Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (200 mg, 0.5 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.35 mL, 2.5 mmol). 3-Methoxybenzenesulfonyl chloride (113 mg, 0.55 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C., the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (120 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:33]([CH3:47])[CH2:34][CH2:35][N:36]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:36][CH2:35][CH2:34][CH:33]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[O:15][C:16]2[N:17]=[C:18]([C:22]#[N:23])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(C#N)n2)c2ccc(C#N)cc2)CC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C(Oc2cccc(C#N)n2)c2ccc(C#N)cc2)CC1

Procedure:
Using general procedure C with 4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 43) (200 mg, 0.48 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (168 mg, 0.77 mmol) and then using general procedure D afforded 6-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-cyano-phenyl)-methoxy]-pyridine-2-carbonitrile as a colourless syrup (40 mg, 22% over 3 steps).
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH:35][C:2]2[C:3]3[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24]
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Reactant: CCOc1ccc(CCNCCN)cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CCNCCNc2nc(C)nc3c2c(C)c(C)n3-c2c(C)cc(C)cc2C)cc1OC

Procedure:
Heat a solution of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (340 mg, 1.1 mmol) and N-(4-ethoxy-3-methoxy-phenethyl)-ethylenediamine in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19].C(OCC)(=O)C>O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to a solution of 20 g (0.5 mol) of sodium hydroxide in 250 ml of water, and the mixture was stirred at 80° C. for 2 hours. The mixture solution was cooled by ice-water, 71.8 g (0.2 mol) of 2-furancarbonyl chloride and a solution of 24 g (0.6 mol) of sodium hydroxide in 100 ml of water were simultaneously added thereto over approximately 1 hour. The reaction solution was slowly returned to room temperature and stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and the mixture was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected, 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried-under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:9])([CH3:8])[O:6][NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH:10]1[CH:19]=[C:18]2[C:20]([O:22][C:23](=O)[C:16]3=[C:17]2[C:12](=[CH:13][C:14]([N+:25]([O-:27])=[O:26])=[CH:15]3)[CH:11]=1)=[O:21]>N1C=CC=CC=1>[Si:5]([O:6][N:7]1[C:23](=[O:22])[C:16]2[CH:15]=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=[C:12]3[C:17]=2[C:18](=[CH:19][CH:10]=[CH:11]3)[C:20]1=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O
Yield: 85.1 %

Procedure:
O-(tert-Butyldimethyl-silyl)hydroxylamine (1.8 g, 12.3 mmol) was added to a solution of 3-nitro-1,8-naphthalic anhydride (2.0 g, 8.2 mmol) in 50 mL of pyridine. The solution was refluxed for 4 hours and concentrated in vacuo. Purification as described in Example A-1 gave 2.6 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccncc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccncc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-4-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(OC)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of compound 53 (22.4 g, 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][CH2:35][CH3:36]>>[CH2:35]([NH:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:24])[CH3:36]
Reactant: CCNc1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CCNc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 2-(aminomethyl)-N-ethyl-5-fluorobenzenamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.1 Hz, CH3), 1.63 (6H, s, 2×CH3), 3.10 (2H, q, J=7.1 Hz, CH2), 4.04 (4H, m, 2×CH2), 4.45 (2H, d, J=6.6 Hz, NCH2), 5.27 (2H, s, OCH2), 6.28 (1H, broad s, aromatic), 6.31 (1H, m, aromatic), 6.98 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics), 7.54 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN4O4 [M+H+]: 481.2251. Found: 481.2254.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:43](Cl)(=[O:45])[CH3:44]>C(#N)C>[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccc(C)c(CCN2CCC(c3c[nH]c4ccc(F)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Polymer bound 3-[1-(2-{5-amino-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1H-indole (100 mg, 100 μmol), triethylamine (90 μL), and dimethylaminopyridine (0.50 mL of an 0.2 M solution in dry acetonitrile) were mixed in a reactor tube. The mixture was cooled to 0° C. and treated with acetyl chloride (0.50 mL of an 1M solution in dry acetonitrile). The reaction mixture was left at 0° C. for 2 h. The resin was filtered off and washed with dry acetonitrile (3×1 mL). The resin was treated for 1 h with 1 mL of a mixture of sodium methoxide (2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) and tetrahydrofuran (50 mL). After filtration, the resin was washed with methanol (1 mL). The combined filtrates were loaded on a pre-conditioned ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, part no. 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. Evaporation of volatile solvents afforded the title compound as a yellow oil (6 mg, 15 μmol). LC/MS (m/z) 394 (MH+), RT=1.98, purity: 88%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε-(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine. Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine was treated with 0.2 M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα-CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: NCCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and phenethylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:28]=2[CH:27]=[CH:26][N:25]=1>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:34]([C:29]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:36])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
(S)-4-[2-(4-Amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg) was dissolved in tetrahydrofuran at room temperature before treatment with triethylamine (129.8 μl) and isoquinoline-5-sulfonyl chloride (141.4 mg), the reaction mixture was then warmed to 50° C. and stirred for 6 hours. Upon evaporation of the solvent in vacuo the residue was purified by flash column chromatography (SiO2; hexane/EtOAc 3:1) to afford title compound (S)-4-{2-[4-(isoquinoline-5-sulfonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (155 mg) as a white solid. MS (ISP): 512.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([F:29])[CH2:20]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([O:10][CH2:20][C:19]([F:30])([F:29])[F:18])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2,6-dichloro-3-hydroxy-benzaldehyde (114, 2.06 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL) were added cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (115, 1.00 g, 34.0%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](Cl)=[O:20])=[CH:11][N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])=[CH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cnc(Cl)nc2C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
N-Methylpiperazine (0.11 mL, 1 mmol) was added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carbonyl chloride (0.24 g, 1 mmol) in DCM (4 mL) at 0° C. The mixture was stirred at that temperature for 1 hr, and the solvent was then removed under vacuum to give (2-chloro-4-trifluoromethylpyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][SH:72])[CH3:65]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][S:72][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12])[CH3:65]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(F)(F)F)cc1F

Procedure:
A solution of 1-bromo-2-fluoro-4-trifluoromethyl-benzene (5.0 g, 20.6 mmol) and DIEA (7.2 mL, 41.1 mmol) in toluene (100 mL) is degased under N2 atmosphere. To this mixture, Pd2 dba3 (753 mg, 0.82 mmol), Xantphos (952 mg, 1.65 mmol) and 3-mercapto-propionic acid 2-ethyl-hexyl ester (5.9 mL, 25.7 mmol) are added and the reaction is heated at reflux overnight. The resulting mixture is filtered over a plug of silica (EtOAc) and the organic is concentrated in vacuo. Purification by silica chromatography (EtOAc/petroleum ether; 3:97) affords the desired product.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[O:16]>O.C1(C)C=CC=CC=1>[CH2:7]([CH:6]1[O:14][C:15](=[O:16])[NH:4][CH2:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: NCC(O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCC(Cc2ccccc2)O1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of KOH (9.4 g) in water (85 ml) was added to a stirred solution of the product from step (b) (5.1 g) in toluene (150 ml) at 0° C. A solution of phosgene (9.8 g) in toluene (78.4 ml =12.5% w/v) was added dropwise over 15 minutes and the mixture brought to room temperature, then stirred overnight. The aqueous-phase was separated and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give the desired product as a white solid (2.2 g), mp 106°-108° C. Elemental analysis was consistent with the proposed structure.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[O:45][CH3:46])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][C:37]=1[O:45][CH3:46])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (154 mg, 0.349 mmol), 4-[(phenethylamino)carbonyl]-3-methoxyphenylboronic acid (115 mg, 0.384 mmol), palladium tetrakistriphenyphosphine (24 mg, 0.021 mmol) and sodium carbonate (89 mg, 0.839 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (64 mg, 32%). 1H NMR (CDCl3-d) δ 1.62 (m, 4H), 2.16 (m, 16H), 2.87 (m, 2H), 3.57 (m, 2H), 3.90 (s, 3H), 4.83 (m, 1H), 7.31 (m, 7H), 7.95 (m, 1H), 8.22 (m, 2H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =569.3, Rt=2.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[S:7](=[O:13])(=[O:12])[N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:9][C:10]1=[O:11]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the title B compound in Example 9, 2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.87 g, 48.4 mmol) and 4-bromomethylbenzoic acid (10.42 g, 48.4 mmol) in CH2Cl2 (150 mL) is added DBU (14.5 mL, 96.9 mmol) at once and the mixture is stirred at RT overnight. The reaction mixture is washed two times with 1N aqueous HCl, one time with brine, then dried over anhydrous MgSO4 and concentrated to a small volume to crystallize the product. The solid is collected by filtration, washed with ethyl ether and dried under high vacuum to afford 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid: mp=175-177° C.; [M−1]−=419.