Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2
Reactant: CCC[C@H]1CC[C@H](C2=Cc3c(cc(F)c(F)c3F)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2)CC1

Procedure:
Ethanol (70 ml), ethyl acetate (30 ml) and 5% palladium-carbon (450 mg) were added to 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indene (4.5 g), and stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified with a silica gel short column (hexane) to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g). Moreover, this was then recrystallized from ethanol to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g, purity: 99.8%). The melting point of this compound was 52° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH2:40])=[N:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[CH:14][CH:13]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[NH:40])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: N=C(NCCCCc1ccc(OCCCN)c2ccccc12)NC(=O)c1nc(Cl)c(N)nc1N

Procedure:
One gram (2.66 mmol) of free amine was stirred with 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (1.55 g, 3.99 mmol) in dry ethanol (25 mL). Di-isopropyl-ethylamine (1.39 mL, 7.98 mmol) of was added and the reaction mixture was warmed to 45° C. overnight. Ethanol was added and the reaction filtered. After concentration of the filtrate, the residue was purified by flash chromatography (0-10% MeOH/CH2Cl2) to give 0.92 g of [3-(4-{4-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester. [3-(4-{4-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (2.7 g was stirred with 4M HCl in p-dioxane for 1 hour at room temperature. Solvents were removed in vacuo.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][CH3:10])[CH2:4][C:5]([O:7]C)=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[CH2:9]([C:3]1[CH2:1][N:19]([CH2:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[C:5](=[O:7])[CH:4]=1)[CH3:10]
Reactant: CCC(C=O)CC(=O)OC
Reactant: NCCc1ccccn1
Solvent: CC(=O)O
Product: CCC1=CC(=O)N(CCc2ccccn2)C1

Procedure:
4-Ethyl-1-(2-(pyridin-2-yl)ethyl)-1H-pyrrol-2(5H)-one is synthesized by a cyclo-condensation between methyl 3-formylpentanoate and 2-(pyridin-2-yl)ethanamine in glacial acetic acid at 70° C. according to a procedure of R. Fisher (DE 4127111, 1992).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH2:24][CH2:25]N(C)C)=[O:4].[CH3:29][C:30]1[NH:31][CH:32]=[CH:33][N:34]=1.N12CCCN=C1CCCCC2.ClC1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH2:24][CH2:25][N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[CH3:29])[NH:7][C:8]([CH3:23])=[C:9]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1=C(C)NC(CCN(C)C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: Cc1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1
Product: COC(=O)C1=C(C)NC(CCn2ccnc2C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A mixture of 4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl-2-(2-dimethylaminoethyl)pyridine 3,5-dicarboxylic acid dimethyl ester (2.14 g, 5mmol), 2-methylimidazole (1.64 g, 20mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.75 g, 5mmol) and chlorobenzene (50ml) was heated at reflux for 24hours. The solution was cooled, diluted with chloroform (25ml), washed with water (100ml), dried and evaporated. The residue was chromatographed on silica gel (50 g, Act I) using chloroform-methanol as eluent to give the title compound. This was suspended in methanol (10ml) and acidified by addition of maleic acid (0.5 g, 5% excess) to give a clear solution which was then diluted with ether (10ml) to precipitate the crystalline maleate salt 1.65 g mp 197°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][CH:3]=1.N[N:19]1[CH:23]=[N:22][N:21]=[CH:20]1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([C:8]2[C:23]3[N:19]([CH:20]=[N:21][N:22]=3)[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Reactant: Nn1cnnc1
Solvent: O
Solvent: CC(=O)O
Product: CC(Oc1ccc(Cl)cc1)c1ccnn2cnnc12
Yield: 9.7 %

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (14.5 g) in glacial acetic acid (100 ml) was added dropwise to a solution of 4-amino-1,2,4-triazole (5.0 g) in glacial acetic acid (100 ml). The solution was boiled under reflux for 4 hours and then poured into water (400 ml). The mixture was extracted with toluene. The combined organic extracts were washed with 10% sodium bicarbonate solution, then with water, dried over anhydrous magnesium sulphate, filtered, and evaporated under reduced pressure. Flash column chromatography of the residue on silica gel, using ethyl acetate/petroleum ether 1:1 as the mobile phase, afforded 1.52 g of 8-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[4,3-b]pyridazine. A pure sample was obtained by recrystallisation from a mixture of ethyl acetate and hexane, m.p. 98-99° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:33][CH:30]3[CH2:32][CH2:31]3)=[O:29])=[CH:18][CH:19]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CC1
Reactant: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)NC3CC3)cc2)ccn1

Procedure:
Phenyl N-(4-[2-(butyroylamino)pyridin-4-yl]oxyphenyl}carbamate (0.116 g), cyclopropylamine (0.034 g), triethylamine (0.041 ml) and tetrahydrofuran (10 ml) were heated together in a sealed tube at 100° C. for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 20 mg of the target substance as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19](C=O)[CH3:20].CNC.C1COCC1>>[CH3:18][N:19]([CH3:20])[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=O
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)benzoic acid (1 g, 4.21 mmol) in DMF (10 ml) CDI (1.025 g, 6.32 mmol) was added. The mixture was stirred at RT for 2 hours. Dimethylamine 2M in THF (3.16 ml, 6.32 mmol) was added, and the mixture stirred at RT for 3 hours. The mixture was poured onto water and extracted with AcOEt (2×). Organic phase was dried over Na2SO4 and evaporated under vacuum to give g 1.25 of Int. 73 which crystallizes on standing.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18]([C:20]1([CH2:25][C@@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:11][C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].CO>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18]([C:20]1([CH2:25][C@@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H](CC1(C(=O)N[C@H](COCc2ccccc2)CC(=O)OCC)CCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@H](CC1(C(=O)N[C@H](COCc2ccccc2)CC(=O)O)CCCC1)C(=O)O

Procedure:
A solution of the ethyl ester from example 17 (70 mg, 0.16 mmol) in sodium hydroxide solution (1 ml, 1N) and methanol (5 ml) was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure to remove the methanol, and the residue was partitioned between ethyl acetate (10 ml) and hydrochloric acid (2N, 10 ml). The phases were separated, the aqueous layer extracted with ethyl acetate (4×10 ml), the combined organic solutions washed with brine (10 ml), dried (MgSO4) and evaporated under reduced pressure to afford the title compound, 50 mg; 1H NMR (CDCl3, 400 MHz) δ: 0.92 (t, 3H), 1.23–2.39 (m, 15H), 2.74 (d, 2H), 3.60 (m, 2H), 4.52 (m, 3H), 6.66 (d, 1H), 7.35 (m, 5H); HRMS: m/z (ES+) 420.2374 [MH+]; C23H33NO6 calculated 420.2381.
Reaction SMILES: ClCCl.C[O:5][C:6]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])=[N:22][C:21]=1[CH3:33])(OC)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[C:23]1[S:24][C:20]([C:6](=[O:5])[CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:21]([CH3:33])[N:22]=1
Reactant: COc1ccc(COCC(OC)(OC)c2sc(-c3ccc(C)cc3C)nc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COCC(=O)c2sc(-c3ccc(C)cc3C)nc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
To dichloromethane (2 ml), 5-[1,1-dimethoxy-2-(4-methoxybenzyloxy)ethyl]-2-(2,4-dimethylphenyl)-4-methylthiazole (35 mg) prepared in the Step 31-1-3 was added, and trifluoroacetic acid (0.3 ml) and water (0.1 ml) were added thereto. Thereafter, the mixture was stirred at a room temperature for 5 hours. To the reaction solution, a saturated sodium bicarbonate solution was added, and then the resulting mixture was subjected to extraction with chloroform. The extract was washed with a saturated saline solution, and then dried over sodium sulfate and concentrated under a reduced pressure. The residue was purified by thin-layer chromatography (hexane:ethyl acetate=3:1, toluene:ethyl acetate=3:1) to give the title compound (18 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[I:22][C:23]1[CH:24]=[C:25]([CH2:29][NH2:30])[CH:26]=[CH:27][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=2)[N:3]=1
Reactant: NCc1cccc(I)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CC(C)O
Solvent: CCCCO
Product: Clc1nc(NCc2cccc(I)c2)c2ncn(C3CCSC3)c2n1
Reaction time: 30 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.114 ml of 3-iodo-benzenemethanamine in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for approximately 30 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum to a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion 90/10, 173 mg of expected product is thus obtained in the form of white-yellow crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[C:14]([NH:26][C:27]2[N:35]=[C:34]3[C:30]([NH:31][C:32](=[O:47])[N:33]3[C@H:36]3[C:45]4[C:40](=[C:41]([F:46])[CH:42]=[CH:43][CH:44]=4)[O:39][CH2:38][CH2:37]3)=[CH:29][N:28]=2)[CH:13]=1>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[NH:26][C:27]1[N:35]=[C:34]2[C:30]([NH:31][C:32](=[O:47])[N:33]2[C@H:36]2[C:45]3[C:40](=[C:41]([F:46])[CH:42]=[CH:43][CH:44]=3)[O:39][CH2:38][CH2:37]2)=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A freshly prepared solution of 30% TFA/DCM (5 mL) was added to (R)-tert-butyl 4-fluoro-2-(9-(8-fluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)phenylcarbamate and the solution was stirred at room temperature for 60 min then the solvents were removed in vacuo to yield (R)-2-(2-amino-5-fluorophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one that was used as such MH+=411.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][C:3]#[N:4])[CH2:27][CH2:28]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 3.22 parts of 2-chloroacetonitrile, 16 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 12.7 parts of sodium carbonate and 225 parts of N,N-dimethylformamide was stirred for 6 hours at room temperature. The reaction mixture was poured onto water. The product was extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 16 parts of 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrile as a residue (compound 147).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]([NH:13][NH:14]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][C:9](=[O:25])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>CO>[Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[N:13]=[N:14][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[C:10]=2[C:9](=[O:25])[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)sc3Cl)C2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Yield: 50.9 %

Procedure:
To a mixture of 5-(2,5-dichlorothiophen-3-yl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), anhydrous potassium carbonate (0.9 g) and methanol (20 ml) was added, under ice-cooling, 1-bromo-3,3,3-trifluoropropan-2-one (1.24 g), and the mixture was stirred at the same temperature for 0.5 hours. To the mixture was added anhydrous potassium carbonate (1.2 g), and the mixture was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in acetic acid (15 ml). To the solution was added concentrated sulfuric acid (0.6 ml), and the mixture was refluxed for 30 minutes. To the reaction solution was added water (120 ml), and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with sodium hydrogen carbonate solution and concentrated. The residue was purified with silica gel column chromatography to give 7-(2,5-dichlorothiophen-3-yl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.867 g) as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])[C:10]2=[O:35])=[CH:5][CH:4]=1.[OH-:36].[Na+].OO>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]([NH2:31])=[O:36])[C:10]2=[O:35])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.11 g; 0.22 mmol) (from Example 5b supra) in dimethyl sulfoxide (1.5 mL) was cooled in an ice-water bath. Aqueous sodium hydroxide (1.0 M; 0.38 mL; 0.38 mmol) was added, followed by aqueous hydrogen peroxide (30% solution; 70 μL; 0.69 mmol). The cooling bath was removed following the additions and the mixture was stirred at room temperature for 3 hours. The solid was collected and washed with water and hot dichloromethane. This crude material was purified by flash chromatography (Biotage; 12M; 99:1 to 80:20 ethyl acetate-methanol gradient) and the pure product crystallized out of solution upon concentration to give (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide as a white solid. (Yield 64.6 mg; 57.9%). Melting Point: 268–273° C. (discolored on melting).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][N:7]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:6]2=[O:24])[CH2:3][CH2:2]1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:6]2=[O:24])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O

Procedure:
A solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl]acetate from Step C (41 mg, 0.125 mmol) in CH2Cl2 (2 mL) and CF3CO2H (1 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo to afford the title compound. MS: m/z=273 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[C:13](=O)([O-])[O-].[Na+].[Na+]>C=O.C(O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:7])[N:8]([CH3:13])[CH2:9][O:12][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1ccc(F)cc1O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1COc2cc(F)ccc2C1=O

Procedure:
A mixture of 4-fluoro-2-hydroxy-N-methyl-benzamide (0.3 g, 1.77 mmol) in formaldehyde (37% aq. soln) (2 mL) and formic acid (2 mL) was refluxed for 1 hour then poured onto ice. The mixture was neutralised with sodium carbonate and extracted into chloroform (3×30 mL). The combined organics were dried (MgSO4), and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 10-50% ethyl acetate in isohexane to give the desired compound as a white solid (0.24 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:13])[CH:16]=[CH:17][C:18]=1[N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)#[N:21]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Product: N#Cc1cc(NC(=O)C2CCc3ccccc3C2)ccc1N1CCC(O)CC1
Yield: 59.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.45 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (0.58 g), the title compound (0.57 g) was obtained. melting point: 163-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:3]=1.N.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:32])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.100 g 4-[4-fluoro-2-((1S,2S)-2-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 51.2), 2.5 ml ammonia in dioxane (0.5M), 0.109 g HATU and 0.046 ml DIPEA in 2 ml DMF was stirred at rt overnight. The reaction mixture was diluted with water, stirred and filtered. The filtercake was dried.
Reaction SMILES: N#N.[O:3]1[CH:7]2[O:8][CH2:9][CH2:10][CH:6]2[CH:5]([O:11][C:12](=[O:40])[NH:13][CH:14]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:15]([OH:32])[CH2:16][N:17](C(OCC2C=CC=CC=2)=O)[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:4]1>[Pd].O1CCCC1>[O:3]1[CH:7]2[O:8][CH2:9][CH2:10][CH:6]2[CH:5]([O:11][C:12](=[O:40])[NH:13][CH:14]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:15]([OH:32])[CH2:16][NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:4]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After displacing the air with N2, palladium on charcoal (10%, 5.00 g, 47.00 mmol, 0.32 equiv) was added followed by the addition of a solution of [1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (78.36 g, 148.80 mmol, 1 equiv) in tetrahydrofurane. For a few minutes vacuum was applied and replaced by H2. After stirring for 24 h at room temperature. N2 was then introduced in the flask to displace the remaining H2. The palladium catalyst was removed by filtration over a bed of dicalite under N2 and the filter was washed with tetrahydrofurane. The filtrate was evaporated under reduced pressure. (58.40 g, 148.80 mmol, quantitative). LRMS (ES+): m/z 393 [M+H]+; 1H-NMR (CDCl3) δ 0.91 (d, 3H, CH3), 0.93 (d, 3H, CH3), 1.45-1.57 (m, 2H, CH2, H4), 1.58-1.83 (m, 1H, CH (isobutyl)), 2.43 (dd, 2H, CH2—N (isobutyl)), 2.66-2.81 (m, 3H, CH2—N and CH of CH2C6H5), 2.87-2.96 (m, 1H, CH, H3a), 3.06 (dd, 1H, CH of CH2C6H5), 3.51-3.57 (m, 1H, CH2, H5), 3.67-3.75 (m, 2H, CH and CH2, H2), 3.81-3.93 (m, 2H, CH—OH and CH2, H5), 3.94-4.00 (m, 1H, CH2, H2), 5.01-5.08 (m, 1H, CH, H3), 5.10 (d, 1H, NH), 5.64 (d, 1H, CH, H6a), 7.16-7.31 (m, 5H, C6H5).