O:7][C:8](=[O:37])[NH:9][C@H:10]([CH2:25][NH2:26])[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(CCOCc1ccccc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Hydrazine (66.6 ml of a 1M solution in THF, 66.6 mmol) is added to a suspension of [(S)-5-benzyloxy-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester (4 g, 8.32 mmol) in ethanol (100 ml), and the resulting solution is heated at 40° C. overnight. A fluffy white precipitate forms. The reaction is allowed to cool to room temperature and diethyl ether (100 ml) is added and the resulting white suspension cooled at 0° C. for 30 minutes. The white precipitate is removed by filtration and the solvent removed in vacuo. The residue is then stirred with diethyl ether (100 ml) for 1 hour, filtered and the solvent is removed in vacuo to afford ((S)-1-Aminomethyl-5-benzyloxy-3,3-dimethyl-pentyl)-carbamic acid tert-butyl ester as a pale yellow oil; [M+H]+ 351.
Reaction SMILES: [Na].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][C:15]#[N:16].CCOCC>C(O)C>[F:12][C:3]([F:2])([F:11])[C:4]1[CH:5]=[C:6]([S:10][CH2:14][C:15]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: N#CCCl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: N#CCSc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To sodium (0.62 g, 27.0 mmol) dissolved in 40 mL of ethanol was added 4.79 g (26.9 mmol) of 3-trifluoromethylthiophenol and 2.04 g (27.0 mmol) of chloroacetonitrile. The reaction mixture was heated at reflux for 1 hour and then stirred overnight at room temperature. To the cooled reaction mixture was added one volume of ether and the precipitated solids were removed by filtration. The filtrate was evaporated on the rotary evaporator to give the product as an oil in essentially quantitative yield. This material was used in the following reaction without further purification.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])([CH3:4])[CH3:3].[CH3:13][C:14]#N.[OH2:16]>CCOCC.[Cl-].[Cl-].[Zn+2]>[OH:11][C:8]1[CH:7]=[C:6]([OH:12])[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=1[C:14](=[O:16])[CH3:13]
Reactant: CC(C)c1ccc(O)cc1O
Reactant: O
Reactant: CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry HCl was passed through a suspension of 4-isopropyl-1,3-benzenediol (17.01 g; 112 mmol), CH3CN (8.3 ml; 158 mmol) and fused ZnCl2 (14 g) in dry ether (100 ml) for 1 h at 0° C. The reaction mixture was then stirred for 1 h at room temperature and filtered. The solid obtained was hydrolyzed with boiling water as reported in the literature. The crude product was purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 15.2 g (69.6%); mp, 142-44° C.; MS (CI): 223 (M++29), 195 (M++1), 179; analysis: C11H14O3 requires: C, 68.02; H, 7.26; found C, 68.40; H, 7.33%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:26])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1CC(CCCl)Sc2ncccc2C1=O
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Sc2ncccc2C1=S

Procedure:
A mixture of 4.3 g (0.017 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepin-5(4H)-one, 100 ml of toluene and 4.8 g (0.012 mole) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was refluxed for 3 hr and then extracted twice with dilute sodium hydroxide. The organic layer was concentrated and the residue chromatographed on the high pressure liquid chromatograph using a silica column and 50% ethyl acetate-50% hexane. The yield of title compound was 2 g, m.p. 160°-162° C.
Reaction SMILES: FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C2C(=CC(OC)=C(C(OC(C)(C)C)=O)C=2)N=CC=1.[F:41][C:42]1[CH:64]=[C:63]([NH:65][C:66]([NH:68][C:69](=[O:81])[CH2:70][C:71]2[CH:76]=[CH:75][C:74]([C:77]([F:80])([F:79])[F:78])=[CH:73][CH:72]=2)=[S:67])[CH:62]=[CH:61][C:43]=1[O:44][C:45]1[C:54]2[C:49](=[CH:50][C:51]([O:59][CH3:60])=[C:52]([C:55]([NH:57][CH3:58])=[O:56])[CH:53]=2)[N:48]=[CH:47][CH:46]=1>>[NH2:65][C:63]1[CH:62]=[CH:61][C:43]([O:44][C:45]2[C:54]3[C:49](=[CH:50][C:51]([O:59][CH3:60])=[C:52]([C:55]([NH:57][CH3:58])=[O:56])[CH:53]=3)[N:48]=[CH:47][CH:46]=2)=[C:42]([F:41])[CH:64]=1.[F:80][C:77]([F:78])([F:79])[C:74]1[CH:75]=[CH:76][C:71]([CH2:70][C:69]([N:68]=[C:66]=[S:67])=[O:81])=[CH:72][CH:73]=1
Reactant: CNC(=O)c1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccc(C(F)(F)F)cc4)cc3F)ccnc2cc1OC
Agent: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)OC(C)(C)C
Product: CNC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Product: O=C(Cc1ccc(C(F)(F)F)cc1)N=C=S

Procedure:
Similar to the synthesis of compound 1d, from compound 46a (50.0 mg) and 4-trifluoromethylphenylacetyl isothiocyanate (53.9 mg), the titled compound 47 was yielded (41.2 mg, yield: 48%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([N:38]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][C:30]2[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Add benzyl bromide (75 mL, 630.55 mmol) to a suspension of potassium carbonate (85 g, 615.006 mmol) and (R)-4-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (80 g, 207.25 mmol) in acetonitrile (900 mL). Heat to reflux for 16 hours, cool to room temperature, and dilute with ethyl acetate (2 L). Wash with ammonium chloride (1.5 L), saturated aqueous sodium chloride (1.5 L), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 5:95 to 20:80 ethyl acetate:hexanes) to give the desired compound as a white solid (102.1 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[CH:55]=[N:56][C:57]2[C:62]([CH:63]=1)=[CH:61][CH:60]=[CH:59][CH:58]=2>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[NH:53][C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc21
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21

Procedure:
A solution of 2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester (1.5 g, 5.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.37 g, 6.27 mmol), N,N-diisopropylethylamine (2.41 mL, 13.8 mmol) and 3-aminoquinoline (0.904 g, 6.27 mmol) in acetonitrile was heated to reflux for 20 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was separated, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexane to give the product, 1.43 g (64%). MS: m/z 390 (MH+). 1H NMR (DMSO-d6): δ 1.54 (s, 9 H), 3.16 (t, 2 H), 4.00 (t, 2 H), 7.57-7.83 (m, 3 H), 7.88-8.00 (m, 4 H), 8.84 (d, 1 H), 9.15 (d, 1 H) and 10.53 (s, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=CC(O)=C[CH:4]=1)=C.C(C1C=CC(O)=CC=1)C.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:3]([C:22]1[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=1)([CH3:8])([CH3:4])[CH3:1]
Reactant: C=Cc1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: CCc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(O)cc1
Reaction time: 5 h

Procedure:
This toluene solution was fed into the second extraction tower at a point 3/4 from the top of the tower so that the rate of feed of all phenols was 0.0422 mol./hr., and otherwise, the total reflux operation was performed in the same way as in the case of the first extraction tower described above. The second extraction tower and a reflux zone attached to the tower had quite the same structure as the first extraction tower and the reflux zone atached thereto. After completion of the total reflux operation, the extracting operation was carried out for 5 hours while maintaining the reflux ratio at 52.4. As a result, 1.06 liters of a toluene solution containing 0.199 mol of purified p-vinylphenol of 99.4 mol% p-vinylphenol, 0.39 mol% p-ethylphenol, 0.20 mol% phenol and 0.01 mol% p-tert.-butylphenol was obtained from the top of the second extraction tower.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15]N=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH:26]([CH3:28])[CH3:27].[C:34]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH:31]([OH:33])[CH2:30][O:29][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:34]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)COCC1CO1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COCC(O)Cn1cc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.056 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added glycidyl isobutyl ether (7.3 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated at 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was filtered to remove excess of K2CO3. The collected solution was concentrated under reduced pressure. The crude product was purified using reverse phase HPLC to give the title compound, 3,4-bis(4-chlorophenyl)-6-(2-hydroxy-3-isobutoxypropyl)imidazo[1,5-b]pyridazin-7(6H)-one (17.8 mg, 65% yield) as a yellow solid. in 65% yield. MS [M+H]+: found 487; 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.23-7.15 (m, 6H), 7.00-6.96 (m, 2H), 4.20-4.00 (m, 3H), 3.41 (d, 2H), 3.11 (d, 2H), 1.80-1.65 (m, 1H), 0.76 (d, 6H).