Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=O)[CH3:5]>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=[N:2][OH:3])[CH3:5]
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=CC(C=NO)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Yield: 60.5 %

Procedure:
Hydroxylamine hydrochloride (69.5 mg) was added to a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in a mixture of chloroform (3 ml) and methanol (2 ml) with stirring at room temperature. The resulting mixture was stirred at the same temperature overnight and evaporated to dryness. The residue was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled under reduced pressure to give a residue which was purified by preparative thin layer chromatography [solvent: methanol-chloroform (10:90)] to give 4-ethyl-2-hydroxyimino-5-nitro-3-hexenaldehyde oxime (65 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]([CH2:6][CH2:7]C(O)=O)=[O:5])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:20])C=CC=CC=1.C([N:32]([CH2:35]C)CC)C>C1C=CC=CC=1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]([CH2:6][CH2:7][N:32]=[C:35]=[O:20])=[O:5])[CH3:12]
Reactant: CCN(CC)C(=O)CCC(=O)O
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCN(CC)C(=O)CCN=C=O

Procedure:
The reaction of 3-(N,N-diethylcarbamoyl)propionic acid and diphenylphosphoryl azide in a solution of triethylamine and benzene provided a solution comprising 2-(N',N'-diethylcarbamoyl)ethyl isocyanate (I.R.: 2290 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[2-(N',N'-diethylcarbamoyl)ethyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]=[O:4].[C:7]([O:11]C(=O)CC)(=[O:10])[CH2:8][CH3:9].Cl(O)(=O)(=O)=O>>[C:7]([O:4][CH:3]([O:11][C:7](=[O:10])[CH2:8][CH3:9])[C:2]([Cl:6])([Cl:5])[Cl:1])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=CC(Cl)(Cl)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)OC(OC(=O)CC)C(Cl)(Cl)Cl

Procedure:
Trichloroacetaldehyde (0.2 mol) and propionic anhydride (0.2 mol) were reacted in the presence of 0.2 ml 70% perchloric acid by the procedure of Example 4. The resulting 2,2,2-trichloroethylidene bispropionate product (13 g) distilled at 65°-66° C (0.1 mm/Hg). Elemental analysis for C8H11Cl3O4 showed: %Cl, calc. 38.3, found 38.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1)#[N:14]>CCOCC>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:23])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=S)N2CCN(c3cnccn3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 45 ml. of anhydrous ether is added a slurry of 4.8 g. of p-cyanophenyl isothiocyanate in 45 ml. of anhydrous ether, dropwise over 10 minutes. Themixture is stirred for 30 minutes and the resulting solid collected. This solid is dissolved in a mixture of 200 ml. of benzene and 200 ml. of ethanol and then cooled. The resulting solid is collected giving 6.95 g. of the desired product, m.p. 208°-210° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(C)CC(=O)O
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, off-white solid (98 mg, 92%), MS (ISP) m/z=429.4 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3,3-dimethyl-butanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]([NH2:10])[C:7]([OH:9])=O)=[O:4].Cl.[CH3:12]CN(CC)CC.[Si](Cl)(C)(C)C.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29]>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([NH:10][CH:6]([C:7](=[O:9])[CH3:12])[CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: Cc1ccc(C(=O)Cl)cc1Br
Reactant: COC(=O)C[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccc(C)c(Br)c1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a suspension of L-aspartic acid β-methyl ester hydrochloride (Sigma, 5.0 g, 27.23 mmol) in chilled (<5° C.) CH2Cl2 (150 mL) was added Et3N (8.33 g, 81.70 mmol) in a steady flow followed by a slow addition of Me3SiCl (6.51 g, 59.92 mmol). The mixture was warmed to 25° C. and stirred for 1 h, cooled again (<10° C.), and 3-bromo4-methylbenzoyl chloride (6.36 g, 27.23 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature slowly with stirring for 16 h. The reaction mixture was then diluted with CH2Cl2 (150 mL) and washed with 1N HCl (50 mL), brine (50 mL), and dried over Na2SO4. The resultant amide product (8.9 g, 95%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (50 mL) and DMAP (0.17 g, 1.38 mmol) was added. Acetic anhydride (26 mL) was added slowly and then the reaction was heated at 90° C. for 2 h. The cooled solution was poured into 200 mL ice water and extracted with EtOAc. The organic layer was washed with 2N HCl (3×100 mL) and 1N NaOH (100 mL), dried over MgSO4, and concentrated to afford the title compound as a off white solid which was taken to the next step (Example 81).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12.O>CS(C)=O>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12)[NH2:1]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(I)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of 4-amino-2-fluorophenol (1.83 g, 14.38 mmol) in DMSO (30 mL) was added potassium tert-butoxide (1.61 g, 14.38 mmol). After 15 min, 7-chloro-2-iodothieno[3,2-b]pyridine (2.5 g, 8.46 mmol, Ragan J. A. et al, Organic Process Research and Development, 2003, 7. 676-683) was added and the reaction mixture was heated at 100° C. for 60 min. The mixture was cooled down to RT then poured into water (250 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water, dried and purified by flash column chromatography on silica gel (eluent 60% EtOAc in Hexane) to afford title compound 268 (1.06 g, 32% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.41 (d, J=5.4 Hz, 1H), 7.75 (s, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.57-6.45 (m, 3H), 3.83 (s, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1.[CH3:23][C:24]1([CH3:40])[C:33](=[O:34])[NH:32][C:31]2[N:30]=[CH:29][C:28](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:27][C:26]=2[CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][C:24]1([CH3:40])[CH2:25][C:26]2[C:31](=[N:30][CH:29]=[C:28](/[CH:35]=[CH:36]/[C:37](=[O:38])[N:11]3[CH2:12][CH2:13][C:14]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[CH:15][CH2:16]3)[CH:27]=2)[NH:32][C:33]1=[O:34]
Reactant: C1=C(Cc2nccs2)CCNC1
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc2NC1=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
DIPEA (0.33 mL, 1.83 mmol) was added to a stirred solution of 2-((1,2,3,6-tetrahydro-pyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (158 mg, 0.73 mmol), (E)-3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (Intermediate-22) (150 mg, 0.61 mmol), HOBt (98 mg, 0.73 mmol) and EDC.HCl (232 mg, 1.22 mmol) in dry DMF (2 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (160 mg, 51%); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 2.79 (s, 2H), 2.18-2.04 (m, 2H), 1.08 (s, 6H); LC-MS: 409.2 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([I:9])[CH3:8]>C1(C)C=CC=CC=1>[I-:9].[CH2:5]([N+:4]1[CH:8]=[CH:7][N:2]([CH3:1])[CH:3]=1)[CH3:6]
Reactant: Cn1ccnc1
Reactant: CCI
Solvent: Cc1ccccc1
Product: CC[n+]1ccn(C)c1
Product: [I-]
Reaction time: 1 h
Yield: 95 %

Procedure:
To a 200 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 32.84 g (0.4 mol) of 1-methyl imidazole and 40 ml of toluene were charged and heated at 50° C., to which 68.63 g (0.44 mol) of ethyl iodide was dropped slowly taking one hour. After dropping and further reacting at 50° C. for 4 hours, precipitates were separated by filtration, subjected to solvent cleaning and dried under a reduced pressure to obtain 90.47 g of 1-ethyl-3-methyl imidazolium iodide salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13]([F:28])=[CH:12][N:11]=1>>[F:28][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Nc1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(OC(F)(F)F)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.61 (bs, 1H), 8.21 (d, 1H, J=4.2 Hz), 7.93 (bd, 1H, J=7.5 Hz), 7.78 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.03 (m, 4H), 6.43 (m, 1H); 19F NMR (DMSO-d6): −16097; LCMS: purity: 85%; MS (m/e): 381 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
(1)-a) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate were added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. After removal of the solvent under reduced pressure, 100 ml of methanol and 2.5 g of sodium hydrogencarbonate were added, and the mixture was cooled to -20° C. Subsequently, 6.0 g of sodium borohydride was added portionwise over 1 hour, and the mixture was stirred at -30° to -20° C. for 1 hour and at -20° to -5° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with diluted hydrochloric acid, and aqueous sodium hydrogencarbonate solution and water, and dried, followed by evaporation of the solvent to give 23.7 g of methyl 5-anilino-5-(4-chlorophenyl)pentanoate as a pale brown oily product. Subsequently, to said oily product were added 75 ml of methanol and 100 ml of an aqueous 10% sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. After removal of the solvent, the residue was diluted with 50 ml of water and then ashed with ether. The aqueous layer was adjusted to pH 6 to 7 with hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 17.8 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (45 mg, 0.15 mmol) in dichloromethane (3 ml) was added cyclopentanone (26 mg, 0.30 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 1.5 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was triturated with ether to afford the title compound (E24). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:28]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14][N:28]3[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OCc1ncc(-c2ccc(Cl)c(Cl)c2)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ncc(-c3ccc(Cl)c(Cl)c3)s2)c1
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of the compound (260 mg, 1.00 mmol) obtained in Example 22a and triethylamine (0.21 mL, 1.50 mmol) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.093 mL, 1.20 mmol), and the mixture was stirred for 30 min. The reaction mixture was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.00 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (85 mg, 22%) as colorless crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[OH:32])[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:1]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:19]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Acetic anhydride (580 μL, 6.2 mmol) was dropwise added to a pyridine (20 ml) solution of 2-(6′-phenyl-2,2′-bipyridine-6-yl)phenol (1.0 g, 3.1 mmol) obtained by Example 14, then the mixture was stirred for 24 hours at room temperature. The solvent was distilled off from the reaction mixture, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 1.05 g of 6-(2-acetoxyphenyl)-6′-phenyl-2,2′-bipyridine as yellow crystal. Yield: 93.0%.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Cl.Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24]N(C=O)C>>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:2]([CH:3]([C:4]([O:6][CH2:7][CH3:24])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:1])=[CH:19][CH:20]=1
Reactant: ClCc1ccncc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)C(C)Cc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
To a suspension of diethyl methyl malonate (2.41 g, 13.9 mmol) in DMF (50 ml) at 0° C. was added sodium hydride (1.66 g, 41.6 mmol, 60%), followed by adding the compound 4-chloromethylpyridine hydrochloride (2.50 g, 15.2 mmol) and stirred for 16 h at room temperature. The reaction mixture was quenched by acetic acid and the product was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.50 g (68.1%) of diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate as pale brown oil.
Reaction SMILES: C[N:2]([C:4]1[CH:12]=[C:11]([C:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([O-:8])=[O:7])C.C1C[O:19][CH2:18]C1.[CH3:21]C(C[AlH]CC(C)C)C>CCOCC>[CH3:21][O:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([CH2:13][CH2:18][OH:19])=[CH:12][C:4]=1[NH2:2]
Reactant: C1CCOC1
Reactant: CN(C)c1cc(C(=O)[O-])ccc1C(=O)[O-]
Reactant: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(CCO)cc1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of dimethylaminoterphthalate (3.07 g, 14.7 mmol) in 30 mL of a 2:1 mixture of THF: Et2O at −78° C. was added neat DIBAL (6.27 g, 44.1 mmol, 3.0 eq.) and the reaction was warmed to 0° C. over 4 hours. The reaction was quenched with 5 mL of methanol followed by 5 mL of saturated aqueous sodium tartrate. The mixture was stirred overnight and then was taken up in ethyl acetate. The layers were separated and the ethyl acetate layer was washed with saturated aqueous NaHCO3and brine and then dried over Na2SO4, filtered and evaporated to an oil. Purification by chromatography on silica gel (50% ethyl acetate-hexane) gave the desired compound (1.03 g, 39%) of 1b as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([Cl:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=3)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3S(C2C=CC=CC=2)(=O)=O)=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:42][CH:43]1[CH2:48][NH:47][CH2:46][CH2:45][N:44]1[CH:49]([CH3:51])[CH3:50].[OH-:52].[Na+].Cl>CC(O)C.CS(C)=O>[CH:9]([OH:10])=[O:52].[Cl:32][C:24]1[N:23]=[CH:22][C:21]([C:19]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:11][C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:47]4[CH2:46][CH2:45][N:44]([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:42])[CH2:48]4)[N:8]=3)=[O:10])[CH:20]=2)=[CH:26][C:25]=1[NH:27][S:28]([CH3:31])(=[O:29])=[O:30]
Reactant: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: [OH-]
Reactant: CC(C)N1CCNCC1C
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2cccc(C(=O)Nc3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)n2)CC1C
Product: O=CO
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-(Chloromethyl)-N-[6-{6-chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.079 mmol) and 2-methyl-1-(1-methylethyl)piperazine (0.5 ml, 0.047 mmol) were placed in a vial and heated in a microwave at 90° C. for 15 min. The amine was blown off under a stream of nitrogen to give an orange gum which was suspended in IPA (2 ml) and 2M NaOH (1 ml) was added. The mixture was stirred at room temperature for 2 hours then neutralised with 2M HCl (aq.) and the solvent was blown off under a stream of nitrogen. The residue was dissolved in DMSO (2 ml) (insoluble salt was filtered off through a filter tube) and purified by MDAP (Method E). The product-containing fractions were concentrated under a stream of nitrogen to give a white solid which was freeze dried to afford the title compound as a white solid (14 mg).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][NH2:21]>C1(C)C=CC=CC=1>[CH3:19][N:20]1[N:21]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Br)cc1
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To a suspension of 2-(4-bromobenzoyl)benzoic acid (15.0 g, 49.2 mmol) in toluene (75 mL) at room temperature was added methylhydrazine (2.88 mL, 54.1 mmol). The reaction mixture was heated to reflux while collecting water in a Dean Stark trap for 3 hours, additional methylhydrazine (2.0 mL) was added and refluxing was continued for 15 minutes. The reaction mixture was cooled to room temperature and the product was collected by filtration and dried in vacuo to afford 13.4 g (87%) of 2-methyl-4-(4-bromophenyl)-1-(2H)-phthalazinone, m.p. 168°-170° C.