Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1
Reactant: O=C1CSc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCS2
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of (2H)1,4-benzothiazin-3(4H)-one (20.0 g, 121.1 mmol) in anhydrous tetrahydrofuran (100 mL) was added to a stirred suspension of lithium aluminum hydride in anhydrous tetrahydrofuran (80 mL) under nitrogen at 0° C. The mixture was heated at reflux for 2 hrs and then poured into a mixture of ethyl acetate (300 mL) and ice (500 g). The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried and concentrated under reduced pressure to provide 17.68 g (96.5%) of the desired compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Yield: 92.9 %

Procedure:
853 mg of 2-chlorophenylboronic acid, 30 cm3 of water, 964 mg of sodium carbonate and 252 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 60 μm3 of dioxane. The reaction medium is then refluxed for 18 hours and filtered through a sinter funnel packed with Celite, and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 70 cm3 of ethyl acetate and the organic phase is washed with 2×30 cm3 of distilled water and then with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1 g of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](B2OC(C)(C)C(C)(C)O2)=[N:25]1>>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methanesulfonyl-benzyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 128. NMR (CDCl3) 3.03 (s, 3H, CH3), 4.20 (s, 3H, CH3), 5.13 (d, H, ArH, J=5.95 Hz), 5.84 (sbr, H, NH), 7.51-7.65 (m, 3H, 3×ArH), 7.79 (d, H, ArH, J=7.72 Hz), 7.91 (d, H, ArH, J=7.77 Hz), 7.93 (s, H, ArH), 8.09 (s, H, ArH), 8.39 (d, H, ArH, J=7.28 Hz), 9.04 (s, H, ArH), 10.13 (sbr, H, NH). MS: (ESI+) MH+=434.10
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO.[Pt]=O>[CH2:12]([NH:24][CH:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: O=[Pt]
Solvent: CO
Product: CCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
1.0 g of platinum oxide was added to a solution of 31.0 g of 2,2,6,6-tetramethyl-4-piperidone and 47.0 g of dodecylamine in 250 ml of methanol. The resulting mixture was then hydrogenated under a hydrogen atmosphere in a Parr hydrogenation apparatus at room temperature for 3 hours. After completion of the reaction, the platinum catalyst was filtered off, and then the solvent was distilled from the filtrate under reduced pressure to give an oily product. This product was purified by column chromatography through silica gel, eluted with a 20:3:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound as an oil. The Rf value of this product on thin layer chromatography was 0.34, using silica gel and a 20:3:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[CH:5]=[N:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([N:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(F)cnn1CC
Agent: Cl
Solvent: C1COCCO1
Product: CCn1ncc(F)c1C(=O)O
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of ethyl 1-ethyl-4-fluoro-1H-pyrazole-5-carboxylate (67 mg) in 1,4-dioxane (3 ml) was added 2M hydrochloric acid (2 ml) was added and the mixture was heated at reflux under nitrogen for 120 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. Toluene (15 ml) was added and the solvent was removed in vacuo to give a solid that was dried in a vacuum oven overnight to give the title compound (26 mg) as a brown solid.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[CH:14]([O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[S:25])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C1C=CC=CC=1>[F:29][C:28]([F:30])([F:31])[CH2:27][N:26]=[C:24]1[N:23]([CH2:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH:14]([CH3:16])[CH3:15])=[CH:19][CH:20]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:25]1
Reactant: CC(C)Oc1ccc(CNC(=S)NCC(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(C)C)cc3)C2=O)cc1
Yield: 36.3 %

Procedure:
1.00 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.40 g of 1-(4-isopropyloxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of benzene, and the solution was heated under reflux for 4 hours. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; eluent: hexane/ethyl acetate (10/1)1 to give 0.75 g of the captioned compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)CSc3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.405 mmol) was reacted with N-(2-azidoethyl)-2-(phenylthio)acetamide (0.096 g, 0.405 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-(phenylthio)acetamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H0, δ 7.19 (m, 5H), δ 7.13 (s, 1H), δ 6.43 (s, 1H), δ 6.13 (bs, 2H0, δ 4.29 (s, 2H), δ 3.68 (s, 2H), δ 3.57 (s, 2H), δ 2.56 (s, 2H), δ 2.35 (s, 2H), δ 1.52 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 187.8, 172.0, 169.1, 162.4, 156.9, 135.0, 129.5, 128.3, 126.8, 121.8, 85.00, 49.4, 39.9, 37.4, 29.4, 28.9, 28.4, 28.2, 27.6, 25.6 ppm; HRMS (ESI) calcd for C25H35N7O3S (M+) 513.2522. Found 513.2522, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(phenylthio) acetamide hydrochloride (0.133 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), δ 7.30 s, 4H), δ 7.19 (s, 1H), δ 6.58 (s, 1H), δ 4.66 (s, 2H), δ 3.76 (s, 2H), δ 3.64 (s, 2H), δ 2.84 (s, 2H), δ 2.34 (s, 2H), δ 1.73 (s, 2H), δ 1.64 (s, 2H), δ 1.26 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 170.9, 159.3, 158.9, 147.2, 135.6, 128.1, 128.9, 127.6, 126.6, 108.7, 108.6, 52, 39.1, 37.5, 37.2, 36.6, 36.1, 30.8, 28.1, 27.9, 27.7, 24.2, 23.7, 23.6 ppm; HRMS (ESI) calcd for C20H27N7OS (M+) 413.1998. Found 413.1991.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:15])[C:7]=1[C:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[F:15][C:6]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=2)=[C:2]([NH:17][C:16](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CN1CC=C(c2c(F)cncc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Product: CN1CC=C(c2c(F)cncc2NC(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-chloro-5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridine (377 mg, 1.663 mmol), tert-butyl carbamate (974.1 mg, 8.315 mmol), sodium tert-butoxide (815.1 mg, 8.481 mmol), BrettPhos pre-catalyst (66.25 mg, 0.08315 mmol) and BrettPhos (44.63 mg, 0.08315 mmol) were placed in a sealable tube an degassed by vacuum/nitrogen cycles (×5). Dry dioxane (10 mL) was added and the resulting mixture was placed into a pre-heated block at 100° C. and stirred at this temperature for 16 hours. Further portions of BrettPhos pre-catalyst (66.25 mg, 0.08315 mmol) and BrettPhos (44.63 mg, 0.08315 mmol) were added and the reaction heated at 100° C. for 8 hours. The reaction mixture was cooled to ambient temperature and quenched with saturated NH4Cl. The mixture was passed through a pre-wetted (EtOAc) celite cartridge (2.5 g). The cartridge was washed with EtOAc/saturated NH4Cl and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give tert-butyl (5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate. MS (ES+) 308.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][C:37]=1[F:44].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][C:37]=1[F:44]
Reactant: O=Cc1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(F)c(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide (740 mg, 1.137 mmol) in dry dioxan (25 mL) was treated with 4N HCl in dioxan (2.8 mL). The reaction was stirred at room temperature for two days. The volatile components were evaporated to dryness and the residue was taken up with Et2O (10 mL), stirred for 1 hour, filtered with suction, washed with Et2O (10 mL), dried at 50° C. under vacuum to afford 358 mg of title compound as a white solid in 77% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O:23][C:24]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)=[O:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][CH:26]([C:24]([OH:25])=[O:23])[CH2:27]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COC(=O)C1CCNC1
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2cc(N3CCC(C(=O)O)C3)nn3ccnc23)nc1OC
Temperature: 180 °C
Yield: 6.4 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1 g, 3.27 mmol), methylpyrrolidine-3-carboxylate (1.69 g, 13.1 mmol), triethylamine (1.32 g, 13.1 mmol) and cesium carbonate (4.26 g, 13.1 mmol) was heated to 180° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxylic acid (80 mg, 6%) as a red solid. LC-MS: 385 [M+1]+, tR=1.258 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(O)cc1
Yield: 70.2 %

Procedure:
Product from step 1 (1.2 g, 3.13 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.0 g) over period of 16 h at rt under H2 balloon. Reaction Mixture was filtered through Celite and concentrated under reduced pressure. The crude mixture was purified by silica gel flash chromatography (20% EtOAc/Hexane) to obtain the title product (645 mg, 70%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Reactant: Nc1ccc(NCCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(NCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Yield: 21.5 %

Procedure:
N4-(2-morpholin-4-yl-ethyl)-naphthalene-1,4-diamine (190 mg, 701 μmol), 3-fluoro-5-morpholinyl benzoic acid (236 mg, 1.05 mmol), HBTU (531 mg, 1.4 mmol) and diisopropylethylamine (0.37 ml, 2.1 mmol) are stirred at room temperature in dimethylformamide (10 ml) for 12 hours. The mixture is poured into ethyl acetate (100 mL) and washed with water (100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 5% methanol in ethyl acetate to give 3-fluoro-5-morpholin-4-yl-N-[4-(2-morpholin-4-yl-ethylamino)-naphthalen-1-yl]-benzamide (72 mg). 1H NMR 300 MHz (CDCl3) 7.7-8.0 (m, 3H), 7.4-7.6 (m, 3H), 7.3 (m, 1H), 7.05 (m, 1H), 6.7 (m, 1H), 6.6 (m, 1H), 5.35 (m, 1H), 3.65-4.0 (m, 8H), 3.2-3.4 (m, 6H), 2.8 (m, 2H), 2.4-2.55 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH2:19][CH3:20].[I-].[K+]>CC(C)=O>[O:17]=[C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:18][CH2:19][CH3:20])[C:11]=2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1
Reactant: CCCc1ccccc1OCCCCCCCBr
Reactant: CCOC(=O)c1cc(=O)c2cccc(O)c2o1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1ccccc1OCCCCCCCOc1cccc2c(=O)cc(C(=O)OCC)oc12

Procedure:
A mixture of 4.84 parts of ethyl 8-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, 12.5 parts of 7-bromoheptyl 2-n-propylphenyl ether, 1 part of potassium iodide and 50 parts of anhydrous acetone was refluxed for 76 hours. After filtration the organic layer was concentrated and chromatographed over silica gel. Elution with benzene/chloroform (1:1) furnished 8.9 parts of ethyl 4-oxo-8-[7-(2-n-propylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylate as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42](=[O:43])[C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:37][CH:38]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.450 g, 1.03 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of 4-(trifluoromethoxy)-1-benzenecarbonyl chloride (0.231 g, 1.03 mmol) in dichloromethane (2.5 mL) drop-wise. The reaction mixture was stirred at −5° C. for 30 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. 1 N sodium hydroxide solution (10 mL) was added, and stirred for 1 h. The organic solvent was removed under reduced pressure. Dichloromethane (10 mL) was added and the layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure and the crude compound was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent to give 0.430 g (67%) N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (0.430 g, 0.688 mmol) in ethyl acetate (15 mL) was treated with a hot solution of maleic acid (0.240 g, 2.07 mmol) in ethyl acetate. A precipitate was formed, filtered under nitrogen, and dried under high vacuum to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate salt.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31](Cl)[N:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([NH:25][C@H:23]([C:14]2[N:13]([C@H:11]3[CH2:12][C@@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10]3)[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH3:24])[N:30]=[CH:29][N:28]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
A mixture of (S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (50 mg, 0.15 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (23 mg, 0.15 mmol) and DIPEA (0.13 mL, 0.74 mmol) in IPA (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM then MeOH and then 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (50 mg, 75%). LCMS (Method B): RT 3.11 min [M+H]+ 458. 110185004