Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][O:34][C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccccc1Cl
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Product: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Ex. 1, intermediate a) and (2-chloro-phenyl)-methanol (CAS Reg. No. 17849-38-6). Light yellow solid (48%). MS (Turbo Spray): m/z=468.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:3].[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[ClH:22]>CCO.O.[Ag-]=O>[Cl-:22].[CH3:1][N+:2]([CH3:3])([CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCI
Reactant: Cl
Reactant: CN(C)CC1(C)COC(=O)N1
Agent: O=[Ag-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC[N+](C)(C)CC1(C)COC(=O)N1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 4-((dimethylamino)methyl)-4-methyloxazolidin-2-one (1.03 g, 6.51 mmol) in EtOH (5 ml) was added propyl iodide (2.5 ml, 26 mmol) in a sealed tube was heated to 50° C. for 16 h, then 70° C. for 6 h, then cooled to RT. Potassium carbonate (300 mg, 2.1 mmol) was added, and the solution was heated to 70° C. for an additional 20 h, cooled to RT, and diluted with H2O (10 ml). Silver (I) oxide (850 mg, 3.67 mmol) was added, and stirred for 30 min, and then 6.0 M HCl (˜400 ul) added until the solution was pH 7. The suspension was filtered through Celite and evaporated. ESI/APCI expected for C10H21N2O2+: 201.16. Found: 201.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[S:22][S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:35])[CH3:36])([OH:39])=[O:38]
Reactant: Cc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 89.2 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5 -methyl-phenyldisulfanyl]-4-methylbenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.8 mmol) from Example 33, 20 mL dichloromethane, 20 mL trifluoroacetic acid and 2.0 mL anisole. The crude product was recrystallized from methanol/water to afford 1.4 g of the title compound, mp 216°-218° C.
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[CH2:31]([NH:38][CH2:39][CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([NH:51][C:52]3[S:53][CH:54]=[CH:55][C:56]=3[C:57](O)=[O:58])=[C:45]2[CH:44]=[CH:43]1>>[CH2:31]([NH:38][CH2:39][CH2:40][NH:41][C:57]([C:56]1[CH:55]=[CH:54][S:53][C:52]=1[NH:51][C:50]1[CH:49]=[CH:48][N:47]=[C:46]2[NH:42][CH:43]=[CH:44][C:45]=12)=[O:58])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Reactant: NCCNCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCNCc1ccccc1)c1ccsc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br. s.) 11.66 (1H, br. s.) 8.27 (1H, t, J=5.73 Hz) 8.15 (1H, d, J=5.52 Hz) 7.48 (1H, d, J=5.86 Hz) 7.25-7.39 (6H, m) 7.15-7.24 (1H, m) 6.98 (1H, d, J=5.47 Hz) 6.92 (1H, d, J=0.10 Hz) 6.46 (1H, dd, J=3.42, 1.76 Hz) 3.73 (2H, s) 3.41 (2H, q, J=6.44 Hz) 2.68 (2H, t, J=6.56 Hz)
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][C:22]([OH:24])=O)[CH:10]=[C:11]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:12]=1[OH:13])[CH2:4][CH3:5])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:16]([CH:15]([O:14][C:11]1[CH:10]=[C:9]([CH:20]=[CH:21][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[C:29]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:30]([OH:37])=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=2)=[O:24])[CH:8]=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:12]=1[OH:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1O
Reactant: CCC(CC)Oc1cc(C=CC(=O)O)cc(OC(CC)CC)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)Oc1cc(C=CC(=O)NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(OC(CC)CC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To the solution of 3-[3,5-bis-(1-ethylpropoxy)-4-hydroxyphenyl]acrylic acid (30 mg, 0.09 mmol) in DMF (0.2 ml) and Et3N (10 μl), was added 4-aminomethyl-2,6-di-t-butylphenol (23 mg, 0.10 mmol) at 0° C. and was added the solution of BOP (44 mg, 0.10 mmol) in CH2Cl2 (0.6 ml). The solution was stirred for 30 minutes at 0° C. and then was stirred for 2 hours at room temperature. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:5), yielding 25 mg (50%) of the title compound as a yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:35].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:35])[C:17]=2[N:26]=1
Reactant: [NH4+]
Reactant: ClCc1nc2cnc3ccccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccccc2c2c1nc(CCl)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (3.8 g of 77% pure material, 14.2 mmol) was added to a stirring solution of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (3.0 g, 9.50 mmol) in dichloromethane (60 mL). After 15.5 hours, ammonium hydroxide (12 mL) and then p-toluenesulfonyl chloride (2.2 g, 11.4 mmol) were added to the stirring solution and the biphasic mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with water (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic fractions dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 3-20% methanol in dichloromethane) to provide 1.6 g of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:43]=[CH:42][C:17]([CH:18]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][O:35][C:36](=[O:41])[CH2:37][C:38]([CH3:40])=O)[CH2:29][CH2:28]2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.[NH2:44]/[C:45](/[CH3:51])=[CH:46]\[C:47]([O:49][CH3:50])=[O:48]>C(O)(C)C>[CH3:40][C:38]1[NH:44][C:45]([CH3:51])=[C:46]([C:47]([O:49][CH3:50])=[O:48])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:37]=1[C:36]([O:35][CH2:34][CH2:33][N:30]1[CH2:29][CH2:28][N:27]([CH:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:43][CH:42]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)=[O:41]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2CCN(CCOC(=O)CC(C)=O)CC2)cc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(OC)cc3)c3ccc(OC)cc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 39.3 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(4,4'-dimethoxybenzhydryl)-1-piperazinyl]ethylacetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dimethoxybenzhydryl)-1-piperazinyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 76°-80° C. (sintering). Yield 39.3%. IR(Nujol)cm-1 : 3330, 1695, 1680(shoulder). NMR(CDCl3) δ: 2.36(6H,s, ##STR21## 3.57(3H,s,--COOCH3), 3.75(6H,s,OCH3), 4.11(1H,s,>N--CH<), 4.15(2H,t,J=6, --COOCH2CH2 --), 5.08(1H,s,C(4) --H), 5.80(1H,broad s, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH3:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(C)c2snc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 36 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and tetramethyltin; MS (m/z): 315.32 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14]C(C#N)=[CH:12][C:11]=3[O:18][CH2:19][CH3:20])[NH:9][C:5]=2[CH:4]=1.[OH-:24].[Na+].[CH2:26]([OH:28])[CH3:27]>>[ClH:2].[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:27]([C:26]([OH:24])=[O:28])=[CH:12][C:11]=3[O:18][CH2:19][CH3:20])[NH:9][C:5]=2[CH:4]=1
Reactant: [OH-]
Reactant: CCO
Reactant: CCOc1cc(C#N)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cl
Agent: [Na+]
Product: CCOc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 5,6-dichloro-2-(4-cyano-2-ethoxyphenyl)benzimidazole hydrochloride (16.3 g, 44.2 mmol), prepared as in Preparation 12, 32% NaOH (40 ml) in ethanol (100 ml) was refluxed for 8 h. After cooling to room temperature the organic solvent was removed under vacuum and the aqueous phase was acidified with 37% HCl, stirred for 1 h. The solid was filtered, washed with water (100 ml) and dried at 50° C. under vacuum to give 12 g of the title compound as a light brown powder (yield 70%), mp>250° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=1[OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.CC(=O)OCC>CO>[CH2:1]([C:6]1[C:7](=[O:8])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(O)ccc1O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCCCCC1=CC(=O)C=CC1=O
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To the solution of 360 mg (2 mmol) of 21 in methanol, 650 mg (2 eq) of FeCl3 was added. The reaction mixture was stirred for 1 hr, and the solvent was removed. Silicagel chromatography (hexane:EA=20:1) gave 210 mg (59% yield) 22 as a brown solid.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH:45]1(N)[CH2:49]CC[CH2:46]1.N[C:52]1C=CC=C[CH:53]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:30][CH2:49][CH2:45][CH2:46]5)=[O:27])=[CH:21][CH:20]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:52][CH2:53]1)[CH2:5][O:12][CH2:9]2
Reactant: NC1CCCC1
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)NC4CCCC4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing cyclopentylamine as the aniline component. (46%, MS=462.4 (M+H))
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH:17]=[CH:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 39 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.383 mmol) was reacted with (3-azido-propenyl)-benzene, which was synthesized using previously reported methods (Rad et al., Tetrahedron Letters 2007, 48, 3445-3449), (0.079 g, 0.460 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.049 g, 39%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), δ 7.44 (d, 2H), δ 7.29 (m, 3H), δ 6.73 (d, 1H), δ 6.53 (s, 1H), δ 6.42 (m, 2H), δ 5.24 (d, 2H), δ 3.07 (t, 2H), δ 2.88 (t, 2H) ppm; 13C 148.6, 145.3, 139.4, 139.2, 129.8, 129.7, 129.6, 128.5, 128.4, 127.6, 54.6, 47.3, 45.9, 26.3, 22.6 ppm; HRMS (ESI) calcd for C16H19N6(M+) 295.1665. found 295.1670.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O.COCCOC.ClCCl.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>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[C:12]1[S:13][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: Brc1ncccn1
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: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncccn2)s1
Yield: 25.9 %

Procedure:
A mixture of Na2CO3 (3.16 g) and 5-formyl-2-thiopheneboronic acid (2.4 g, 15.1 mmol) in water (15 mL) were added to a solution of 2-bromopyrimidine (2 g, 12.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (480 mg, 0.46 mmol) in DME (30 mL) and the mixture was heated to reflux for 24 hr. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 620 mg (26%) of the title compound. MS 191 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:3]=1.OS(O)(=O)=O.C([O-])(O)=[O:19].[Na+].[CH3:23][CH2:24][OH:25]>>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]([O:25][CH2:24][CH3:23])=[O:19])[CH:3]=1
Reactant: CCO
Reactant: Cn1nc(C(C)(C)C#N)cc1N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc(N)n(C)n1
Yield: 44 %

Procedure:
A mixture of 2-(5-amino-1-methyl-1 H-pyrazol-3-yl)-2-methylpropanenitrile (1.4 g, 8.5 mmol) in EtOH (30 mL) was treated with cone. H2SO4 (3 mL) and the resulting mixture was refluxed for 10 days. The reaction mixture was neutralized with saturated aq NaHCO3 solution, and the mixture was extracted with EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. Recrystallization (EtOAc/petroleum ether) provided ethyl 2-(5-amino-1-methyl-1 H-pyrazol-3-yl)-2-methylpropanoate (0.8 g, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ5.13 (s, 1 H), 5.04 (s, 2 H), 4.00 (q, J=6.9 Hz, 2 H), 3.41 (s, 3 H), 1.11 (t, J=6.9 Hz, 6 H); MS (ESI) m/z: 212.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:13])[CH2:4][CH3:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:29]=O.S(O)(O)(=O)=O.[CH3:40][S:41][C:42](=[NH:44])[NH2:43].C([O-])(=O)C.[Na+]>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]2[C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[C:10]([CH2:9][O:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[NH:44][C:42]([S:41][CH3:40])=[N:43]2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CCOCC(=O)CC(=O)OCCCc1ccccc1
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOCC1=C(C(=O)OCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(SC)N1
Temperature: 60 °C
Yield: 6.2 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate (2.0 g, 5.96 mmol), 3,4-dichlorobenzaldehyde (1.15 g, 6.56 mmol), 2-methyl-2-thiopseudourea sulfate (0.913 g, 3.28 mmol) and sodium acetate (0.27 g, 3.28 mmol) was stirred in N,N-dimethylformamide (10 mL) for 24 hours at room temperature, then heated to 60° C. for 5 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. This oil was further purified by flash chromatography and RP-HPLC to give the title compound (114 mg) as an oil. The oil can be converted into a mono or dihydrochloride salt, by dissolution in ether and addition of one or two equivalents of hydrogen chloride. Electrospray MSm /z 564/566 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].O1CCCC1>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1nc2scnc2c(=O)n1Cc1ccccc1)N(CCN(C)C)Cc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
A solution of 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}-propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (14, 1 equiv) and 4-bromobenzaldehyde (2 equiv) in methanol is treated with a solution of sodium cyanoborohydride in tetrahydrofuran (1M, 2 equiv). Acetic acid is added to obtain a pH of 6-7 and the reaction is warmed at 60° C. for 18 h. An additional 2 equivalents of 4-bromobenzaldehyde and sodium cyanoborohydride are added after 18, 42 and 66 hours while maintaining the pH at 6-7 with acetic acid. After warming 90 h at 60° C., the reaction is concentrated and the residue is partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer is washed with brine, dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with EtOAc to 5% NH3-EtOH/EtOAC gives 6-benzyl-5-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)[1,3]thiazolo[5,4-d]pyrirnidin-7(6H)-one (2-1).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].F[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1.O>COCCOC.C(OCC)(=O)C>[CH:1]1([O:6][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(OC2CCCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
Cyclopentanol (25 ml, 275 mmol) was added to sodium tert-butoxide (4.05 g, 42.2 mmol) to give a thick suspension which was diluted with 1,2-dimethoxyethane (35 ml) and heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5 g, 10.54 mmol) was added to the resulting solution which was then stirred under nitrogen at 50° C. for 20 hours. The mixture was cooled and water and ethyl acetate were added. The layers separated and the aqueous layer washed again with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure at 40° C. The residue was loaded in cyclohexane (50 ml) onto 330 g silica cartridge and eluted firstly with a 0-100% ethyl acetate in cyclohexane gradient over 10 column volumes and then with a 0-30% methanol in ethyl acetate gradient. Product-containing fractions were combined and evaporated to give the title compound as a white foam (2.51 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.94) (0.349 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.267 g, 50%). MS (ISP) 532.1 [(M+H)+]; mp 209° C.