Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[NH2:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15](Cl)[N:14]=1.S([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C)C.C(OC(C)C)(C)C.O>[NH2:12][C:13]1[N+:18]([O-:5])=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCNc1cc(Cl)nc(N)n1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: CCCCCCNc1ccnc(N)[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
5.95 g of urea/H2O2 complex and 9.07 g of phthalic anhydride were suspended in 90 ml of isopropanol, in a three-necked flask. The mixture was stirred for 30 min at room temperature (20-25° C.). 10 g of 2-amino-4-hexylamino-6-chloropyrimidine were then added while controlling the exotherm at +30° C. After reaction for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin to destroy the residual oxidizing agents. The mixture was permitted to separate out by settling and the upper phase was concentrated under vacuum. The residue obtained was taken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture. The solid obtained was reimpasted in 150 ml of isopropyl ether. The solid was filtered off and washed. It was dried in a heated desiccator. 4.52 g of the expected compound were thus obtained, for a yield of 42%.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24](=[O:26])[CH3:25])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1(C)C=CC=CC=1.O1CCCC1.O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([C:24]([OH:26])([CH3:1])[CH3:25])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(C(C)(C)O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a dry round bottom flask was added via syringe 16 ml methyl magnesium bromide in toluene/tetrahydrofuran (75:25, 1.4 M). The flask was cooled in an ice bath under a stream of nitrogen. A solution 4-acetyl-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (337 mg, 1.02 mmol) in 5 ml tetrahydrofuran was added dropwise to the flask over 20 minutes and the resulting mixture was stirred at 0° C. for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was quenched by slow addition of 150 ml saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The yellow residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (7.5:2.5) to give the title compound (242 mg, 67%).
Reaction SMILES: I[CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20]O4)[CH:12]=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.[SH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[C:31]([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[O:17]([C:13]1[CH:12]=[C:11]([C:6]23[CH2:7][CH2:8][C:3]([CH2:2][S:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([CH2:10][CH2:9]2)[CH2:4][O:5]3)[CH:16]=[CH:15][CH:14]=1)[C:18]1[CH:31]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCS
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)CCSCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.6 %

Procedure:
A mixture of 4-(iodomethyl)-1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octane (7A; 41 mg, 0.098 mmol), methyl 3-mercaptopropanoate (21.14 μl, 0.195 mmol), and K2CO3 (135 mg, 0.976 mmol) in acetonitrile was stirred at rt for 2 days. The reaction was diluted with DCM (5 mL) and then filtered. The filtrate was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (35 mg, 87% yield) as a clear oil. LCMS, [M+H]+=413.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.[CH3:36][S:37][C:38](SC)=[N:39][C:40]#[N:41]>CC(O)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][C:38](=[N:39][C:40]#[N:41])[S:37][CH3:36])[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CSC(=NC#N)SC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCc2nnn(CCNC(=NC#N)SC)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 60.8 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (1.04 g) and dimethyl N-cyanoimidodithiocarbonate (0.30 g) in propan-2-ol (10 ml) was heated under reflux for 16 hours and then evaporated. The residual oil was triturated with hexane containing a small amount of methanol and the resulting solid was collected washed with hexane and dried to give 5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-[2-(3-cyano-2-methyl-1-isothioureido)ethyl]tetrazole (0.75 g), m.p. 78°-80° C. Found: C,48.53; H,4.93; N,17.60. C25H28Cl2N8O5S requires C,48.23; H,4.34; N,18.00%.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[O:20][CH:19]=[CH:18][C:17]=3[CH:16]=[C:15]([F:22])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>>[ClH:23].[F:22][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:21]2[O:20][CH:19]=[CH:18][C:17]=2[CH:16]=1
Reactant: Fc1cc(C2CCN(Cc3ccccc3)C2)c2occc2c1
Reactant: CC(Cl)OC(=O)Cl
Product: Cl
Product: Fc1cc(C2CCNC2)c2occc2c1

Procedure:
1-Benzyl-3-(5-fluorobenzofur-7-yl)pyrrolidine was debenzylated with 1-chloroethyl chloroformate and converted to the free amine, essentially as described in EXAMPLE 3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C1=NC(O)(C(F)(F)F)CN1c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(C)(=O)=O)cc1
Yield: 73.4 %

Procedure:
A mixture of 2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 3 (3.97 g, 0.01 mol) and p-toluenesulfonic acid monohydrate (0.60 g, 0.0032 mol) in 250 mL of toluene was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the crude product was purified by recrystallization from ethyl acetate/hexane to give 2.8 g of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (73%): mp 160–161° C. Anal. Calc'd. for C17H14F3N3O2S: C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.58, Ho 3.88, N, 11.02, S, 8.51.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][C:14](=[O:15])[C:13](=[O:17])[NH:12]2
Reactant: COc1cc(N)c(N)cc1OC
Reactant: O=C(O)C(=O)O
Product: COc1cc2[nH]c(=O)c(=O)[nH]c2cc1OC

Procedure:
6,7-Dimethoxy-1,4-dihydroquinoxaline-2,3-dione was prepared from 1,2-dimethoxybenzene. Nitration of 1,2-dimethoxybenzene gave 1,2-dimethoxy-4,5-dinitrobenzene, which was reduced to 1,2-diamino-4,5-dimethoxybenzene. Condensation of the diamine with oxalic acid gave 6,7-dimethoxy-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Fc1cccc(C(F)(F)F)n1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=363.1.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-(trifluoromethyl)pyridine.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[N:5]([C:14]([N:18]=[C:19]=[O:20])([CH2:16][CH3:17])[CH3:15])=[N:6][C:7]([N:11]=[C:12]=[O:13])([CH2:9][CH3:10])[CH3:8].[N-]=[C:22]=[O:23]>O>[N:5]([C:14]([NH:18][C:19]([O:23][CH3:22])=[O:20])([CH2:16][CH3:17])[CH3:15])=[N:6][C:7]([NH:11][C:12]([O:2][CH3:1])=[O:13])([CH2:9][CH3:10])[CH3:8]
Reactant: CO
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Reactant: [N-]=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(C)(N=NC(C)(CC)NC(=O)OC)NC(=O)OC
Reaction time: 2 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back down to 30° C., 5.6 grams (0.025 moles) of 2,2'-azobis(2-isocyanatobutane) was added dropwise over 2 minutes from an eyedropper. The reaction mixture exothermed to 45° C. over this period. The reaction mixture was stirred an additional 11/2 hours, poured into 200 ml water and the product extracted with a solution of 75 ml of pentane and 40 ml methylene chloride. The organic layer was separated, washed twice with water, once with 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to leave 2.0 grams (28% crude yield) of an orange liquid. The product had a strong carbonyl band at 1700 cm-1 and a sharp NH band at 3340 cm-1 and there is no isocyanate band at 2200 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)O1.C1(C)C=CC=CC=1.[C:40](=O)([O-])[O-:41].[Na+].[Na+]>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.C(OCC)(=O)C>[CH3:40][O:41][C:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:30]=[CH:29][C:28]=1[OH:31]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cncc(N[C@H](C)c3ccccc3)n2)ccc1O

Procedure:
Under a nitrogen atmosphere a mixture of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (0.611 g, 2.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.785 g, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) and toluene (3 mL) was treated with 2M aqueous sodium carbonate solution (1.6 mL, 2.6 mmol). The resulting mixture was stirred vigorously whilst being heated under reflux for 24 hours. Once cool ethyl acetate was added and the mixture dried (MgSO4) and filtered. Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane:diethyl ether (99:1→90:10) as eluent: (0.619 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[ClH:11].C[OH:13]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[N+:4]([O-:13])[CH:5]=[CH:6][C:7]=1[Cl:11]
Reactant: Cl
Reactant: O=[N+]([O-])c1ccncc1Br
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: [O-][n+]1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97 %

Procedure:
To a well stirred solution of 3-bromo-4-nitro pyridine (12.0 g, 54.794 mmol) in methanol (120 mL) was bubbled dry hydrochloride gas at about 0-5° C. for about 1-2-hours. The reaction mixture was then stirred at ambient temperature for about 6-8 hours. The solvent was evaporated under reduced pressure, the residue obtained was diluted with 20% aqueous solution of sodium hydroxide (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3-bromo-4-chloro-pyridine-N-oxide as an off-white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][C@@H:9]([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12])[CH3:20]
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)CO[C@@H](C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 69.4 %

Procedure:
1.16 g (6.61 mmol) of (S)-(2-hydroxy-propyl)-carbamic acid t-butyl ester was dissolved in 20 mL of dichloroethane, then 0.66 mL (9.84 mmol) of ethyl diazoacetate was added thereto. 57 mg (0.12 mmol) of rhodium acetate was dropwise added thereto, and then heated to at 80° C. for 2 hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 1.2 g (4.59 mmol) of the title compound in a yield of 69%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCCN
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: NCCCCNc1ccccn1
Yield: 67 %

Procedure:
2-Bromopyridine (10 g), 1,4-diaminobutane (35 ml) and pyridine (7 ml) were heated together under reflux for 4 hr. The excess of diaminobutane was evaporated at reduced pressure and the residue was dissolved in water. The solution was extracted with chloroform at pH 7 and then made alkaline to pH 13. The alkaline aqueous solution was extracted with more chloroform and was dried (K2CO3). The chloroform was evaporated and the residue was distilled at reduced pressure to give 2-(4-aminobutylamino)pyridine 7.0 g (67%) b.p. 136°-138° C., 2 mm Hg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[OH:22])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[O:22][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a one liter round bottom flask equipped with a mechanical stirrer and a thermometer was added 157.13 grams (1.14 moles--1.3 equiv.) of potassium carbonate, followed by 215.27 grams (0.875 mole--1.0 equiv.) of 89.9% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, and 230 mL (%Wt/Vol. Phenol to Solvent--93.6%) of N,N-dimethylformamide. The mixture was vigorously stirred and heated to 110° C., and then 139.3 grams (1.14 moles--1.3 equiv.) of methyl 2-chloropropanoate was added during a one hour period. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction mixture was heated at 110° C. for seven hours. After this time, the reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered, and the orange filtrate was kept under a nitrogen atmosphere for about 48 hours. After this time, the filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury to yield a red, brown liquid. The liquid was taken up in 200 mL of toluene, and the resulting solution was washed with two 500 mL portions of an aqueous saturated sodium chloride solution. The organic layer was separated from the aqueous layer, dried with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury, yielding 252.7 grams of 83.6% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]propanoate (78.6% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
4-Morpholinylcarbonyl chloride (35 μl, 0.3 mmol) was added dropwise to a ice-cooled mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol) and diisopropylethylamine (63 μl, 0.36 mmol) in dichloromethane (5 ml). At the end of the addition, the mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine and dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 1% to 2% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (100 mg, 64%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[NH2:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:17][C:9]1[S:10][C:11]2[C:16]([N:8]=1)=[CH:15][CH:14]=[CH:13][N:12]=2
Reactant: Nc1nc2cccnc2s1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Fc1ccccn1
Product: c1ccc(Oc2ccc3ncnc(Nc4nc5cccnc5s4)c3c2)nc1

Procedure:
The compound of Example 82 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-fluoropyridine, thiazolo[5,4-b]pyridin-2-yl-amine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: C1(CN2CCN(C3SC(C(O)=O)=CN=3)C2=O)CC1.[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([OH:41])=O)=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1>>[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([NH:52][CH2:51][C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)=[O:41])=[C:33]([C:35]([F:37])([F:36])[F:38])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1
Reactant: O=C(O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Reactant: NCc1cccnc1
Agent: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Product: O=C(NCc1cccnc1)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 37 %

Procedure:
Following the procedure as described in Example 26, making variations as required to replace 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 37% yield: mp 161-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.31-7.22 (m, 3H), 7.05-7.00 (m, 2H), 6.55-6.47 (m, 1H), 4.61 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 4.09-4.03 (m, 2H), 3.48-3.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.9, 159.5, 159.0, 155.2, 149.2, 135.6, 132.9, 131.0, 130.1, 127.2, 123.7, 122.2, 118.6, 116.0, 47.3, 41.9, 41.6, 30.9; MS (ES+) m/z 480.5 (M+1).
Reaction SMILES: C1CCN(C(CNCC2C=CC3OCOC=3C=2)=S)CC1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:33][C:32]2=[O:44])=[CH:25][CH:24]=1.[OH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[OH:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][C:32]3=[O:44])=[CH:25][CH:24]=2)[CH2:48][CH2:47]1
Reactant: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Agent: S=C(CNCc1ccc2c(c1)OCO2)N1CCCCC1
Product: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CN2CCC(O)CC2)cc1

Procedure:
1-{2-[4-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-ethyl}-4-phenoxy-1H-pyridin-2-one is prepared as example 16.2c from 100 mg (0.26 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-phenoxy-1H-pyridin-2-one (example 16.2b) and 105 mg (1.04 mmol) 4-hydroxy-piperidine.