Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:15]=1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
A mixture of 2-[6-(aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.40 g, 1.0 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was stirred at room temperature for 20 minutes. Successively, N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (40:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.24 g, 68%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[F:13][C:2]([F:1])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)([CH3:5])[CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirred mixture of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine prepared as described in Example 259A (2.34 g, 12.06 mmol) and potassium carbonate (5 g, 36 mmol) in dry dichloromethane (50 mL) at 0° C., was added a solution of phenyl chloroformate (2.83 g, 18 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was warmed to room temperature and stirred for a further 15 h, then additional phenyl chloroformate (1 g, 6.3 mmol) was added and stirring was continued for a further 3 h. The reaction mixture was partitioned between water (200 mL) and dichloromethane (500 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and then concentrated under reduced pressure to give a yellow oil. Purification via silica gel flash chromatography (eluting with 5% to 50% ethyl acetate in hexanes) afforded phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (2.63 g, 69%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (brs, 1H), 7.38-7.43 (m, 2H), 7.17-7.29 (m, 3H), 6.85 (s, 1H), 1.57 (s, 6H); LC-MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:10].CN1CCOCC1>ClCCl>[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:2]([O:4][CH3:5])=[O:3])[N:12]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:10]
Reactant: CCOC(=O)C1CCC(CNCC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(CN(CC(=O)OC(C)(C)C)C(=O)OC)N1C(=O)OC(C)(C)C
Yield: 88.3 %

Procedure:
Methyl chloroformate (0.065 mL, 0.85 mmol) was added to a solution of 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (300 mg, 0.77 mmol) and 4-methylmorpholine (0.12 mL, 1.2 mmol) in dichloromethane (10 mL) at 0° C. After 15 minutes the mixture was diluted with dichloromethane (30 mL) and washed with water (15 mL), saturated ammonium chloride (15 mL) and saturated sodium chloride (15 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol, 88%). C21H36N2O8 calculated 444.3, observed [M+1]+445.3; rt=2.58 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:48][C:49]1[CH:65]=[C:64]([C:66](=[NH:69])[NH:67]O)[CH:63]=[C:62]([CH3:70])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>CN(C=O)C>[Cl:48][C:49]1[CH:65]=[C:64]([C:66]2[N:67]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:69]=2)[CH:63]=[C:62]([CH3:70])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)OC(C)(C)C)c(Cl)c3)no2)cc(C2CCCC2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A mixture of 2-cyclopentyl-6-methoxy-isonicotinic acid (33 mg, 0.149 mmol), TBTU (50 mg, 0.156 mmol) and DIPEA (62 mg, 0.479 mmol) in DMF (2 mL) is stirred at rt for 15 min before tert-butyl 4-(2-chloro-4-(N-hydroxycarbamimidoyl)-6-methylphenoxy)butanoate (51 mg, 0.149 mmol) is added. The mixture is stirred at rt for 1 h before another portion of TBTU (50 mg, 0.156 mmol) is added. Stirring is continued at rt for 2 h. The mixture is heated to 110° C. and stirring is continued for another hour. The mixture is concentrated and the crude product is purified by prep. HPLC to give tert-butyl 4-(2-chloro-4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy)butanoate (33 mg) as a colourless glass; LC-MS: tR=1.28 min, [M+H]+=528.37.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:10]2[C:11]3[C:2](=[O:1])[NH:3][N:4]=[C:5]4[CH:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:13][NH:12][C:7]([C:6]=34)=[CH:8][CH:9]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccccc2-c2ccc3c4c(n[nH]c(=O)c24)C(c2ccccc2)CN3)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) 552 (M+1)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][OH:16].N1C=CN=C1.CN([CH:25]=[O:26])C>>[Si:1]([O:16][CH2:15][CH2:14][C:10]1[S:9][C:13]([CH:25]=[O:26])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: OCCc1cccs1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
tert-Butyldimethylsilylchloride (2.82 g) was added portionwise to a stirred solution of 2-(thiophen-2-yl)ethanol (2 g) and imidazole (1.275 g) in DMF (20 mL) at 20° C. over a period of 20 minutes. The mixture was stirred at 20° C. for 18 hours and then partitioned between ethyl acetate and water, the organic layer was washed with water, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 1-4% ethyl acetate in isohexane. The residue (2.7 g) was dissolved in THF (50 mL) and the solution cooled to −78° C., n-butyllithium (2.5M in hexanes, 5.06 mL) was added dropwise over 10 minutes and the resultant mixture stirred at 0° C. for 1 hour. The reaction mixture was cooled to −78° C. and DMF (5.7 mL) was added dropwise over 5 minutes. The mixture was stirred at 20° C. for 3 hours. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with water, dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 7% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2.3 g.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[Pd]>[OH:8][NH:9][C:10](=[O:30])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[CH:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CC(C)C(C(=O)Nc1ccc(C(=O)NOCc2ccccc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(C(=O)Nc1ccc(C(=O)NO)cc1)c1ccccc1
Yield: 90 %

Procedure:
Compound 3 (6.1 g; 15.2 mmol) was dissolved in 1:1 methanol/THF (120 ml), and 10% palladium on charcoal (0.6 g, 10% w/w) was added. The mixture was treated with hydrogen under atmospheric pressure for 2 h, and filtered. The solvent was evaporated and the residue was recrystallized with ethyl acetate, yielding 4.2 g (90% yield).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:5][CH2:6][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]4[NH:35][N:36]=[C:32]([CH2:31][CH2:30][C:24]5[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=5)[CH:33]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(C2CCN(C3CC3)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(C4CCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Yield: 35.8 %

Procedure:
Methyl 4-(1-cyclopropylpiperidin-4-yl)benzoate (0.259 g, 1 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (10 ml) was treated with a 2M solution of trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, under nitrogen. The reaction mixture was heated at 60° C. for 18 h. The reaction mixture was cooled and the reaction quenched with methanol (40 ml) and acidified with 2N HCl (1 ml). The crude reaction mixture was purified by ion exchange chromatography, using an SCX column. The crude product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product crystallised from DCM/diethyl ether to give the title compound (0.170 g, 35.8%) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.C(O[C:38](=[O:40])[CH3:39])(=O)C>ClCCl.C1COCC1>[OH:40][CH2:38][CH2:39][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (30 mg, 0.07 mmol, Example 26a) was dissolved in dichloromethane (1 mL) and THF (1 mL). Acetic anhydride (6.61 μL, 0.07 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated under reduced pressure, the crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (5.9 mg, 17.91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[S:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: Nc1ncnc2snc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nsc3ncnc(N)c23)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A mixture of Example 96F (0.95 g, 3.5 mmol), iron (0.78 g, 13.9 mmol), and NH4Cl (0.19 g, 3.5 mmol) in 9:1 ethanol/water (80 mL) was heated to 60° C. for 4 hours, cooled to room temperature, and filtered through a pad of diatomaceous earth (Celite®). The pad was washed with THF and the filtrate was concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 0.82 g (97% yield) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11].[CH2:14]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][C:18]=1[O:25][CH3:26])[CH3:15].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:14]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:11])=[CH:19][C:18]=1[O:25][CH3:26])[CH3:15]
Reactant: CCOc1ccc(CN)cc1OC
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(CNC(=O)n2cc(F)c(=O)[nH]c2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Fluorouracil, 1.14 g, was dissolved in 30 ml of pyridine, 2.46 g of phosgene was blown into the solution at 5° C., and the solution was allowed to stand at room temperature for 1 hr. Then 1.5 g of 4-ethoxy-3-methoxybenzylamine and 3.2 ml of triethylamine were added to it while cooling with ice, and the solution was stirred at room temperature for 1 hr. Triethylamine hydrochloride was removed from the solution by filtration. The filtrate was concentrated and exsiccated. The residue was dissolved in 100 ml of dichloromethane, and the solution was washed with hydrochloric acid water, dried, concentrated and exsiccated again. The residue was recrystallized from ethanol, and 2.3 g of 1-(4-ethoxy-3-methoxybenzylcarbamoyl)-5-fluorouracil (melting point: 153° C.) was obtained (Compound No. 5). NMR: (DMSOd6) 1.4-1.6 (3H, m, CH3) 3.85 (3H, s, OCH3) 4.04 (2H, q, OCH2) 4.44 (2H, d, CH2) 6.8 (2H, s, C6H2) 7.2 (1H, s, C6H) 8.42 (1H, d, H of the 6-position) 9.2 (1H, m, NH).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH:6]=1)[CH3:3].C(N(CC)CC)C.[C:23]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C>[ClH:32].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)(=[O:31])=[O:30])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1=Cc2ccc(N)cc2CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CC1CCc2cc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Product: Cl
Reaction time: 3 h
Yield: 59 %

Procedure:
6-[(N,N-Dimethylamino)methyl]-7,8-dihydro-2-naphthalenamine (200 mg, 0.72 mmol) obtained in Example 41-2) was dissolved in acetonitrile (30 ml). Triethylamine (0.401 ml, 2.88 mmol) and [1,1′-biphenyl]-4-sulfonylchloride (200 mg, 0.79 mmol) were added to the solution under ice-cooling, which was stirred for 3 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue, and extraction was conducted. The ethyl acetate layer was concentrated, and the residue was purified by alumina column chromatography (development solvent; ethyl acetate: n-hexane=33:67). 4N Hydrogen chloride-ethyl acetate solution was added to the resulting oily substance, which was concentrated. The residue was recrystallized from methanol-ethyl acetate, to give the titled compound (194 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)n2)CC1
Temperature: 160 °C
Yield: 10.9 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). 1-methylpiperazine (0.029 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by using Mass Directed Automated Preparative HPLC (Method E). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (12.8 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[Cl:10]N1C(=O)CCC1=O>CO>[Cl:10][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH3:1])[C:8]=1[OH:9]
Reactant: Cc1c(O)cccc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: Cc1c(O)ccc(Cl)c1O
Reaction time: 6 h
Yield: 64.8 %

Procedure:
To a solution of 2-methylresorcinol (40 g, 322 mmol) in 750 ml of methanol was added (45.17 g, 0.338 mol) of N-chlorosuccinimide. The mixture was stirred for 6 hours. The solvent was evaporated and the resulting solid was triturated in 500 ml of a 2:1 mixture of hexane and ethyl acetate. The brown crystalline precipitate (succinimide) was filtered off and rinsed with a little extra solvent. The filtrate was concentrated to give the crude product, which was further purified on silica eluting with 4:1 hexanes/ethyl acetate. Appropriate fractions were combined, and evaporated. The product was crystallized from about 1:8 ether/hexanes to afford 33.1 g (65%) of the desired substituted resorcinol 15b. 1H NMR (DMSO-d6) δ: 9.38 (s, 1H), 8.83 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.33 (d, J=8.5 Hz, 1H), 2.00 (s, 3H).
Reaction SMILES: [C:1]([N:8]1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][CH:21](O)[CH2:22][C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH-:30].[NH4+]>ClCCl>[Si:13]([O:20][CH2:21][CH:22]([C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[O:30][C:1](=[O:2])[NH2:8])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC(O)Cc1ccc(Cl)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [OH-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OC(N)=O)c1ccc(Cl)s1
Reaction time: 1 h

Procedure:
Imidazole (0.45 g) was added to a solution of 1(5-chloro-2-thienyl)-1,2-ethanediol (1.0 g, 5.6 mmol) and tert-butyldimethylsilyl chloride (0.80 g) in N,N-dimethylformamide (5 ml) at 5°. The reaction mixture was allowed to come to room temperature and stirred 1 hour, extracted with ethyl acetate, washed with 0.5N aqueous hydrochloric acid, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered, concentrated in vacuo. 1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)ethan-1-ol (1.14 g) was obtained as a colorless oil after a chromatographic purification. 1,1′-Carbonyldiimidazole (0.95 g) was added to a solution of the foregoing alcohol (1.14 g 3.9 mmol) in dichloromethane (20 mL) at 5°. The reaction mixture was allowed to come to room temperature and stirred 1 hour. Ammonium hydroxide (equivalent to 28% ammonia in water, 10 ml) was added at 5°. The reaction mixture was stirred for 1 hour at room temperature, extracted with ethyl acetate, washed with 0.5N aqueous hydrochloric acid, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered, concentrated in vacuo. 1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)-2-carbamoyloxyethane (0.47 g) was obtained as a colorless oil after a chromatographic purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:36][CH:35]=1)=[O:32].CS(C)=O>CO>[O:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31](=[O:32])[C:30]2[CH:47]=[CH:48][CH:49]=[C:28]([NH:27][C:2]3[C:7]([C:8]4[N:9]=[C:10]([NH:14][C:15]5[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=5)[N:11]=[CH:12][N:13]=4)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:29]=2)=[CH:39][CH:38]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1
Reactant: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(Nc2ncnc(-c3cccnc3Nc3cccc(C(=O)Nc4ccc(Oc5ccccc5)cc4)c3)n2)cc(OC)c1OC
Temperature: 90 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 2, Step 4)(103 mg, 0.275 mmol) was added 3-amino-N-(4-phenoxyphenyl)-benzamide (297 mg, 0.975 mmol) and DMSO (150 ml), and the mixture was heated overnight at 90° C. The residue was treated with IpOH and MeOH, triturated, sonicated, and filtered to obtain N-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide as a yellow solid: MS m/z 642.5=[M+H]+. Calc'd for C36H31N7O5: 641.24.