Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=O.[CH3:7][O:8][C:9](=[O:52])[C@H:10]([CH:49]([CH3:51])[CH3:50])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1.[C:53]1(C)[CH:58]=CC=C[CH:54]=1.C(=O)(O)[O-].[Na+]>O>[CH3:7][O:8][C:9](=[O:52])[C@H:10]([CH:49]([CH3:50])[CH3:51])[N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:17][CH:18]=1)[C:1](=[O:6])[CH2:2][CH2:54][CH2:53][CH3:58]
Reactant: O=C(O)C(=O)O
Reactant: Cc1ccccc1
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)OC)C(C)C
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
N-[[2′-(1-Triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester oxalate (150 g, 0.215 mole) was added to the mixture of toluene (450 ml) and DM water (300 ml), and basified with 10% w/w aqueous sodium bicarbonate solution (450 ml) at 20-30° C. The organic layer was separated and washed successively with DM water (150 ml) followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and reacted with valeryl chloride (33.7 g) in the presence of N,N-Diisopropylethylamine (55.6 g) at 0-5° C. The reaction mixture was stirred for 3 h at 5-10° C. and washed with DM water (150 ml), 10% w/w sodium carbonate solution (68 ml) followed by 10% w/w aqueous oxalic acid solution (40 ml). The organic phase was concentrated completely under reduced pressure to dryness to yield N-[[2′-(1-triphenylmethyltetrazol-5-yl]biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester as oily mass (141.3 g)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([CH2:17][CH3:18])[N:11]=1>C(OCCO)C>[CH2:17]([C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[CH:15]=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:11]=1)[CH3:18]
Reactant: Nc1cccc(O)c1
Reactant: CCc1nc(Cl)cc(Cl)n1
Solvent: CCOCCO
Product: CCc1nc(Nc2cccc(O)c2)cc(Nc2cccc(O)c2)n1
Reaction time: 5 h

Procedure:
After dissolving 3-aminophenol (1.09 g, 10.0 mmol) in 2-ethoxyethanol (5.0 mL), 4,6-dichloro-2-ethylpyrimidine (0.89 g, 5.0 mmol) was added and stirring carried out for 5 hours at 130° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([O:25]CC)=[O:24])[CH2:3][CH2:2]1.[OH-].[Li+]>CO.O1CCCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=4[F:20])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([OH:25])=[O:24])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
410 mg of ethyl 2-cyclopropyl-8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 27A, 1.1 mmol, 1 equivalent) were initially charged in 15 ml of methanol/tetrahydro-furan (1:1), and 5.5 ml of a 1 N aqueous lithium hydroxide solution (5.5 mmol, 5 equivalents) were added. The reaction mixture was stirred at RT overnight, another 5.5 ml of 1 N aqueous lithium hydroxide solution were added, and the mixture was stirred at RT for another night. The mixture was concentrated and the residue was taken up in water and acidified with 1 N aqueous hydrochloric acid. The precipitated product was filtered off and dried under high vacuum. This gave 293 mg (77% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[O:6][C:5](=O)[CH:4]=1)[CH3:2].[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[C:12]=2[C:3]([CH2:1][CH3:2])=[CH:4][C:5]1=[O:6]
Reactant: CCc1cc(=O)oc2c1C(=O)CCC2
Reactant: CN
Product: CCc1cc(=O)n(C)c2c1C(=O)CCC2

Procedure:
Prepared from 4-ethyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine solution over 31 hours at ambient temperature.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35]([OH:38])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) is cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) is added dropwise over 20 minutes to the cooled solution. The reaction mixture is stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) is added dropwise over 30 minutes. The reaction mixture is then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-3-pyrrolidone (0.15 mol) in THF (500 mL) is then added dropwise to the cooled solution over one hour. After addition is complete, the reaction is stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture is extracted with ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatrography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-3-hydroxy-3-tributylstannyl pyrrolidine.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([S:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2)(=[O:4])[CH3:2]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: CC(O)=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 0 °C

Procedure:
Under ice cooling and stirring, 1.25 ml of thioacetic acid was added to 7.03 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 dissolved in a mixed solution of 58 ml of trifluoroacetic acid and 30 ml of methylene chloride and the mixture was stirred at the same temperature for 3 hours. 300 ml of ice water was added to the reaction mixture, crystals precipitated by neutralization with a 1N-sodium hydroxide aqueous solution were collected by filtration and these crystals were dissolved in methylene chloride. Then, this organic layer was washed with water and dried over anhydrous sodium sulfate and then the solvent was removed. The resulting residue was applied to silica gel column chromatography to obtain 4.6 g of the title compound as white powder.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[F:10][C:11]([F:15])([F:14])[CH2:12]I>[Pt](=O)=O>[F:10][C:11]([F:15])([F:14])[CH2:12][N:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1
Reactant: FC(F)(F)CI
Reactant: c1cc2cn[nH]c2cn1
Agent: O=[Pt]=O
Product: FC(F)(F)Cn1ncc2c1CNCC2

Procedure:
1H-Pyrazolo[3,4-c]pyridine was alkylated with 1,1,1-trifluoro-2-iodoethane, then reduced via hydrogenation over platinum(IV) oxide to afford 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=1[C:11]([O:13][CH3:14])=[O:12].C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>COCCOC>[C:20]([C:6]1[N:1]=[C:2]([C:11]([O:13][CH3:14])=[O:12])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1ccc[n+]([O-])c1C(=O)OC
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C#N)nc1C(=O)OC
Temperature: 0 °C

Procedure:
To a solution of dimethyl pyridine-2,3-dicarboxylate 1-oxide [Niiyami et al. (2002) Bioorg. Med. Chem. Lett. 12, 3041] (15.3 g, 72.5 mmol) and trimethylsilyl cyanide (15.7 mL, 117 mmol) in DME (161 mL) was added dimethylcarbamoyl chloride (10.5 mL, 114 mmol). The reaction mixture was heated at reflux for 72 h, and then cooled to 0° C. Saturated aqueous NaHCO3 (800 mL) was added slowly and the quenched mixture was extracted with EtOAc (2×1 L). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=221 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[C:7](N(OC)C)=[O:8].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[C:7]([C:6]1[CH:5]=[C:4]([Cl:13])[S:3][C:2]=1[Cl:1])(=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)c1cc(Cl)sc1Cl
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cc(Cl)sc1Cl
Temperature: -30 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a stirred solution of 2,5-dichloro-N-methoxy-N-methyl-3-thiophenecarboxamide (350 mg, 1.46 mmol) in THF (5 mL) was added 3M solution of phenylmagnesium bromide in diethyl ether (1.2 mL, 3.6 mmol) at −78° C., and the mixture was stirred for 4 hours at −30° C. Saturated ammonium chloride solution was added, and the whole was extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with hexane-ethyl acetate (12:1) to provide the title product as a yellow oil. (212 mg, 56% yield).
Reaction SMILES: [O-:1][P:2]([O:5][P:6]([O:9][P:10]([O-:13])([O-:12])=[O:11])([O-:8])=[O:7])(=[O:4])[O-:3].P(O[CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[N:33]=[N+:34]=[N-:35])(O)(O)=O.[N-]1C=CN=C1.[O-]P(OP([O-])([O-])=O)(=O)[O-].C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC>CN(C=O)C>[P:10]([O:13][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[N:33]=[N+:34]=[N-:35])([O:9][P:6]([O:5][P:2]([OH:1])([OH:3])=[O:4])([OH:8])=[O:7])(=[O:12])[OH:11]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)OP(=O)(O)OP(=O)(O)O

Procedure:
The triphosphate can be prepared according to the procedure of Hoard et al., J. Am. Chem. Soc., 87(8), 1785-1788 (1965). For example, 3'-azido-2',3'-dideoxyuridine monophosphate is activated (by making a imidazolide, according to methods known to those skilled in the art) and treated with tributyl ammonium pyrophosphate in DMF. The reaction gives primarily 3'-azido-2',3'-dideoxyuridine triphosphate, with some unreacted monophosphate and some diphosphate. Purification by anion exchange chromatography of a DEAE column is followed by isolation of CS-87 triphosphate, e.g., as the tetrasodium salt.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C-:21]#[N:22].[K+]>CS(C)=O>[C:21]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1F
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1C#N
Temperature: 80 °C
Reaction time: 24 h

Procedure:
1,1-Dimethylethyl {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}carbamate (1.17 g, 4 mmol) was dissolved in dimethylsulphoxide (5 ml) and treated with potassium cyanide (0.260 g, 4 mmol). The mixture was then heated at 80° C. under argon for 1.5 hrs and then at 120° C. overnight (16 hrs). Additional potassium cyanide (0.260 g, 4 mmol) was then added and heating continued at 120° C. for a further 24 hrs. The mixture was then cooled to room temperature, quenched with water, and diluted with ethyl acetate. The organic extracts were separated and washed three times with water and then with saturated aqueous sodium chloride solution. Drying and evaporation gave a brown gum which was purified by silica-gel column chromatography, eluting with a 1:10-1:5 gradient of ethyl acetate in hexanes, to give partially pure 1,1-dimethylethyl {[2-cyano-3-(trifluoromethyl)phenyl]methyl}carbamate as a dark solid/semi-solid which was used in the next step without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:28])([F:27])[CH2:14][N:15]=[C:16]([NH2:26])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>C(O)C>[F:28][C:13]([F:12])([F:27])[CH2:14][N:15]=[C:16]([NH2:26])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:25])=[O:9])[N:19]=1
Reactant: CSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
3-Chloroperbenzoic acid (0.8 g.) was added to a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (0.5 g.) in ethanol (50 ml.) and the solution left at room temperature for 18 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate, the solution washed with aqueous potassium carbonate solution and then dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (0.5 g.) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[C:7]([CH2:9]Br)=[CH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[C:1]([O:5][C:6](=[O:11])[C:7]([CH2:9][N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-(bromomethyl)propenoic acid t-butyl ester (20 g, 90.5 mmole) in dry acetonitrile (360 ml), cooled to 0° C., was treated with solid potassium carbonate (15.63 g, 113 mmole), followed by a solution of dibenzylamine (17.83 g, 90.5 mmole, in dry acetonitrile (600 ml), producing a 10° C. exotherm. The reaction was stirred at 0° C. for 0.5 hours, followed by 1 hour at room temperature, and then partitioned between water and diethyl ether. The ether phase was washed again with water, dried (sodium sulphate) and evaporated to yield the crude product (31 g) which was filtered through a pad of silica, eluting with hexane/CH2Cl2 (1:1), to yield 2-(dibenzylaminomethyl)propenoic acid t-butyl ester (23.8 g, 78%) as a solid, m.p. 62°-63° C. Found C,78.09; H,8.20; N,4.18. C22H27NO2 requires C,78.3; N,8.06; N,4.15 %.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:32]=[C:31]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=3)=[O:27])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:41]([C:31]1[CH:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:13]=3)=[CH:16][CH:17]=2)[N:33]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:32]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methoxyacetyl chloride (64.2 μl, 0.703 mmol) was added slowly to a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (8) (89 mg, 0.176 mmol) and DIPEA (153 μl, 0.878 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for a further 20 min and then warmed to RT. After 2.5 hr, the reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL), and the resulting mixture stirred for a further 45 min. The volatiles were removed in vacuo and the residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL) and subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The crude material was purified by flash column chromatography (SiO2; 12 g) eluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane to give N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (62 mg, 61%) as a white solid: m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.31 (3H, s), 3.99 (2H, s), 6.41 (1H, s), 6.70 (1H, dd), 7.32-7.40 (3H, m), 7.44-7.48 (2H, m), 7.55-7.61 (1H, m), 7.63-7.67 (2H, m), 7.84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, s), 9.13 (1H, s), 10.02 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[NH4+:11]>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [OH-]
Product: Cc1nc(N)cc(Cl)n1
Temperature: 25 °C
Yield: 82 %

Procedure:
Charge a 5 L steel pressure vessel (autoclave) with 4,6-dichloro-2-methylpyrimidine (400 g, 2.45 mol) and ammonium hydroxide (2.8 L) at RT. Heat the reaction to 90° C. for 5 h. Cool the reaction mixture to RT and then filter the solid through a Buchner funnel. Wash the filtercake with water (200 mL) and hexane (200 mL) and then dry under vacuum to afford the title compound as a white solid (290 g, 82%). LC-ES/MS m/z 144.0 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=[O:28].C(Cl)Cl.CO>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1c(F)cccc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 174 mg of 2,6-difluorobenzoyl chloride in 4 ml of tetrahydrofuran. After three successive purifications by silica chromatography (eluent: CH2Cl2/MeOH; gradient of 100/0 to 98/02 then 98/1 and 98/2), 22 mg of (8S)-9-[(2,6-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C([SiH](CC)CC)C.O.C(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: O=C(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(c3)CCN4)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (30 mg, 0.0780 mmol, described in WO9717329, p. 52) in trifluoroacetic acid (0.9 ml), triethylsilane (45 ml, 0.2808 mmol, 3.0 eqM) was added while cooling on ice, and the mixture was stirred for 4 hours and 30 minutes at room temperature under a nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate, neutralized with saturated bicarbonate water, extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to obtain the title compound (20 mg, 0.0620 mmol, 66.28%) as light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.C(Cl)Cl>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:18]3[CH:19]=[N:20][C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)[S:22][C:23]=2[CH:29]=1)=[O:4]
Reactant: CN1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(-c3nc4ccc(NC(=O)C(F)(F)F)cc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-amine trifluoroacetate (0.12 g, 0.27 mmol), ethyl chloroformiate (36 μL, 0.38 mmol) and diisopropylethylamine (0.238 mL, 1.44 mmol) in DCM/THF (1:1, 7 mL) was stirred at r.t. overnight. Additional DCM was added before washing the sol. with sat. sodium hydrogencarbonate and then brine. The sol. was then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC, to give intermediate 2,2,2-trifluoro-N-{2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-yl}acetamide (43 mg). MS m/z (M+H) 422, (M−H) 420. To this intermediate (43 mg) in THF (5 mL) was added lithium aluminium hydride (12 mg, 0.3 mmol). The r.m. was refluxed for 1.5 h then allowed to come to r.t. Two drops of sat. Na2SO4, followed by ethyl acetate was added and the mixture was stirred for a few minutes. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC to yield the title compound (25 mg) as a pale yellow solid. 1H NMR (MeOH-D4) δ 8.59 (d, 1H) 7.97 (dd, 1 H) 7.60 (d, 1 H) 7.11 (d, 1 H) 6.75-6.87 (m, 2 H) 3.80 (q, 2 H) 3.55-3.70 (m, 4 H) 2.50-2.61 (m, 4 H) 2.33 (s, 3 H); MS m/z (M+H) 408, (M−H) 406.