Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: CCS
Reactant: OCc1ccccc1O
Product: CCSCc1ccccc1O

Procedure:
49.6 g (0.4 mol) of 2-hydroxymethyl-phenol were reacted with 24.8 g (0.4 mol) of ethylmercaptan in 200 ml of solvent or diluent for 5 hours at 170° C. under autogenous pressure in a VA stirred autoclave. Depending on the solvent or diluent, working up by distillation gave the following yields of 2-ethylthiomethyl-phenol (Table 1):
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>>[N:4]1[CH:3]=[C:2]([CH2:11][CH2:10][CH2:9][CH2:8][OH:12])[CH:7]=[N:6][CH:5]=1
Reactant: C#CCCO
Reactant: Brc1cncnc1
Product: OCCCCc1cncnc1

Procedure:
5-bromopyrimidine and 3-butyn-1-ol was reacted as above, to give 5-pyrimidinebutanol as a colorless oil, bp 175°-180° C. (0.3 mm). Analysis Calculated for C8H12N2O: C, 63.13; H, 7.95; N, 18.41. Found: C, 62.83; H, 7.98; N, 18.63.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:29])[CH2:8][CH2:7][CH:6]([C:9]2[S:28][C:12]3[N:13]=[C:14]([CH3:27])[N:15]=[C:16]([CH2:17][NH:18][CH:19]4[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]4)[C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.CI.[C:32]([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[ClH:1].[CH3:2][C:3]1([CH3:29])[CH2:4][CH2:5][CH:6]([C:9]2[S:28][C:12]3[N:13]=[C:14]([CH3:27])[N:15]=[C:16]([CH2:17][N:18]([CH3:32])[CH:19]4[CH2:20][CH2:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24]4)[C:11]=3[CH:10]=2)[CH2:7][CH2:8]1
Reactant: Cc1nc(CNC2CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc(CN(C)C2CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}tetrahydro-2H-thiopyran-4-amine-1,1-dioxide hydrochloride (100 mg), CH3I (16 μL) and DMF (2.0 mL) was added K2CO3 (60 mg), followed by stirring at 50° C. overnight. The reaction mixture was left to be cooled, and a saturated aqueous NH4Cl solution was added thereto, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, and dried over MgSO4. The residue was purified by silica gel column. The obtained purified product was dissolved in EtOAc, and 4 M HCl/EtOAc (55 μL) was added dropwise thereto. The precipitate was collected by filtration and then dried to obtain N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-N-methyltetrahydro-2H-thiopyran-4-amine 1,1-dioxidehydrochloride (69 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([NH:32][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CC(C)(C)N
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC(C)(C)C)c(=O)n12
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -20° C. during 20 minutes. After stirring for 5 minutes, 6.47 g (0.088 mol) of tert.-butylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -18° C. and -20° C. during 50 minutes. The reaction mixture is stirred for 1 hour at the same temperature and then let to stand in the refrigerator overnight. For working up, the mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 15.5 g (74.7%) of the named product as light beige crystals after recrystallization from ethanol, m.p.: 164°-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCN1
Reactant: OCCc1cccc(Br)c1
Product: O=C1CCCN1c1cccc(CCO)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 2-(3-bromophenyl)ethanol and 2-pyrrolidinone. Purification was achieved by flash chromatography on silica gel eluting with ethyl acetate.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:30][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O)cc2)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a solution of 4-[l-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.40 g, 3.45 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.00 g, 5.18 mmol) and triphenylphosphine (1.36 g, 5.18 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g, 5.18 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.00 g (yield: 49.8%)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[SH:11][CH2:12][CH2:13][C:14]([NH2:16])=[O:15]>C1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]2[S:11][CH2:12][CH2:13][C:14](=[O:15])[NH:16]2)=[CH:3][CH:4]=1
Reactant: NC(=O)CCS
Reactant: COc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2NC(=O)CCS2)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 13.6 g of p-anisaldehyde and 10.5 g of 3-mercaptopropionic acid amide in 150 ml of benzene was heated at 80° C. for 2 hours. The crystals which separated out after leaving the reaction mixture for a night were collected by filtration and recrystallized from hot benzene to obtain colourless minute aciculates melting at 185.5° to 186.5° C. in an amount of 21 g corresponding to a yield of 94%.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]>CN(C)C=O>[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:8](=[O:10])[CH3:9])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]
Reactant: CC(=O)Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Triethylamine (80 μL, 0.57 mmol) and acetyl chloride (33 μL, 0.46 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 100 mg, 0.39 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (41 mg) as a green-brown solid (Yield 35%).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]=[C:19]2[S:20][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)=[CH:16][CH:17]=1)#[N:11]
Reactant: NC1(CCl)CCCC1
Reactant: N#Cc1ccc(N=C=S)cc1
Agent: Cl
Product: N#Cc1ccc(N=C2NC3(CCCC3)CS2)cc1

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1a to give 2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.O>CN(C=O)C.C(OCC)(=O)C>[Si:15]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(O)c1

Procedure:
A solution of 3-(2-hydroxyethyl)phenol (7.55 g, 0.0546 mol), TBSCl (8.22 g, 0.0546 mol) and imidazole (3.71 g, 0.0546 mol) in DMF was stirred for 18 h at room temperature. Water (200 mL) and ethyl acetate (200 mL) were added; the organic layer was separated and washed with water (2×100 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the desired product as a clear oil which was used without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([O:8]C)=[O:7].N1CC2C(=CC=CC=2)C[C@H]1C(O)=O.CO>O.O1CCCC1>[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Agent: O=C(O)[C@@H]1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of sodium hydroxide (0.62 g, 15.5 mmol) in water (100 mL) was added to a solution of 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (5.62 g, 14.0 mmol) in tetrahydrofuran (100 mL). The solution was stirred overnight at room temperature. Tic indicated that the reaction was not complete. 1 M NaOH (20 mL) was added and the mixture was heated at reflux for 6 h. Methanol (100 mL) was added and the mixture was stirred overnight at room temperature. Again, tic indicated that the reaction was not complete so the reaction mixture was heated at reflux for 2 h, 1 M NaOH (100 mL) was added and the solution was heated at reflux for a further 4 h. The reaction mixture was allowed to stand overnight at room temperature, then the solvent was evaporated, and water (100 mL) and 1 M HCl (200 mL) were added. The mixture was stirred for 20 min and then the white solid was filtered off and dried overnight in a vacuum oven (25 mm Hg, 60° C.) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid (4.84 g, 89%) as a white solid, mp 213–215° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>>[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Oc1cnccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccncc1OC[C@@H]1CCCN1

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (792 mg, 3.94 mmol), 4-bromo-3-pyridinol (685 mg, 3.94 mmol), DEAD (485 uL, 4.33 mmol) and PPh3 (1.14 g, 4.33 mmol) were allowed to react as described in Example 2a. The crude product was directly treated with trifluoroacetic acid (5 mL) at room temperature for 3 hours. The trifluoroacetic acid was removed under reduced pressure, and water (8 mL) was added. The mixture was extracted with EtOAc (2×20 mL), and the resultant aqueous layer was basified with excess solid sodium bicarbonate. The resultant slurry was washed extensively with EtOAc (4×10 mL). The combined organic layers were dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with CHCl3 /MeOH/NH4OH (10:1.5:0.02 and 10:1.5:0.1) to provide 371 mg (37% yield from 4-bromo-3-pyridinol) of the title compound. TLC Rf 0.16 (10:1:0.02 CHCl3 /MeOH/NH4OH). MS (DCI/NH3) m/e 257 with 79Br and 259 (M+H)+ with 81Br. 1H NMR (CDCl3, 300 MHz) δ: 8.25 (s, 1H, ArH), 8.08 (d, J=6.6 Hz, 1H, ArH), 7.48 (d, J=6.6 Hz, 1H, ArH), 4.28 (dd, J=4.8, 10.2 Hz, 1H, OCHH), 4.17 (dd, J=6.3, 10.2 Hz, 1H, OCHH), 3.90-3.80 (m, 1H, NCH), 3.30-3.14 (m, 2H, NCH2), 2.18-1.80 (m, 4H, 2CH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:19])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Brc1cccc(-c2nc3ccccc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Br)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
2-(3-bromophenyl)-1H-benzimidazole (7.8 g, 28.6 mmol) was completely dissolved in dry THF (300 ml), then NaH 60% m/m (1.49 g, 37.2 mmol) was added portionwise to the clear yellow solution. The light brown suspension was stirred 1 h rt, then CH3I (2.5 ml, 40.0 mmol) was added dropwise. The reaction mixture was stirred rt overnight. The reaction was quenched with H2O (300 ml), and extracted with EtOAc (2×450 ml). The organic extracts were dried over MgSO4, filtered and evaporated, to afford the compound as a brown-yellow solid (7.4 g, 70%).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:16][C:17]2[CH:30]=[CH:29][C:20]3[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)c1c(C)oc2cc(N)ccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C)oc2cc(Nc3ccnc(Cl)n3)ccc12
Yield: 80 %

Procedure:
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 6-amino-N,2-dimethylbenzofuran-3-carboxamide (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was subjected to extraction with EtOAc. The organic layers were combined, washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give 6-(2-chloropyrimidin-4-ylamino)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 80%.
Reaction SMILES: [C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:35][C:36]1[CH:37]=[C:38]([O:44][CH3:45])[C:39]([O:42][CH3:43])=[CH:40][CH:41]=1>CC(O)C>[C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: CC(C)O
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.40 mmol) (from Example 19a supra) and 4-amino-veratrole (80.0 mg, 0.52 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 10 minutes. After cooling, it was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.09 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:19][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22](I)=[N:21]1)[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[N:7]2.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:19][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)=[N:21]1)[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[N:7]2
Reactant: Nc1ncnc2c1c(I)nn2Cc1cc2c(Cl)cccc2nc1-c1ccccc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CN(C)C=O
Product: Cn1cc(-c2nn(Cc3cc4c(Cl)cccc4nc3-c3ccccc3Cl)c3ncnc(N)c23)cn1

Procedure:
Prepared according to Procedure J using 1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.060 g, 0.110 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.032 g, 0.164 mmol, 1.5 eq), tetrakis(triphenylphosphine)palladium (0.006 g, 10 mol %), and sodium carbonate (2M aq. Sol., 6 eq) in DMF (0.2M)). 1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.56 (s, 1H), 8.01-8.05 (m, 3H), 7.87 (d, 1H, J=5.0), 7.80-7.83 (m, 1H), 7.65 (s, 1H), 7.47 (d, 1H, J=5.0), 7.34 (t, 1H, J=5.0), 7.24 (t, 1H, J=5.0 Hz), 7.15 (d, 1H), 5.63 (s, 2H), 3.89 (s, 3H), Mass Spectrum (ESI) m/e=502 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([C:19](OCC)=[O:20])#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[O:20]=[C:19]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]2[C:2]([CH2:3][O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=32)=[N:1]1
Reactant: NC1=Nc2ccccc2OC1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1-c1ccccc1OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
A solution of the compound of formula II, 3-amino-2H-1,4-benzoxazine(1.75 g, 11.08 mmol, described in Example 3) and diethyl acetylenedicarboxylate (2.2g, 12.9 mmol) dissolved in ethanol (30 ml) was stirred at room temperature for 21/2 hours. The precipitate was collected to give 1.30 g of the title compound as colourless crystals; mp 174°-175° C. (after recrystallization from ethyl acetate-hexane); IR(CHCl3) 1738, 1650 cm-1 ; NMR(CDCl3)δ1.2 (t, J=7Hz, 3H), 4.3(q,J=7Hz, 2H), 4.92 (s, 3H), 6.68 (s,1H), 7.3 (m,4H); M+ 272; Anal. Calc'd: C, 61.76%; H, 4.44%; N, 10.29%; Found: C, 61.99%; H, 4.35%; N, 10.32%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC>C(O)(=O)C>[CH3:15][O:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[NH:16][C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])=[N:1][C:2]=3[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COc1ncccc1-c1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: COc1ncccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-(2-methoxypyridin-3-yl)phenylamine 3 obtained from above reaction (0.215 g, 1 mmol) in acetic acid (2 mL) cooled to 0° C. was added methyl trichloroacetimidate (0.193 g, 1.1 mmol) under N2 atmosphere and resulting reaction mixture was stirred at room temperature for 3 h. Acetic acid was evaporated to give crude 5-(2-methoxypyridin-3-yl)-2-(trichloromethyl)-1H-benzimidazole which was used as such in the following step (0.3 g). Reference: Louvet, P.; Lallement, G.; Pemot-Marino, I.; Luu-Duc, C.; Blanchet, G. Eur. J. Med. Chem. 1993, 28, 71-75.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:19][C:18]1[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:21])=[N:14][C:15]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:16][CH:17]=1
Reactant: O=C(NC1CC1)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC4CC4)n3)cc2)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-cyclopropyl-2((2,5-dichloropyrimidin-4-yl)amino)benzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 38% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.64 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.44 (m, 2H), 7.25 (d, 2H, J=8.2 Hz), 7.07 (t, 1H, J=7.5 Hz), 6.38 (bs, 1H), 3.50 (s, 2H), 2.93 (q, 1H, J=3.4 Hz), 2.55 (bs, 8H), 2.35 (s, 3H), 0.92 (m, 2H), 0.65 (m, 2H); MS (ESI): 492.1 [M+H]+.