Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:26]1[N:27]=[C:28]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][N:32]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:29]2=[N:30][CH:31]=1>CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:26]3[N:27]=[C:28]4[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][N:32]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:44])([CH3:43])[CH3:45])[C:29]4=[N:30][CH:31]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of 6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole (0.51 g, 0.616 mmol), methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.18 g, 0.486 mmol) in 6 mL of DMF were added CuI (0.04 g, 0.21 mmol) and Pd(PPh3)4 (0.057 g, 0.045 mmol) in one portion under nitrogen at room temperature. Then the reaction mixture was degassed by bubbling nitrogen for 10 minutes and stirred at 90° C. under nitrogen for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give methyl 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.182 g, 85.2%) as a yellow solid. LCMS: (M+H)+=440; 1H NMR (300 MHz, DMSO): δ 9.13 (s, 1H), 8.83-8.78 (m, 1H), 8.70 (s, 1H), 7.63 (dd, 1H, J1=9.6 Hz, J2=2.1 Hz), 7.23 (dt, 1H, J1=9.3 Hz, J2=2.1 Hz), 6.30 (s, 2H), 4.13 (s, 3H), 3.92 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][C:9]=2[CH2:11][CH3:12])[C:4](I)=[N:3]1.[C:17]([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][C:9]=2[CH2:11][CH3:12])[C:4]([CH3:17])=[N:3]1
Reactant: CCc1cc(C(=O)O)cc2c(I)nn(C)c12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(C(=O)O)cc2c(C)nn(C)c12
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a degassed solution of methyl 7-ethyl-3-iodo-1H-indazole-5-carboxylic acid (100 mg, 0.30 mmol) in DME (2.5 mL) was added degassed boroxine solution (50%, 0.28 mL) followed by palladium tetrakistriphenylphosphine (3.5 mg, 0.003 mmol) and 2 M Na2CO3 (0.57 mL). The mixture was heated in a microwave reactor (very high absorption setting) at 125° C. for 10 minutes and then at 165° C. for 10 minutes. The reaction was extracted with EtOAc and washed with saturated aqueous NaCl. The organic extract was reduced and the crude material was purified by silica gel chromatography (40 g column) using 0-40% EtOAc/heptane to afford methyl 7-ethyl-3-methyl-1H-indazole-5-carboxylic acid (18 mg, 27%).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][N:39]([CH3:40])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCC(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(S(=O)(=O)CCN(C)C)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (59 mg, 0.11 mmol) and 40% aqueous dimethylamine (5 mL) in THF (25 mL) was stirred at room temperature for 15 min. The solvent was removed under vacuum and the residue was diluted with water to give 63 mg (99% yield) of N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.99 (d, J=7.9 Hz, 1H), 7.55 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 4.02-3.89 (m, 6H), 3.85-3.78 (m, 4H), 3.14-3.11 (m, 2H), 2.97 (dt, J=12.2, 2.6 Hz, 2H), 2.84-2.77 (m, 3H), 2.28 (s, 6H), 2.17 (br dd, J=13.2, 2.6 Hz, 2H), 2.00 (ddd, J=25.1, 11.8, 4.1 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([C:33]([OH:35])=[O:34])[C:24]=1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36]([C:24]3[C:25]([C:33]([OH:35])=[O:34])=[CH:26][C:27]4[C:32]([CH:23]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:37])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc2ccccc2cc1C(=O)O

Procedure:
To 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,3-naphthalenedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL) was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative hplc (Gilson) to yield 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenecarboxylic acid. This compound was dissolved in 3 mL of DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol) to which was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and purified by preparative hplc (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to an amine column which was rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.7 mg (3.4%) of the above named product. LC-MS m/z 798 (M+H)+, 1.42 min (ret time).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[CH2:12][CH2:11]1.[OH-].[Na+]>C1COCC1.CO>[CH3:24][C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:17][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:26])=[O:2])[CH2:11][CH2:12]2)=[O:25])[N:19]=1
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)Cn2nc(C)cc2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)O)CC2)n1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid methyl ester (0.848 g, 2.38 mmol) is dissolved in 10 mL of 1:1 THF/MeOH. 2 mL of 15% aq NaOH is added and the mixture is stirred overnight. The mixture is concentrated to dryness and suspended in 50 mL of H2O. The pH of the solution is adjusted to 4 by careful addition of conc. HCl. The aqueous phase is extracted with 3×100 mL of CH2Cl2. The organic phase is dried with MgSO4, filtered and concentrated to give 0.730 g of {4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid in 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC1CC1
Yield: 67 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (53 mg, 67%) which was obtained as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCCC3)cc(Cl)c1O2

Procedure:
Cyclopentyl amine (0.27 ml, 2.7 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was processed as described in the synthesis of Example 139k to obtain the title compound. Yield: 0.37 g, (83%); 1H NMR (CDCl3): δ 1.38 (m, 2H, CH2), 1.72 (m, 4H, 2CH2), 1.87 (m, 2H, CH2), 2.7 (s, 3H, CH3), 2.96 (s, 1H, NH), 3.15 (m, 1H, CH), 3.38 (s, 2H, CH2), 3.92 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.57 (s, 1H, Ar), 7.83 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar), 9.64 (s, 1H, NH); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: C[C@@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,4,4,4-pentafluoro-butylamine, the title compound was prepared in the same manner as described for example 1c. White solid (85%). MS: m/e=622(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145) (50 mg, 0.19 mmol) was coupled to aniline (60) (43 mg, 0.23 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13]([C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[O:31])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc2c(Sc3nc4ccccc4[nH]3)cccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccnc2c(S(=O)c3nc4ccccc4[nH]3)cccc12

Procedure:
The product of step (b) above (390 mg) in ethyl acetate (20 ml) was cooled to -5° and treated with m-chloroperbenzoic acid (273 mg of 85% pure material). The temperature was allowed to rise to ambient. The reaction mixture was then diluted with ethyl acetate and methylene chloride, and then washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The solution was dried and evaporated. Column chromatography (SiO2 /ethyl acetate) gave the title compound 140 mg, mp 178°-9° (d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([Cl:18])=[N:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)(C)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:13][C:12]([Cl:18])=[N:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2nc(Cl)nc(Cl)c2CN1Cc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C1c2nc(Cl)nc(N3CCOCC3)c2CN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
6-benzyl-2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidin-7(6H)-one (cw) (0.125 g, 0.000425 mol), isopropyl alcohol (2.90 mL), N,N-diisopropylethylamine (0.150 mL, 0.861 mmol) and morpholine (0.0556 mL, 0.638 mmol) were mixed and the mixture was stirred for 30 minutes. The reaction mixture was concentrated. The resulting residue was chromatographed through silica gel (40 g, 0-5% MeOH in dichloromethane) to give the compound cx (0.126 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([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)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:36][CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3cc(-c4ccc(CC(=O)Nc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
A mixture of cis-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.18 mmol), N1-phenyl -2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (0.81 g, 2.40 mmol), tetrakis(triphenyl-phosphine)palladium (70 mg, 0.131 mmol) and sodium carbonate monohydrate (0.65 g, 2.40 mmol) in ethylene glycol dimethyl ether (16 mL) and water (8 mL) was heated at 85° C. under an atmosphere of nitrogen for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane/methanol (9:1) as an eluent to give N1-phenyl-2-(4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-5-yl}phenyl)acetamide (0.74 g, 62%): 1H NMR (DMSO-d6, 400 MHz) 10.20(s, 1H), 8.66(s, 1H), 7.81(s, 1H), 7.62(d, 2H), 7.52(d, 2H), 7.41(d, 2H), 7.31(t, 2H), 7.04(t, 1H), 4.83(m, 1H), 3.70(s, 2H)<2.05-2.5(m, 13H), 2.17(s, 3H), 1.59-1.77(m, 4H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-100% acetontrile over 10 min, 1 mL/min) tr 8.23 min.; MS:MH+ 543.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[O:9][N:8]=2)[CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[O:9][N:8]=2)[CH:2]=1
Reactant: CC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
A solution of the product of Example 68 (265 mg, 1.0 mmol) in ethanol (5 mL) was stirred with sodium borohydride (Aldrich, 83 mg, 2.2 mmol) at room temperature for 16 hours. The inorganic solid was filtered off with a syringe filter and the liquid mixture was purified by preparative HPLC (Gilson, column, Xbridge® 5 μm, 30×100 mm. eluting solvent, acetonitrile/water (pH=10, NH4HCO3—NH3.H2O buffer), v. 5/95 to 95/5 over 35 minutes, flow rate, 40 mL/minute, uv, 234 nm). Fractions of the desired product were collected and concentrated to give the desired product. 1H NMR (300 MHz, CD3OD) δ 1.51 (d, J=6.7 Hz, 3H), 4.97 (q, J=6.6 Hz, 1H), 7.57-7.73 (m, 3H), 8.13 (dt, J=7.6, 1.5 Hz, 1H), 8.28 (t, J=1.8 Hz, 1H), 8.57 (dt, J=7.9, 1.8 Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz, 1H), 9.30 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCl/NH3) m/z 268 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:11]1)[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:11][C@@H:10]1[CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
Acetic anhydride (0.035 ml, 0.38 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (123 mg, 0.25 mmol) and triethylamine (0.069 ml, 0.50 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (92 mg) as a pale yellow solid.
Reaction SMILES: [K].[CH2:2]([O:4][C:5]([C:7]1[O:11][C:10](=[S:12])[NH:9][N:8]=1)=[O:6])C.IC.[CH3:15][CH2:16]O>>[CH2:15]([SH:12]=[C:10]1[NH:9][N:8]=[C:7]([C:5]([O:4][CH3:2])=[O:6])[O:11]1)[CH3:16]
Reactant: CCO
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Agent: [K]
Solvent: CI
Product: CC[SH]=c1[nH]nc(C(=O)OC)o1
Yield: 50 %

Procedure:
Following the procedure of Partyka and Crenshaw in U.S. Pat. No. 4,001,238, a solution of ethyl-1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (4.1 g, 24 mmol) and iodomethane (6.7 g, 47 mmol) are heated for 1 hour at reflux in EtOH (20 mL). A solid is removed by vacuum filtration, and the filtrate is concentrated. Water (40 mL) is added to the resultant material, a solid is isolated by vacuum filtration, dried at 50° C./0.5 mmHg overnight to afford the desired product (2.3 g, 50%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C)C>C(Cl)Cl>[CH:2]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23](=[O:36])[C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][CH:29]=3)[CH:9]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C=O)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Yield: 24 %

Procedure:
Following the same procedure as described in Example 20, step 6 (scheme 20), but substituting compound 190 for compound 199, title compound 200 was obtained in 24% yield [after column chromatography (eluent: 5% isopropanol in DCM)].
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:25]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:32]2[C:27]([N:28]([CH3:43])[C:29](=[O:42])[N:30]([CH3:41])[C:31]2=[O:40])=[CH:26]1)[CH2:4][S:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:1][CH2:2][C@H:3]([N:25]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:32]2[C:27]([N:28]([CH3:43])[C:29](=[O:42])[N:30]([CH3:41])[C:31]2=[O:40])=[CH:26]1)[CH2:4][S:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:54])=[O:53]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CO)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](COS(C)(=O)=O)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-6-(1-Hydroxy-3-(tritylthio)propan-2-yl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (2.5 g, 4.25 mmol) was dissolved in DCM (80 mL) and triethylamine (1.186 mL, 8.51 mmol) was added followed by methanesulfonyl chloride (0.398 mL, 5.10 mmol). The mixture was stirred at room temperature for 2 hours, further methanesulfonyl chloride was added and the mixture stirred for 50 mins. The reaction mixture was quenched with sat. NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc in iso-hexane gave the title compound.