Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCN(CC1)CC2.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][OH:16])=[CH:12][CH:11]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>ClCCl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,4-Diazabicyclo[2.2.2]octane (5.61 g, 0.050 mol) and 4-bromophenethyl alcohol (5.0 g, 0.025 mol) were combined in dichloromethane (100 mL). The resulting mixture was cooled to 0° C. in an ice bath and a solution of tosyl chloride (5.67 g, 0.029 mol) in dichloromethane (50 mL) was added via an addition funnel over 15 min. After stirring for about 1 h at 0° C., water (30 mL) was added and stirring was continued for another 30 min. The aqeuous layer was then separated and discarded. The organic layer was dried (NaSO2), filtered, and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](I)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](/[CH:8]=[C:4](\[CH2:1][CH2:2][CH3:3])/[C:5]([OH:7])=[O:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Reactant: C=C(CCC)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Propylacrylic acid (5.0 g, 43.80 mmol) was added to a solution of toluene-4-sulfonyl iodide (14.32 g, 65.70 mmol) in dichloromethane (100 ml). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (12.2 ml, 87.6 mmol) was added and the solution was stirred for 1 hour then allowed to warm to room temperature over 2 hours. The organic solution was washed with water (100 ml), 1N hydrochloric acid ((100 ml) 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (5 g) in water (100 ml). The aqueous layer was washed with ethyl acetate (20 ml) and then acidifed with conc. sulfuric acid (3 ml). The product was extracted into ethyl acetate (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 85% yield. This yellow solid was dissolved in methanol (100 ml ) and stirred with activated charcoal (1 g). Filtration and evaporation gave a pale yellow solid which was slurried in dichloromethane:heptane 20:80. Filtration gave the title compound as white crystals (8.3 g, 70%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:60][C:61]1([CH2:65]O)[CH2:64][O:63][CH2:62]1>O1CCCC1>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:60][C:61]3([CH3:65])[CH2:64][O:63][CH2:62]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC1(CO)COC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC3(C)COC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), (3-methyloxetan-3-yl)methanol (0.29 g) and tetrahydrofuran (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was extracted with water and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.68 g, 56%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:20][NH:21][CH3:22]>O1CCOCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[CH:4][CH:5]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: CNC
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1ccc(CN(C)C)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
In an atmosphere of argon, 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) was put into a 25 ml capacity eggplant type flask equipped with a cold finger and dissolved in dioxane (3 ml), followed by the addition of 50% dimethylamine aqueous solution (3 ml) at room temperature. After 2.5 hours of stirring at 80° C. and subsequent removal of dioxane by evaporation, the resulting residue was diluted with ethyl acetate (30 ml). The thus diluted solution was dried on anhydrous sodium carbonate, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether-ethyl acetate-ethyl acetate:methanol=10:1) to obtain 284 mg (100%) of the title compound in the form of colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[C:37]([C:40]1[CH:49]=[CH:48][C:43]([O:44][CH2:45][CH2:46][OH:47])=[CH:42][CH:41]=1)(=[O:39])[CH3:38].[H-].[Na+].Cl>CC(N(C)C)=O>[C:37]([C:40]1[CH:49]=[CH:48][C:43]([O:44][CH2:45][CH2:46][O:47][C:2]2[N:7]=[C:6]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:5]=[C:4]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:3]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:42][CH:41]=1)(=[O:39])[CH3:38]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(=O)c1ccc(OCCO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of N-{6-chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (1.05 g) and 2-(4-acetylphenoxy)ethanol (728 mg) in dimethylacetamide (12 ml) is added sodium hydride (240 mg) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/acetonitrile=2:1), and recrystallized from ethyl acetate/n-hexane to give N-[6-{2-(4-acetylphenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (482 mg) as crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:14][C:13]=3[NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:6]1.O1CCCC1.[BH4-].[Li+].O>O1CCCC1>[CH:25]1([NH:24][C:13]2[CH:14]=[C:15]([CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH:16]=[C:17]3[C:12]=2[NH:11][C:10]([C:7]2[S:8][CH2:9][C@@H:5]([CH2:4][CH2:3][OH:2])[N:6]=2)=[CH:18]3)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(CS(C)(=O)=O)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The compound (720 mg, 1.60 mmol) prepared in Example 68 was dissolved in tetrahydrofuran (20 ml). 2 M lithium borohydride tetrahydrofuran solution (1.6 ml, 3.2 mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (292 mg, Yield 43%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:12]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(CO)cc1F

Procedure:
Into a cooled solution (−78° C.) of 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; see step (i) above) in 40 mL of CH2Cl2 and 5 mL of methanol was bubbled ozone (50 L/h, 29 g/m3) for 30 min. Argon was subsequently bubbled through to remove excess ozone. Sodium borohydride (0.67 g, 0.018 mol) was added and the cooling bath was removed. The mixture was stirred and allowed to react for 1 h. The mixture was evaporated and 2M HCl was added. The mixture was extracted twice with diethyl ether and the combined ether fraction was dried (Na2SO4) and evaporated. The crude product crystallised. Yield: 1.1 g (81%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:5][O:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:1](=[O:3])[CH3:2])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)N1CCc2cc(C(C)=O)ccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
Acetyl chloride (10.66 mL, 0.15 mol) was added slowly to a mixture of 2,3-dihydro-indole-1-carboxylic acid methyl ester, Preparation 17 (17 g, 0.1 mol), and aluminum chloride (40 g, 0.3 mol) in carbon disulfide (150 mL) at 0° C. The reaction mixture was warmed to room temperature and heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water. The resulting mixture was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica using ethyl acetate/hexane (30%) to provide the title product (8.8 g, 40%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[O:16])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]([C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[O:16])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step A in 4 mL DMF was added 0.125 g (0.698 mmol) of 1-bromopinacolone and 0.455 g (1.39 mmol) of Cs2CO3. The reaction mixture was stirred at room temperature for 1 h, then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–75% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:34])([F:33])[C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[C:20](=[O:27])[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:33])([F:34])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[CH:20]([OH:27])[CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(O)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of LiAlH4 (200 mg) in anhydrous ether (15 ml) is added at 0° a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (400 mg) in ether (5 ml). After addition is complete, the reaction mixture is stirred at RT for about one hour. Excess of the hydride is decomposed using wet ether and water, the mixture is filtered and filtrate concentrated. The oily product is purified by prep. thin layer chromatography to give 4-[4-(4-trifluoromethylphenoxy)phenoxy]-pentane-1,3-diol, MS m/e 500 (M+).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:16])([F:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20].[OH-].[Na+]>N1C=CC=CC=1>[F:5][C:6]([F:16])([F:15])/[C:7](=[N:27]\[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:19]([O:18][CH3:17])=[O:20])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccnc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Thionyl chloride (2.2 ml) was added at 0° C. to a pyridine (4.8 ml) solution of 2,2,2-trifluoro-1-phenylethanone (5.1 g) and 2-aminopyridine-4-carboxylic acid methyl ester (4.5 g). The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 1 hour. Thereafter, the reaction solution was poured into a 1 N sodium hydroxide aqueous solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=2:1-1:1), so as to obtain the title compound (2.5 g) in the form of a yellow liquid.
Reaction SMILES: I.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[N:9][NH2:10].Cl.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:2]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]3=[N:9][N:10]=2)=[CH:14][CH:15]=1
Reactant: NN=C1NCCCCN1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Product: c1cc(-c2nnc3n2CCCCN3)ccn1
Temperature: 160 °C
Yield: 207.3 %

Procedure:
A mixture of 1,3-diazepan-2-one hydrazone hydroiodide(1.00 g, 3.9 mmol) and isonicotinoyl chloride hydrochloride (695 mg, 3.9 mmol) was heated in a microwave reactor at 160° C. for 10 min. The reaction mixture was poured into NaaCO3 solution, sat., and extracted with DCM. The organic phase was dried and concentrated. Flash chromatography (DCM/MeOH 20:1) gave 1.74 g crude title compound which was used directly in the next step. 1H NMR: 1.89 (s, 4H), 3.15 (m, 2H), 3.86 (m, 2H), 7.44 (d, 2H), 8.66 (d, 2H).
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]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH2:5]2.[H-].[Na+].O.[O:20]1CC[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([CH3:14])([O:16][C:21](=[O:20])[CH3:22])[CH3:15])[CH2:5]2
Reactant: CC(C)(O)CN1Cc2cc(Br)ccc2C1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(C)(C)CN1Cc2cc(Br)ccc2C1=O
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 50 mg of 5-bromo-2-(2-hydroxy-2-methyl-propyl)-1-oxo-isoindoline obtained in Example 177-1) was dissolved in tetrahydrofuran. 21 mg of acetatic anhydride and 20 mg of sodium hydride were added and the mixture was heated under reflux for 4 hours. The reaction solution was cooled down to room temperature, water was added and the products were extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2) to obtain 44 mg of the above compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12]([O:16]NC1C=CC(C(O)=O)=CC=1C)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)O)ccc1NOC(C)(C)C
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(C)(C)ONc1ccc(C(=O)O)c(Cl)c1
Yield: 79 %

Procedure:
4-amino-2-chloro-benzoic acid was converted to product in 79% yield, using the procedure described for the synthesis of 4-tert-Butoxyamino-3-methyl-benzoic acid. 1H NMR (DMSO-d6): δ 1.49 (s, 9 H), 7.46 (d of d, 1 H), 7.71 (br s, 1 H), 7.80 (d, 1 H), 9.87 (s, 1 H) and 13.00 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:24]=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:26][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:24]([OH:25])[CH3:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
A solution of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetaldehyde (128 mg, 0.29 mmol) in THF (2.9 mL) was added dropwise over 30 min to a solution of methyl magnesium chloride (290 μL, of 3 M solution diluted in 2.9 mL THF) at 0° C. The crude mixture was partitioned between CH2Cl2 and 2 M hydrochloric acid. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were passed over a phase separator and concentrated under reduced pressure. The reaction was repeated with another 80 mg of starting 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetaldehyde and the combined crude mixtures were purified by column chromatography (silica gel, gradient 50 to 100% ethyl acetate/isohexane). Additional preparative HPLC purification yielded 7.2 mg of Compound 91.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[P:32]([O:44][CH2:45]Cl)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[P:32]([O:44][CH2:45][N:21]1[CH:20]=[CH:19][S:18]/[C:17]/1=[N:16]\[S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:8]([C:22]#[N:23])[CH:9]=1)(=[O:14])=[O:15])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:33]
Reactant: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)/N=c2\sccn2COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1C#N
Yield: 84.9 %

Procedure:
4-[4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide, (Example 170, 200 mg, 0.000424 mol), di-tert-butyl chloromethyl phosphate (J. Med. Chem. 51 (2008) p 1111-1114, supplimentary data) (160 mg, 0.000619 mol) and cesium carbonate (420 mg, 0.00129 mol) were stirred in dimethylformamide (2 mL) at 60° C. for 18 hours. The mixture was cooled then partitioned between tert-butylmethyl ether (80 mL) and water (40 mL), the organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a pale yellow gum, (250 mg).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[S:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22](#[N:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]3([CH:23]([C:22]#[N:25])[CH2:24]2)[N:7]1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=13
Reactant: C=CC#N
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O

Procedure:
4.08 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and 1.95 ml of acrylonitrile were heated together under reflux overnight in 250 ml of toluene. After evaporation of the solvent in vacuo, the residue was recrystallized from acetonitrile. There was obtained 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH -benzo[a]quinolizine-1carbonitrile of m.p. 225°-226°.