Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH2:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:62]([C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:29])([F:31])[F:30])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:8][CH2:7]2)=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Br)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3c(c2C=Cc2ccccc2)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Yield: 83.9 %

Procedure:
A mixture of N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.525 g), palladium diacetate (0.011 g), tris(o-tolyl)phosphine (0.03 g), triethylamine (0.15 g) and styrene (0.16 g) were combined in acetonitrile and warmed to reflux for 23 h. The mixture was cooled, partitioned between dichloromethane/water, the organic phase separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate/hexane mixtures as eluant) to provide the title compound (0.46 g).
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)N.N[C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=1OC)[C:14]([NH:16]C1C=CC(F)=C(F)C=1)=[O:15]>>[C:14]([NH2:16])(=[O:15])[C:13]1[CH:25]=[CH:26][CH:27]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Nc1cc(Cl)cc(Cl)c1
Product: NC(=O)c1ccccc1
Yield: 5.9 %

Procedure:
The title compound was synthesized in the same manner as Example 1 using 3,5-dichloroaniline (1.0 g, 6.2 mmol), CSI (0.64 mL, 4.4 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.24 g, 7.0 mmol) to give 0.05 g of pure benzamide, 3-[[[[[(3,5-dichlorophenyl)amino]-carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-. Microanalysis: C21H16Cl2F2N4O5S; calculated: C=46.25; H=2.96; N=10.27; found: C=46.30; H=3.32; N=9.93. MS: M++1=544.9 Da.
Reaction SMILES: C([O-])(=O)C([O-])=O.[Na+].[Na+].[C:9]([OH:18])(=[O:17])[CH:10]([CH:12]([C:14]([OH:16])=[O:15])[OH:13])[OH:11]>>[C:9]([OH:18])(=[O:17])[C@@H:10]([C@H:12]([C:14]([OH:16])=[O:15])[OH:13])[OH:11]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 6 h

Procedure:
After approximately 6 hours of boiling a small amount of solids appeared. 1H-NMR and IR analysis showed this solid to be primarily sodium oxalate, a tartaric acid degradation product.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH:13]([CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][C:9]=2[CH:17]=1)([O-])=O>CO.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH:13]([CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][C:9]=2[CH:17]=1
Reactant: CCC1CNCc2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC1CNCc2cc(N)ccc2O1

Procedure:
7-Nitro-2-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazapine hydrochloride (3.4 g, 13.1 mmol) was dissolved in methanol (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd-C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]1)[CH2:9][CH2:8][CH2:7]2)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:20][CH2:21]1)[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(C2CCN(CCC3CCCc4cc([N+](=O)[O-])ccc43)CC2)cc1OC
Solvent: CO
Product: COc1ccc(C2CCN(CCC3CCCc4cc(N)ccc43)CC2)cc1OC

Procedure:
A suspension of 3.2 g of 1-(2-(6-nitrotetralin-1-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine in 50 ml of methanol is hydrogenated in the presence of 1.6 g of Pd/C (5%) until the absorption of hydrogen has come to a standstill. The catalyst is filtered off, and the filtrate is worked up in the customary manner and gives 1-(2-(6-aminotetralin-1-yl) ethyl)-4-(3,4-dimethoxyphenyl)piperidine.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:10][C:9]=1[N+:21]([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:10][C:9]=1[NH2:21]
Reactant: COc1c([N+](=O)[O-])cc(C2(C)CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C2(C)CC2)cc1N
Temperature: 25 °C
Yield: 51.1 %

Procedure:
Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution of 2-methoxy-5-(1-methyl-cyclopropyl)-1,3-dinitro-benzene (2.21 g, 8.76 mmol) in ethyl acetate (30 mL). The mixture was heated to reflux for 0.25 h upon which the solution became red in color. The solution was cooled to rt and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, eluted through a plug of silica gel (1% ammonium hydroxide in methylene chloride), and the filtrate was concentrated. The residue was redissolved in Et2O and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to pH=12 with 2.0M NaOH and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide 2-methoxy-5-(1-methyl-cyclopropyl)-benzene-1,3-diamine (860 mg, 52%) as a red oil. ESI MS (m/z 193, M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.I[C:27]1[CH:28]=[N:29][N:30]([CH:32]2[CH2:38][CH:37]3[N:39]([CH3:40])[CH:34]([CH2:35][CH2:36]3)[CH2:33]2)[CH:31]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:33][CH:34]4[N:39]([CH3:40])[CH:37]([CH2:36][CH2:35]4)[CH2:38]3)[CH:31]=2)[CH:15]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: CN1C2CCC1CC(n1cc(I)cn1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Temperature: 80 °C

Procedure:
A suspension of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (95.6 mg, 0.271 mmol, 1.2 eq), 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (69.1 mg, 0.218 mmol, 1.0 eq), (1,1′-bis-(diphenylphosphino)-ferrocene) palladium dichloride (16.0 mg, 0.0219 mmol, 10 mol %), and K2CO3 (92.0 mg, 0.666 mmol, 3 eq) in a 4:1 ratio of DME to H2O (2.5 mL) was evacuated and charged with nitrogen several times, after which the sample was heated in the microwave reactor to 80° C. for 30 min. The reaction mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layers were washed with water (1×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness. The emulsion that had formed was collected separately and extracted with CH2Cl2 (2×), washed with brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. All organics were combined. The crude material was adsorbed onto silica gel and purified by column chromatography on silica gel [10″×0.5″ column, eluting with neat EtOAc→7N NH3(MeOH):EtOAc 2%→3%→5%]. Fractions containing product were pooled and concentrated in vacuo. The product was recrystallized from neat acetonitrile [heated until boiling, cooled to −20° C. for 16 h], giving the title material as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.72-1.79 (m, 2H), 2.05 (ddd, J=13.1, 5.8, 3.3 Hz, 2H), 2.13-2.25 (m, 4H), 2.40 (s, 3H), 3.29-3.40 (m, 2H), 4.49-4.63 (m, 1H), 7.12 (br s, 2H), 7.39-7.44 (m, 1H), 7.50 (ddd, J=8.2, 7.2, 1.3 Hz, 1H), 7.71 (s, 1H), 7.72 (s, 1H), 7.92 (dd, J=7.9, 0.6 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.1, 0.5 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H). MS (ES+): m/z=417.13 (24) [MH+]. HPLC: tR=2.12 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:12](OC2C=CC(F)=CC=2F)=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:15][CH:16]=1)=O)[CH3:7])(=[O:4])=[O:3].N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC(C)(C)C)(=O)[NH:57][NH2:58]>ClCCl>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[N:13]=[C:12]2[NH:57][N:58]=[C:9]([NH:8][C@H:6]([CH3:7])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]2=[CH:16][N:15]=1
Reactant: C[C@H](CS(C)(=O)=O)NC(=O)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@H](CS(C)(=O)=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidine-5-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide (61.16 g, 122.5 mmol) was added to 600 mL dry dichloromethane, and the mixture was stirred under nitrogen. 2,6-lutidine (43.0 mL, 184 mmol) was added, and the mixture was cooled to 0° C. in an ice bath for 30 minutes with stirring. Trifluoroacetic anhydride (31.0 mL, 184 mmol) was added dropwise over five minutes, and the reaction mixture was stirred for 10 minutes at 0 ° C. The ice bath was removed and the reaction mixture was stirred for 3.5 hours. The reaction mixture was then cooled to 0 ° C. in an ice bath for 30 minutes, and tert-butyl carbazate (24.36 g, 184 mmol) was added in portions over five minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was again cooled to 0° C. in an ice bath for 30 minutes, and trifluoroacetic acid (200 mL) was added in portions over 15 minutes. The reaction mixture was stirred for another 15 minutes, then the ice bath was removed and stirring was continued for two hours. The reaction mixture was concentrated under reduced pressure, and 500 mL dichloromethane was added to the residue. The mixture was cooled in an ice bath for 15 minutes, and 1.5 L of saturated aqueous sodium bicarbonate was slowly added in portions with stirring, resulting in an aqueous solution of pH=8 and the formation of a precipitate. The precipitate was collected by filtration and rinsed with water, followed by dichloromethane, and dried under vacuum at 80° C. to give 30.15 g (60%) of [6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-((R)-2-methanesulfonyl-1-methyl-ethyl)-amine. Mp=177.7-178.8° C., MS(M+H)=384.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:5][CH2:6]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(C)cc5)nc34)CC2)cc1
Yield: 41 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 41%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[C:25]4=[O:32])=[C:19]([CH3:33])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:25]4=[O:32])=[C:19]([CH3:33])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccn(-c2c(C)cc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2C)c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(O)c1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
830 mg (1.70 mmol) of the compound from Example 71A are dissolved in 50 ml of anhydrous dichloromethane and cooled to −78° C. At this temperature, 3.40 ml (3.40 mmol) of a 1 normal boron tribromide solution in dichloromethane are added dropwise such that the temperature does not exceed −65° C. The mixture is stirred at −78° C. for 2 h and then at RT for 2.5 h and kept at −20° C. for 15 h. At room temperature, the solution is carefully added to a saturated aqueous sodium bicarbonate solution. After phase separation, the aqueous phase is extracted three times with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure. This gives 907 mg (69% of theory, purity according to LC-MS 61%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH2:47][C@@H:48]3[CH2:52][CH2:51][CH2:50][N:49]3[C:53](=[O:57])[CH2:54][C:55]#[N:56])[N:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][C:34]=3[F:46])[C:25]=12>CC#N.C(Cl)Cl.O>[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH2:47][C@@H:48]3[CH2:52][CH2:51][CH2:50][N:49]3[C:53]([C:54](=[CH:3][C:2]([CH3:5])([N:6]3[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[CH3:1])[C:55]#[N:56])=[O:57])[N:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:35][C:34]=3[F:46])[C:25]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CN1CCN(C(C)(C)C=O)CC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: O
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 2-methyl-2-(4-methylpiperazin-1-yl)propanal (108.3 mg, 0.6400 mmol) in MeCN (6 mL), was added pyrrolidine (0.11 mL, 1.27 mmol). The reaction mixture was cooled to 0° C., followed by the addition TMS-Cl (0.11 mL, 0.85 mmol). The ice bath was removed and the mixture stirred for 10 min before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (100 mg, 0.210 mmol). The mixture was stirred for 3 h at room temperature, checking progress by TLC and LC-MS. To the mixture was added 15 ml water and extracted with dichloromethane. The combined organic layer was washed by brine, dried over by Na2SO4, filtered, and evaporated. The residues was loaded on TLC plate and purified using MeOH:CH2Cl2=9:100 to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (93 mg, 0.1491 mmol, 70.30 2% yield) as a light yellow powder. LC-MS (ES, m/z): 625 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), 3-(hydroxymethyl)benzeneboronic acid (0.555 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate) followed by trituration with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 449 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a white solid, mp 186-187° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4C=CC=CC=4)([C:28]4C=CC=CC=4)[C:22]4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH:47]1([C:52](Cl)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[CH:47]1([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([CH3:22])([CH3:34])[CH3:28])[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)n1cnc(-c2ccc3c(c2)c(-c2cccc(NC(=O)C4CCCC4)c2)nn3C2CCCCO2)n1

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added cyclopentanecarbonyl chloride (0.060 mL, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). Completion of the reaction necessitated the addition of 2 more equivalents of reagents and a total reaction time of 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 699 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][CH:18]2[CH2:24][O:25][CH2:26][CH:17]12)=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C:14]([N:16]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][CH:18]2[CH2:24][O:25][CH2:26][CH:17]12)=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1C2COCC2C[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N1C2COCC2C[C@H]1C(=O)O

Procedure:
Dissolve 1-[N-benzyloxycarbonyl-(S)-alanyl]hexhydrofuro[3,4-b]pyrrole-2(S)-carboxylic acid in methanol. Add 10% palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. Filter the mixture and concentrate in vacuo to give 1-[(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2(S)-carboxylic acid.
Reaction SMILES: COC([C:5]1([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:9][CH:8]=[C:7]([OH:10])[C:6]1=[O:11])=O.O1CCOCC1.Cl>O>[OH:11][C:6]1[C:7](=[O:10])[CH2:8][CH2:9][C:5]=1[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COC(=O)C1(Cc2ccc3ccccc3c2)CC=C(O)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(Cc2ccc3ccccc3c2)=C1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
Step b) A mixture of 3-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-cyclopent-3-enecarboxylic acid methyl ester (3.0 g, 10.71 mmol), dioxane (50 ml), and HCl (10N, 50 ml) was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, poured into H2O and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether gave a brown solid (1.75 g, 69%): m.p. 120°-122° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3]O.[BrH:16]>>[Br:16][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Br
Reactant: CC(C)CCCC(C)CCCC(C)CO
Product: CC(C)CCCC(C)CCCC(C)CBr

Procedure:
A 21.44 g. (0.10 mol) portion of (±)-2,6,10-trimethylundecan-1-ol was stirred and heated to 140° C. as HBr gas was bubbled through the liquid for 4.0 hr. The two-phase mixture was cooled, diluted with petroleum ether (B.P. 30°-60° C.) and washed with H2O, saturated aqueous NaHCO3 solution and brine. The solution was filtered through 100 g of Woelm neutral alumina III, stripped of solvent, and distilled to give (±)-1-bromo-2,6,10-trimethylundecane as a colorless liquid: bp 97°-99° C./0.10 mmHg.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:29])[C:20]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([CH3:29])[C:20]([S:25]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Cc1ccccc1S(=O)(=O)N1CCN(c2cccc3nc(N)nc(N)c23)CC1
Yield: 37 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and o-toluenesulfonyl chloride (78.2 mg; 0.41 mmol) to obtain 29.3 mg. (37% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (br s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.73 (m, 3H), 7.47 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 6.99 (m, 2H), 6.82 (d, J=7.2 Hz, 1H), 5.93 (br s, 2H), 3.67 (d, J=12 Hz, 2H), 3.12 (d, J=12.0 Hz, 2H), 2.94 (t, J=11.5 Hz, 1H), 2.78 (t, J=11.5 Hz, 2H), 2.62 (s, 3H).