Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=O)[N:4]=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]1[N:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[C:29]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:30]([C:36]1[CH:41]=[CH:40][C:39]([C:42]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45][C:44]4([O:49][CH2:48][CH2:47][O:46]4)[CH2:43]3)=[CH:38][CH:37]=1)=[N:31]2)[NH2:25].C(O)(=O)C>CC(N(C)C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:35]3[C:26]([C:27]4[CH:28]=[C:29]([C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)[C:30]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45][C:44]7([O:49][CH2:48][CH2:47][O:46]7)[CH2:43]6)=[CH:38][CH:37]=5)=[N:31][C:32]=4[CH:33]=[CH:34]3)=[N:24][N:25]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CC7(C6)OCCO7)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (7.0 g, 56 mmol) in DMA (200 mL) was added EDC (11 g, 56 mmol) and HOBt (8.5 g, 56 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Then tert-butyl {2-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-10) (30 g, 56 mmol) was added and the reaction stirred at room temperature for an additional 1 hour at which time acetic acid (17 g, 280 mmol) was added and the reaction was stirred overnight at 80° C., The reaction mixture was cooled to room temperature, quenched with 1N NaOH, poured into saturated sodium bicarbonate, extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude residue was purified by column chromatography eluting with 10% methanol in DCM. The appropriate fractions were concentrated and the resulting solid was recrystallized from methanol to give tert-butyl (2-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]oct-2-yl)carbamate (1-11) as a white solid. MS (M+H)+: 630.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[N:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([NH:24][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(NN1CCCCC1)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 316.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH3:17][O:18][C:19]([CH2:21][CH2:22][CH2:23][C:24](Cl)=O)=[O:20]>>[CH2:1]([N:5]([CH2:24][CH2:23][CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CC(C)CNCCc1c[nH]c2ccccc12
Product: COC(=O)CCCCN(CCc1c[nH]c2ccccc12)CC(C)C
Yield: 73.5 %

Procedure:
10 g of N-isobutyl-tryptamine (i.e., 3-(2-isobutylaminoethyl)-indole) and 9.1 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 11.23 g of N-isobutyl-N-(4-methoxycarbonylbutyl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 70.5%
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[C:7](OC)=[O:8])[CH2:3][CH2:2]1.[BH4-].[Li+].Cl>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[CH:12][C:13]=2[C:14]([F:16])([F:17])[F:15])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(C2CC2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)c(C2CC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution in dehydrated tetrahydrofuran (50.0 mL) of the compound (1.42 g) obtained in step (1) above, lithium borohydride (380 mg) was added and the mixture was stirred at 60° C. for 4 hours. Subsequently, 1 mol/L hydrochloric acid was added under cooling with ice. Following extraction with ethyl acetate, the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate and removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-75:25) to give [3-cyclopropyl-4-(trifluoromethyl)phenyl]methanol as a colorless oil (1.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Yield: 85.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 3,4-dichlorophenyl isocyanate (102 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 71 mg of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=O)=[C:13]2[N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH:31]1[CH2:37][C:35](=[O:36])[NH:34][C:32]1=[O:33].N1CCCCC1>O>[CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[C:37]3[NH:31][C:32](=[O:33])[NH:34][C:35]3=[O:36])=[C:13]2[N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(SCc3ccccc3)cc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(SCc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 80 °C
Yield: 92 %

Procedure:
To the reaction flask, 7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.7 g, 9.3 mmol) was added to ethanol (31 mL) along with hydantoin (933 mg, 9.3 mmol) and piperidine (920 μL, 9.3 mmol). The reaction was heated at 80° C. for 3 days then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a yellow solid in 92% yield. LCMS (M+1=477)
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3CCc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCC=C2c3ccccc3CCc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-{4-[2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-ethoxy]-phenyl}-2-ethoxy-propionate (2.3 g, 53.7 mmol) was dissolved in ethanol (25 ml), 15% sodium hydroxide (7 ml) was added, and the mixture stirred at room temperature for 3 h and stood overnight. The solution was evaporated, water (30 ml) added to the residue, and the mixture acidified to pH 6 with acetic acid (1.6 ml). The product was extracted with dichloromethane (3×20 ml), and the dichloromethane solution washed with water (20 ml), brine (20 ml), dried (MgSO4) and evaporated. The residue was crystallised from a mixture of toluene (8 ml) and n-heptane (8 ml) to give the title compound; 1.60 g (74.4%).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:57][O:58][C:59](=[O:66])[C:60]([CH3:65])([CH3:64])[CH2:61][O:62][CH3:63]>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[N:15]=[C:14]([O:16][CH2:57][O:58][C:59](=[O:66])[C:60]([CH3:65])([CH3:64])[CH2:61][O:62][CH3:63])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COCC(C)(C)C(=O)OCCl
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 45 mg) and DMF (2 mL), cesium carbonate (29 mg) and 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (20 mg) were sequentially added, and the resulting mixture was stirred at 60° C. for 4 hours. The resulting mixture was poured into ethyl acetate (30 mL) and water (20 mL). After shaking the mixture, the organic layer was collected. The organic layer was sequentially washed twice with water (30 mL) and with saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (20 mg).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][N:51]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: O=Cc1cnc(Cl)nc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 1.00 g (1.48 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 5 ml of 1-methyl-2-pyrrolidone, 0.23 g (1.6 mmol) of 2-chloro-5-formyl pyrimidine and 265 μl (1.78 mmol) of diazabicycloundecene were added, and the reaction solution was stirred at room temperature for 1 hour. Then, 0.023 g (0.16 mmol) of 2-chloro-5-formyl pyrimidine was added thereto and the reaction solution was further stirred at room temperature for 0.58 hours. Furthermore, 0.023 g (0.16 mmol) of 2-chloro-5-formyl pyrimidine was added thereto and the reaction solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=40/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 1.00 g of the title compound as a light yellow solid (yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 10% Pd/C (53% water; 0.020 g) and tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A125) (0.092 g, 0.17 mmol) in DMF (5 mL) and Et3N (0.5 mL) was stirred at room temperature for 18 hours under a hydrogen atmosphere. The resulting mixture was filtered through Celite, and the filter cake washed with EtOAc (250 mL). The combined filtrates were washed with water (3×100 mL) and brine (3×100 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A126 as a pale brown oil (80 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=0.4 Hz, 1H), 7.25-7.15 (m, 4H), 6.92 (s, 1H), 4.31-4.15 (m, 3H), 3.70 (s, 2H), 3.66 (s, 3H), 3.08 (dd, J=9.4, 6.3 Hz, 2H), 2.90 (dd, J=9.5, 6.3 Hz, 4H), 2.15-2.07 (m, 2H), 2.05 (s, 3H), 2.00-1.85 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 6.195 min; m/z 535.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](N)(=[O:5])=[O:4].Cl.[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]2[C:18]2[CH:17]=[CH:16][C:15]([OH:34])=[CH:14][C:13]=2[N:12]=1.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]([F:8])([F:7])[S:3]([O:34][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[C:20](=[N:21][N:22]([CH2:32][CH3:33])[C:23]=3[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]([NH2:10])=[N:12][C:13]=2[CH:14]=1)(=[O:5])=[O:4]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CCn1nc2c(N)nc3cc(O)ccc3c2c1CCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc2c(N)nc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2c1CCc1ccccc1
Reaction time: 6 h
Yield: 91.9 %

Procedure:
N-Phenyl-bis(trifluoromethanesulfonamide (0.187 g, 0.447 mmol) was added to a stirred solution of 4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-ol hydrochloride (0.15 g, 0.41 mmol) and triethylamine (0.280 mL, 2.03 mmol) in DMF (5 mL). After 6 hours, water (25 mL) was added and a precipitate formed that was isolated by filtration, washed with water, and dried to yield 0.175 g of 4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-yl trifluoromethanesulfonate as a white powder, mp 178-179° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([F:30])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>CN(C=O)C.[Pd].C(OCC)(=O)C>[F:30][C:21]1[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH3:29])[NH:25]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A suspension of 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (8.2 g, 19.1 mmol), ammonium formate (12 g, 190 mmol) in DMF (50 ml) containing 10% palladium on carbon (2 g) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ethyl acetate and filtered over diatomaceous earth. A solid precipitated out of the filtrate. The solid was filtered off. The filtrate was washed with aqueous sodium hydrogen carbonate, followed by brine and dried over magnesium sulphate. The volatiles were removed under vacuum. The residual solid was combined with the solid previously isolated from the filtrate and was then triturated with acetonitrile under cooling. The precipitate was filtered, washed with acetonitrile followed by diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (6.48 g, quant.).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:5][N:4]=1.[C:17](NC1C=CC=C(C2C=CC=CN=2)C=1)(=[O:19])[CH3:18]>>[C:17]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([N:2]([CH3:16])[CH3:1])=[N:4][CH:5]=2)[CH:10]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc(-c2ccccn2)c1
Reactant: CN(C)c1ncc(-c2cccc(N)c2)cn1
Product: CC(=O)Nc1cccc(-c2cnc(N(C)C)nc2)c1

Procedure:
2h is acetylated as described for 2g in Example 5 to yield 2i. Mp 183-188° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1.[OH-].[Na+].Cl>>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]([CH:3]=[CH2:2])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1
Reactant: CN1CCN(c2ncc3c(=O)c(C(=O)O)cn(CCCl)c3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=Cn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C)CC3)nc21
Yield: 70.3 %

Procedure:
A solution of 8-(2-chloroethyl)-5,8 -dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (1.0 g) in 20 ml of a 10% aqueous solution of sodium hydroxide was heated at 95°C for three hours. The reaction mixture was then neutralized with hydrochloric acid under ice-cooling and chilled. The resulting precipitate was collected to give 0.63 g of the product. Recrystallization from a mixture of chloroform and ethanol gave the product as pure state.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:27].Cl>C1COCC1>[C:3]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]([C:14]2[CH:15]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[CH3:27])=[O:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(=O)(=O)O)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(=O)(=O)O)c1
Reaction time: 17 h
Yield: 23 %

Procedure:
Sodium hydride (26 mg, 0.66 mmol) was added to a stirred solution of 3-(4-tertbutylbenzamido)benzenesulfonic acid (0.10 g, 0.30 mmol) in THF (5 mL), and after 30 min iodomethane (37 μL, 0.60 mmol) was added. The reaction was stirred for 17 h, and 1 M aqueous hydrochloric acid (1 mL) was added. The solvent was removed under vacuum, and the residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 3-(4-tert-butyl-N-methylbenzamido)benzenesulfonic acid (24 mg, 23% yield). LC/MS: m/z 348.3 (M+H)+ at 3.82 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: N1C2C=CC=CC=2N=C1.[CH3:10][Si:11]([CH3:26])([CH3:25])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.C([Li])CCC.[I:32]I>C1COCC1>[I:32][C:17]1[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:26])([CH3:25])[CH3:10])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Reactant: II
Agent: [Li]CCCC
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 63.2 %

Procedure:
Preparation of 2-iodo-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole. A solution of 1-(2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem, 51, 1891-1894 (1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25 min at −78° C., the flask was warmed to 0° C. for 10 min, then cooled again to −78° C. This solution was then added via cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C. Once the addition was complete (˜5 min), the cooling bath was removed, and stirring was continued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite (2×100 mL) to remove the dark iodine color, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C13H19IN2OS) C, H. Calculated: C, 41.71; H, 5.12; I, 33.90; N, 7.48. Found: C, 41.90; H, 5.09; I, 34.00; N, 7.37.