Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19]([OH:21])=[O:20])[NH:10]1.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23].S(Cl)(Cl)=O>C(#N)C.C1C=CC=CC=1>[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28]([N:10]1[CH:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:8])=[O:29])(=[O:24])[CH3:23]
Reactant: O=C1NC(C(=O)O)Cc2ccccc21
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)SCC(C)C(=O)N1C(=O)c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g of triethyl amine was added to a suspension of 1-oxo-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (1.0 g) in 10 ml of acetonitrile. The suspension was cooled by ice and a solution of 3-acetylthio-2-methyl propionic chloride in 5 ml of acetonitrile was added drop by drop, the 3-acetylthio-2-methyl propionic chloride being prepared by adding 2.0 g of thionyl chloride to a benzene solution of 3-acethylthio-2-methylpropionic acid (0.85 g), stirring overnight at room temperature and distilling off the solvent and the excess amount of thionyl chloride. The mixture was then stirred for two hours at room temperature, the solvent distilled off, 20 ml of ethylacetate and 10 ml of water added, then the solution was shaken and the organic phase separated. After washing the organic phase, it was dried over anhydrous Glauber's salt, the solvent distilled off and then purified by silicagel column chromatography (benzene-acetic acid; 50:1 V/V) to obtain 1.05 g of 2-(3-acetylthio-2 -methylpropionyl)-1-oxo-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid as an oily material.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].IC.[CH3:24]C(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH3:24][NH:18][C:9]1[N:8]2[N:19]=[CH:20][N:21]=[C:7]2[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Solvent: O
Product: CCOCCc1c(-c2ccccc2)nc(NC)n2ncnc12
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (0.01 mole) of 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine, ca. 3 g of iodomethane, and ca. 1 g of potassium t-butoxide in t-butyl alcohol was stirred with heating for five hours. The solution was cooled to room temperature and then poured into 200 ml of cold water and extracted with several portions of ethyl acetate. The organic phase was washed with aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to dryness. Column chromatography on silica gel afforded 175 mg of the title monomethylated product.
Reaction SMILES: SCC(OCC)=O.[H-].[Na+].[H][H].[C:12]([C:20]1[C:21]([S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:12]2[C:20]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[S:26][C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)CSc1ncccc1C(=O)c1ccccc1
Agent: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ncccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-mercaptoacetate (0.6 mL, 5.5 mmol) in dry DMF (10 mL) under nitrogen and cooled with an ice bath was added sodium hydride (220 mg of 60% dispersion in oil, 5.75 mmol). After hydrogen evolution had ceased the cooling bath was removed and the reaction stirred at room temperature for 30 mins. A solution of Intermediate 1 (920 mg, 4.6 mmol) in DMF (5 mL) was added and the reaction stirred at room temperature for 3 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give a mixture of the title compound and uncyclised ethyl 2-(3-benzoylpyridin-2-ylsulfanyl)acetate. This crude mixture was dissolved in EtOH (10 mL) and sodium ethoxide (10 mL of 0.5M solution in EtOH, 5.0 mmol) added. The reaction was stirred at room temperature for 45 mins after which time complete conversion of uncyclised material to title compound was observed. The reaction was diluted with EtOAc (50 mL), washed with water (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (10% EtOAc in isohexane) to give the title compound as a white solid (780 mg, 60%). δH (CDCl3) 8.63 (1H, dd, J 4.5, 1.4 Hz), 7.78 (1H, dd, J 8.2, 1.5 Hz), 7.41 (3H, m), 7.33–7.32 (2H, m), 7.24 (1H, dd, J 8.2, 4.6 Hz), 4.18 (2H, q, J 7.1 Hz), 1.15 (3H, t, J 7.1 Hz) LCMS (ES+) RT 3.90 minutes, 284 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=1>C(Cl)Cl>[F:18][C:16]1[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH:29]=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 2-L round bottom flask was charged with DCM (900 mL) and oxalylchloride (25.36 g, 0.20 mole, 1.3 eq.) and cooled to −78° C. Dimethylsulfoxide (DMSO, 31.22 g, 0.40 mole, 2.6 eq.) was added dropwise and the mixture was stirred at −78° C. for 10 min. Then, {1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol (43.2 g, 0.15 mole, 1.0 eq, dissolved in 100 mL of DCM and a few mL DMSO) was added slowly. After stirring for another 30 min at −78° C., TEA (93.14 g, 0.92 mole, 6.0 eq.) was added slowly. The suspension was then stirred at −78° C. for 30 min, then warmed to room temperature over 2 h. The mixture was diluted with 300 mL DCM and washed with 2×200 mL 2M HCl, 1×100 mL saturated NaHCO3, and then dried over MgSO4, and concentrated to afford 1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde (35.4 g, 82%) as a brown oil. The material was used in the next step without further purification. MS (ES) m/e 280 [M+H]+. 1HNMR (CDCl3) δ(ppm): 9.72 (s, 1H), 7.56 (d, 1H), 7.04 (m, 2H), 6.90 (d, 1H), 6.82 (m, 1H), 4.40 (m, 1H), 4.00 (m, 1H), 3.36 (m, 1H), 3.22 (m, 1H), 2.56-2.64 (m, 1H), 2.02 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:21]([OH:23])=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][C:25]1(C)OC(=O)CC(=O)[O:26]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:25](=[O:26])[CH:24]=[C:21]([OH:23])[CH:11]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C[C@H](Nc2ccc(C#N)c(Cl)c2)C(=O)O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CC2C(O)=CC(=O)N2c2ccc(C#N)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)-4-cyanophenylalanine (1.57 g), Meldrum's acid (0.76 g) and 4-(N,N-dimethylamino)pyridine (0.88 g) in tetrahydrofuran (70 mL) was added N,N′-carbonyldiimidazole (0.94 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as pale-yellow crystals (yield: 578 mg, 34%).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31]C)=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2O)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenoxy]acetate (see example 20) (190 mg, 0.414 mmol, 1.0 eq) in DCM (5 mL) at 0° C. under N2 was added AlCl3 (330.8 mg, 2.48 mmol, 6.0 eq) and EtSH (154.2 mg, 2.48 mmol, 6.0 eq). The resulting mixture was stirred for 1.5 h at room temperature then the reaction was quenched by dropwise addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1 v/v) to give the title compound as an oil (90 mg, 49%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3nccnc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]/[N:26]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl 4-(2-formylphenyl)piperidine-1-carboxylate (229 mg, 0.79 mmol) in toluene (4 mL) was added 3,3 dimethylbutylamine (88.09 mg, 117.1 μL, 0.8705 mmol) and 4 Å molecular sieves. The resulting suspension was stirred at rt overnight. Filtered out molecular sieves and concentrated the mixture with a flow of N2 to give 282 mg of tert-butyl 4-(2-((E)-(3,3-dimethylbutylimino)methyl)phenyl)piperidine-1-carboxylate as an thick off-white oil which was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30].O>CN(C)C=O>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[N:17]=[C:16]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH3:25]
Reactant: COCCOC(=O)Cl
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOC(=O)N(c1ccc(Cl)cc1)c1nc(-n2nc(C)cc2C)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (520 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (60% in mineral oil, 90 mg, 2.2 mmol) was added and mixture was stirred at room temperature for 30 minutes. 2-Methoxyethyl chloroformate (0.26 mL, 2.2 mmol) was added and stirring was continued at room temperature over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/methanol as eluent) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-carbamic acid 2-methoxy-ethyl ester (280 mg, 42%) as a white solid.
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=O)[CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1>>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:56][CH2:57]2)=[CH:48][CH:47]=1
Reactant: O=C(CC1OCCc2cc(Br)ccc21)N1CCN(c2ccc(Cl)cc2)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: Clc1ccc(N2CCN(CCC3OCCc4cc(Br)ccc43)CC2)cc1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 4-chlorophenylpiperazine (XI) and the resulting amide, 1-(4-chlorophenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 1.39 mmol) is reduced according to the general procedure of EXAMPLE 50 making non-critical variations, to give the title compound, mp 94°-96°; IR (mull) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102, 815 cm-1 ; NMR (300 MHz, CDCl3) 7.32-7.26, 7.19, 6.97, 6.83, 4.78, 4.14-4.07, 3.78-3.69, 3.16, 3.00-2.90, 2.7-2.48, 2.15-1.90; CMR (75 MHz, CDCl3) 149.6, 137.1, 136.0, 131.4, 129.1, 128.7, 126.3, 124.6, 120.0, 116.9, 74.0, 62.6, 54.3, 53.3, 53.0, 48.9, 33.0 and 28.6 δ.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:9])([CH2:7][NH2:8])[CH2:5][NH2:6].Cl.[NH2:11][C:12](N)=N.C[O-].[Na+]>>[F:3][C:4]1([F:9])[CH2:7][NH:8][C:12]([NH2:11])=[N:6][CH2:5]1
Reactant: N=C(N)N
Reactant: NCC(F)(F)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NCC(F)(F)CN1
Temperature: 150 °C

Procedure:
A mixture of 2.95 g (16.12 mmol) of 2,2-difluoro-1,3-propandiamine dihydrochloride (Tetrahedron (1994) 50(29), 8617-8632), 1.54 g (16.12 mmol) of guanidine hydrochloride and 2.19 g (32.23 mmol) of sodium methylate was heated at 150° C. during 18 h. The cooled mixture was used as such in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[N:9]=1
Reactant: COc1ccc2cc(-c3ccccc3OC)[n+]([O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3ccccc3OC)nc(Cl)c2c1

Procedure:
7-Methoxy-3-(2-methoxyphenyl)isoquinoline-2-oxide (0.60 g) and phosphorus oxychloride (5 ml) were reacted at 110° C. for 2 hr. The reaction solution was concentrated, and to the resulting residue were added ethyl acetate and an aqueous saturated sodium bicarbonate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.56 g of the title compound as a white solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][NH:54][CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]>CN(C=O)C>[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][N:54]([C:9](=[O:11])[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: O=C(O)COc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)COc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of phenoxy acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatograph to obtained the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([OH:25])[CH:16]=2)[N:3]=1.O[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:25][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])[N:5]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1OCCCCCCNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 36 %

Procedure:
methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-hydroxybenzoate (100 mg, 0.264 mmol), tert-butyl 6-hydroxyhexylcarbamate (68.9 mg, 0.317 mmol), Triphenylphosphine (139 mg, 0.528 mmol), were dissolved in DCM then DIAD (0.103 mL, 0.528 mmol) was added. The reaction was stirred for 16 h. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography using 20% EtOAc/Hexanes. The product fractions were collected and the solvent was removed under vacuum to give 55 mg (36%) methyl 2-(6-(tert-butoxycarbonylamino)hexyloxy)-4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:29][CH2:28]3)=O)[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.C([O-])(=O)C([O-])=O.[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:61].Cl>C1COCC1.O>[ClH:40].[ClH:61].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[CH2:31][CH2:32]3)[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:10][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of 4.68 g of lithium aluminum hydride (61.7 mmol, 50% in oil; washed 3 times with hexane) in 160 ml of THF was added dropwise a solution of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl}-N-methylaminoacetyl}-4-(4-chlorophenoxy)piperidine (liberated from 34.7 g, 0.105 mol, of the oxalate) in 160 ml of dry THF. The mixture was stirred at reflux for 16 hours, allowed to cool to room temperature and subsequently cooled in an ice bath. To the mixture were added slowly, dropwise, 3 ml of water, 3 ml of 15% NaOH and 9 of ml water. The mixture was filtered and the residue washed with THF. Evaporation of the solvent provided an oil. The oil was washed with water, dried over potassium carbonate and the solvent evaporated to provide an oil. The yield of the dihydrochloride was 11.98 g (63%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:33]=3[O:32][CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: COc1cccc(C(=O)Cl)c1OC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OC(C)=O)[C@@H](COC(C)=O)O3)c2=O)c1OC
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
15.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 15 ml of triethylamine were dissolved in 75 ml of dry dioxane, and the resulting solution was cooled with ice. To the solution was added 13.6 g of 2,3-dimethoxybenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 90° C. for 30 minutes. The crystals produced were filtered off, and the filtrate was concentrated under reduced pressure. To the oily residue was added 200 ml of ethanol. Upon heating, the mixture began to separate crystals while the oily residue was dissolved. After dissolving the oily residue completely, the mixture was cooled, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-3-(2,3-dimethoxybenzoyl)-5-fluorouridine as crystals. Recrystallization of the product from ethanol afforded 19.65 g (yield: 88.4%) or colorless needles having a melting point of 139 to 141° C. The structure was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+]([C:13]1[CH:14]=C(S(O)(=O)=O)C=[CH:17][CH:18]=1)([O-])=O.P(=O)(O)(O)O.C(=O)/C=C/C.O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[C:18]([CH3:17])[CH:13]=[CH:14]2
Reactant: Nc1cc(F)ccc1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: C/C=C/C=O
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2c(F)ccc(Br)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.0 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (65.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, crotonaldehyde (4.64 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane, and then dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.31 g of 8-bromo-5-fluoro-2-methyl-quinoline as a yellowish white solid (yield: 21.8%).