Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[H-].[Na+].Cl[S:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([N:12]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)(=[O:25])=[O:24])=[O:19])([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1cccn2c(C)c(NC(=O)OC(C)(C)C)nc12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3c(C)cccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a solution of compound 2-B (0.799 g, 3.06 mmol) in DMF (22 mL), cooled to 0° C., was added 60% NaH (0.147 g, 3.67 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (2.15 g, 9.17 mmol) was added in small portions and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 2-C as a white solid (0.693 g, 49%). 1H-NMR (CDCl3): δ 8.38-8.40 (dd, 2H), 8.23-8.25 (dd, 2H), 7.75-7.77 (d, 1H), 7.00-7.02 (d, 1H), 6.79-6.83 (m, 1H), 3.98 (s, 3H), 2.51 (s, 3H), 1.59 (s, 3H), 1.34 (s, 9H); MS: m/z 460.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CCN[C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Reactant: CCN(CCN)CCOc1cccnc1[N+](=O)[O-]
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1[N+](=O)[O-]
Yield: 71 %

Procedure:
This compound was prepared, starting from compound 59 (600 mg, 2.36 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2C2/EtOH, 99/1, v/v) to give compound 60 (902 mg, 1.68 mmol) as a light sensitive brown oil. Yield 71%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.46; IR (CCl4) ν 1117, 1289, 1526, 1549, 1683, 2800-3000, 3410 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.08 (t, 3H, J=7.1 Hz), 2.70 (q, 2H, J=7.1 Hz), 2.83 (t, 2H, J=6.1 Hz), 2.99 (t, 2H, J=5.3 Hz), 3.57 (q, 2H, J=6.1 Hz), 4.17 (t, 2H, J=5.3 Hz), 7.36 (dd, 1H, J=4.2, 8.4 Hz), 7.43 (dd, 1H, J=1.7, 8.4 Hz), 7.61 (d, 1H, J=8.8 Hz), 7.94 (dd, 1H, J=1.7, 4.2 Hz), 7.99 (dd, 1H, J=1.8, 8.8 Hz), 8.29 (m, 1H), 8.53 (d, 1H, J=1.8 Hz), 9.57 (s, 1H); ESI-MS m/z 536.9 [M+H]+.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[C:11](Cl)(=[O:13])[CH3:12].C(Cl)C>>[C:11]([P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CCOP(OCC)OCC
Agent: CCCl
Product: CCOP(=O)(OCC)C(C)=O
Yield: 97.7 %

Procedure:
166.2 grams (1 mole) triethyl phosphite was added dropwise with stirring to 78.4 grams (1 mole) of acetyl chloride over a period of 30 minutes at a temperature of 30° to 35° C maintained by cooling. Ethyl chloride was evolved. The temperature was increased to 60° C over the next 1 hour and 15 minutes, at which time the evolution of ethyl chloride was complete. The product was distilled under vacuum yielding 176 grams of diethyl acetylphosphonate (DEAP) in 98% yield, B.P. about 80° C at 5 mm and having a refractive index of 1.4240 at 200° C.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]=[C:6](S(C)(=O)=O)[N:5]=1.[NH3:19]>C(Cl)Cl>[F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]=[C:6]([NH2:19])[N:5]=1
Reactant: CS(=O)(=O)c1nc(OC(F)F)cc(OC(F)F)n1
Reactant: N
Solvent: ClCCl
Product: Nc1nc(OC(F)F)cc(OC(F)F)n1
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of 4,6-bis(difluoromethoxy)-2-methylsulfonylpyrimidine in 20 ml of methylene chloride are added, with vigorous stirring, 5 ml of a 30% aqueous ammonia solution, in the course of which the reaction mixture warms up and is stirred for a further 2 hours. The solution is subsequently concentrated by evaporation and crystallised to thus obtain, in quantitative yield, (0.8 g) 4,6-bis(difluoromethoxy)-2-aminopyrimidine, m.p. 67°-69° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.CC([O-])(C)C.[K+].CS(C)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:6][CH:4]4[CH2:5][NH:2][CH2:3]4)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of Azetidin-3-ol hydrochloride (Oakwood) (461 mg, 4.21 mmol), KOtBu (1.02 g, 9.11 mmol), and dry DMSO (4.2 mL) was stirred at rt for 30 min until a translucent solution resulted. Then 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 4.41 mmol), as prepared in Example 12b, was added, and the resulting opaque orange mixture (no visible precipitate) was stirred at rt for 3.5 hr. The reaction was then shaken with water (40 mL) and extracted with DCM (1×20 mL) and 9:1 DCM/MeOH (1×20 mL). The combined organic layers were washed with 0.2 M K2CO3 (3×20 mL), dried (Na2SO4), and concentrated to give 1.715 g of the title compound as an off-white solid (“106%” crude yield). LC/MS (ESI): calcd mass 384.2, found 385.3 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(OCCCBr)cc1
Reactant: Brc1ccc2c(c1)N(C1CCNCC1)CC2
Product: Fc1ccc(OCCCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Yield: 89.2 %

Procedure:
1-(Piperidin-4-yl)-6-bromoindoline (1.6 g) and 4-fluorophenoxypropyl bromide (1.6 g) were treated as in Example 2 to give the title compound (2.2 g) as a white powder (yield: 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:8])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a slurry of 215.1 g of 2,4-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 196.2 g of morpholine. Next 76.5 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and slowly poured into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and dried to yield 231.7 g of N-(2,4-dinitrobenzoyl)morpholine, mp 159°-161° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 95.4 %

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (4.24 g) and (rac)-1,1,1-trifluoro-propan-2-ol (4.563 g) in acetonitile (50 ml) under an argon atmosphere was added at RT Cs2CO3 (13.04 g) and the mixture was refluxed for 10 h. It was then acidified with diluted aqueous HCL and partitioned between ethyl acetate and water. The layers were separated, dried over Na2SO4 and the solvent was then evaporated off to give (rac)-1-nitro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene as brown oil (6.74 g) that was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:20]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Yield: 88 %

Procedure:
Crude 4-(4-{[(2-tert-butyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester, prepared as in the previous step (5.1 g, 10 mmol) was treated with a mixture of trifluoroacetic acid (40 mL) and dichloromethane (40 mL) at room temperature for 0.5 h. The mixture was concentrated in vacuo, redissolved in dichloromethane (25 mL) and basified with 1M aqueous sodium hydroxide (15 mL). The organic layer was removed, and the aqueous layer re-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product as a brown foam (3.6 g, 8.8 mmol, 88%). (m/z): [M+H]+ calcd for C24H37N5O, 412.31. found 412.6.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:40]2[CH:41]=[C:36]3[N:35]=[C:34]([CH2:33][CH2:32][C:28]4[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=4)[NH:43][C:37]3=[N:38][CH:39]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc(Br)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)NCc5ccccc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 53.3 %

Procedure:
A mixture of 0.49 g of N-benzyl-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 22-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate/acetonitril (1:1) gives 0.26 g of the title compound as a solid of m.p. 211-212° C. The mass spectrum shows the molecular peak MH+ at 500.3 Da.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([OH:41])[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:40])[CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:9]=1)(C)(C)C.Cl>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2([OH:41])[CH2:15][CH2:16][CH:17]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=4)=[O:40])[CH2:21]3)[CH2:18][CH2:19]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Agent: Cl
Solvent: ClCCl
Product: Nc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of [3-(1-Hydroxy-4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 25 mg) in DCM (1 mL) was added 4N HCl (200 μL). The reaction was stirred at RT and concentrated in vacuo resulting in the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:3]1([O:13][CH2:16][CH2:17][C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: c1ccc2c(OCCc3c[nH]cn3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of 1.73 g (12 mmol) of 1-naphthol in 10 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour under nitrogen. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are added. The mixture is heated at 100° C. for 3 days and the solvent is then evaporated under reduced pressure. The remaining oily residue is taken up in dichloromethane and an aqueous sodium carbonate solution and treated with active charcoal. The dichloromethane solution is separated and evaporated and the remaining residue is chromatographed on a column of silica gel (10/1 dichloromethane/methanol) to give the title compound in the base form. The oxalate is prepared from isopropanol and is crystallized from ethanol, M.p.: 187°-189° C.
Reaction SMILES: ClCCl.C(OC([N:11]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:39])[CH2:14][CH2:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CCCCCC>[O:45]1[C:44]2[CH:49]=[CH:50][C:41]([CH2:40][NH:11][CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]4[C:29]5[C:24](=[C:25](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[CH:23]=[CH:22][C:21]4=[O:39])[CH2:16][CH2:17]3)=[CH:42][C:43]=2[O:48][CH2:47][CH2:46]1
Reactant: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.15 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 10 with 20% aqueous sodium hydroxide solution, under ice-cooling. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, hexane was added and the resulting solid was filtered to give 0.12 g of ethyl (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate as a light brown solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[N:30]=[C:29]([C:43]#[N:44])[N:28]=1>ClCCl>[O:23]=[CH:24][CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=2)[N:30]=[C:29]([C:43]#[N:44])[N:28]=1
Reactant: N#Cc1nc(CCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 140.9 %

Procedure:
Dess-Martin periodinane (104 mg) was added to a solution of 4-(3-hydroxy-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (50 mg) in dichloro-methane (5 mL), and the resulting suspension stirred at room temperature for 45 min. The mixture was then washed with water (3×10 mL), dried over sodium sulphate, and evaporated at reduced pressure to afford 4-(3-oxo-propyl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile as a brown solid (70 mg). MS m/z 306.1 (M+1), 100%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:33][C:30]([C:26]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:19]([NH2:21])=[O:20])=[N:28][C:27]=1[CH3:29])([CH3:32])[CH3:31]
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Reactant: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1nc(Nc2sc(-c3ccc(N4CCOCC4)nc3)nc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide (Example 22, Step 2) (104 mg, 0.34 mmol), 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (Example 13, Step 1) (63 mg, 0.34 mmol), Pd2(dba)3 (31 mg, 0.034 mmol), X-PHOS (81 mg, 0.17 mmol), potassium carbonate (47 mg, 0.34 mmol), and tert-amyl alcohol (0.68 mL) as starting materials. 1H NMR (500 MHz, d6-DMSO): δ 11.10 (s, 1H), 8.69 (d, 1H), 8.08 (dd, 1H), 7.72 (d, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 6.93 (d, 1H), 6.92 (d, 1H), 5.01 (s, 1H), 3.70 (m, 4H), 3.53 (m, 4H), 2.74 (s, 3H), 1.49 (s, 6H). LRMS (APCI) calc'd for C22H27N6O3S [M+H]+ 455.2, found 455.1.
Reaction SMILES: N1C(=O)C2N(C)C=NC=2N(C)[C:2]1=O.CCN(C1C=CC=CC=1)CC.[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.[I:36][CH3:37].[H-].[Na+]>CN(C)C=O>[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([N:30]([CH3:2])[CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.[I:36][CH3:37]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCN(CC)c1ccccc1
Product: Cn1cnc2nc(Cl)nc(Cl)c21
Yield: 10 %

Procedure:
2,6 dichloro-7-methyl-7H-purine was prepared from theobromine (a-1) in 10% yield following the procedure of Uretskaya, G. Ya., Rybinka, E. I., and Men'shikov, G. P. Zh. Obshch. Ki., 1960, 30, 327 with the modification of N,N, diethylaniline disclosed by Stanovik, B. et at in the Australian Journal of Chemistry, 1981, 34, 1729. 1H NMR was identical in all respects to the material prepared by alkylation of commercially available 2,6 dichloropurine with base and iodomethane. For example, the procedure reported by Feng et al. (WO2004/087053) utilizes 60% NaH as base, dimethylformamide (DMF) as the solvent and iodomethane yielded a 1:1 mixture of the N-7/N-9 methylated products which were separated via silica chromatography. The procedure reported by Lewi et et al (WO2005/028479 A2) utilizes potassium carbonate as the base, acetonitrile as solvent (rt 70 h) and iodomethane and yielded a 2:1 isolated yield of methylated purines after silica chromatography (60% yield N9Me/30% yield N-7 Methylated). Similarly acetone can replace acetonitrile as the solvent and after refluxing with potassium carbonate and iodomethane for 24 h a 3:1 mixture of N9/N7 is obtained. The N-7 methylated product was isolated in 16.3% purified yield after silica chromatography. A report by Chi-Huey Wong et al. (see, Bioorg & Med Chem 13 (2005) 4622-4626) utilizes tetrabutylammonium fluoride as the base (1M solution THF) and iodomethane to give similarity a 3:1 ratio of the N-9/N-7 methylated purines which could be separated by silica chromatography. 1H NMR (400 MHz, DMSO d6) 8.79 (s, 1H, H8), 4.06 (s, 3H, N7Me).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22](C)([CH3:27])[C:23](OC)=O)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH:22]([C:11]1[S:12][C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)([CH3:27])[CH3:23]
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nc(C(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 32 %

Procedure:
A solution of 4,5-bis(p-methoxyphenyl)-α,α-dimethyl-2-thiazoleacetic acid, methyl ester (0.70 g.; 0.0018 mole), 6 N sodium hydroxide (1.6 ml.) and methanol (15 ml.) was stirred at ambient temperature for 16 hours. Methanol was removed by rotary evaporation; the residue was slurried in water (30 ml.) and then adjusted to pH 2 with conc. hydrochloric acid. Decarboxylation occurred while the mixture stirred at ambient temperature for 1.75 hours. The mixture was extracted with methylene chloride. The extracts were dried (sodium sulfate) and concentrated by rotary evaporation to afford 0.59 g. of oily product. The material crystallized slowly at -10° over a period of several days. Recrystallization from pentane afforded 0.19 g. (32% yield) of 2-isopropyl-4,5-bis(p-methoxyphenyl)thiazole; m.p. 61°-65° C.