Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1)=[O:19]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 75 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (621 mg, 1.38 mmol, 75%) was obtained.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[CH2:1]([S:8]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NS(=O)(=O)Cc1ccccc1

Procedure:
The sulfonamide was synthesized from benzyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mol) by general Method C. It was purified by recrystallization from EtOH (0.87 g, 33%) EI-MS m/z 263 (M+H)+.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC([O-])=O.[Na+].C[O:36][CH:37]1[CH:41]([CH:42]=O)[CH2:40][CH:39](OC)O1>C(Cl)Cl.O>[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([N:29]5[CH:39]=[CH:40][C:41]([CH:37]=[O:36])=[CH:42]5)[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Reactant: COC1CC(C=O)C(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5ccc(C=O)c5)C4)n23)cc1
Temperature: 40 °C
Yield: 33.3 %

Procedure:
To a suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.175 g, 0.373 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.100 g, 1.22 mmol) in DCM (3 mL) and water (2 mL) was added 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (0.600 g, 3.37 mmol). The reaction was heated to about 40° C. for about 24 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown residue. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 20-100% EtOAc in DCM to give 1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.059 g, 33%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=2.10 min; MS m/z: 475 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:15][NH2:16]>C(O)C>[CH2:2]([C:1]1[CH2:6][C:7](=[O:9])[NH:16][N:15]=1)[CH2:3][CH3:4]
Reactant: NN
Reactant: CCCC(=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: CCO
Product: CCCC1=NNC(=O)C1
Reaction time: 2 h

Procedure:
Methyl butyrylacetate (4 g, 27.7 mmol) was stirred in ethanol and acetic acid (10:1, 8:0.8 mL) and treated with hydrazine (1.05 mL, 33.3 mmol). After 2 hrs, the resulting solid was filtered off and washed with a minimum amount of acetonitrile to yield 3-propyl-1H-pyrazol-5(4H)-one. Then, the 3-propyl-1H-pyrazol-5(4H)-one (4.68 g, 11.8 mmol) and 4-chloroquinoline N-oxide (1.5 g, 11.8 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated, and the resulting solid filtered off, washed with a minimum amount of methanol, and treated with hydrazine (0.84 mL, 26.7 mmol) in methanol (12 mL) to yield Example 23 as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.33 Hz, 3H) 1.66-1.76 (m, 2H) 3.02 (t, J=7.07 Hz, 2H) 7.62 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.10 (d, J=8.34 Hz, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](=O)[NH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([CH:27]([NH2:28])[CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCCN
Reactant: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(C(N)CCN(C)C)nc(C)nc2c1S(=O)(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 123 b), from 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one and 3-dimethylamino-1-propylamine there was obtained (8-benzenesulphonyl-2-methyl-7-methylsulphanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-N′,N′-dimethyl-propan-1,3-diamine which was converted with HCl/diethyl ether into the corresponding hydrochloride (1:1.75), m.p. 249-250°.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(CO)(CO)CO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 87 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 743.1 g (5 mol) of diethyl oxalate, 56.9 g (0.42 mol) of trimethylolpropane and 0.55 g (0.8 mmol) of dibutyltin dilaurate, and mixed at 130° C. for 5 hours. After removing 58.6 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 158.7 g of crude triethoxalyltrimethylolpropane (yield 87%).
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:25].C(OCC)(=O)C.[ClH:32]>O1CCCC1>[ClH:32].[CH3:4][NH:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:12]1[S:11][CH:15]=[CH:14][N:13]=1)=[CH:24]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CNc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Under ice-cooling, formic acid (6.0 mL) was added dropwise to acetic anhydride (12.5 mL). After dropwise addition, the reaction mixture was stirred at 60° C. for 2 hr. Tetrahydrofuran (10 mL) was added to the reaction mixture, and a solution of 2-(1,3-thiazol-2-yl)-1H-indole-7-amine (10 g) in tetrahydrofuran (10 mL) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 min and concentrated. Tetrahydrofuran (10 mL) was added to the obtained residue, and borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution, 30 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, and methanol (5 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr, concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1). To the obtained a yellow oil was added 4N hydrogen chloride-ethyl acetate solution (30 mL). The obtained yellow crystals were collected by filtration, and washed with diethyl ether and hexane to give the title compound (10 g, yield 70%) as yellow crystals. melting point 89° C.
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]([OH:24])[C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCCC1>[C:30]([O:29][C:27]([CH2:26][O:24][C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C@H:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion; 161 mg, 4.03 mmol) in dry tetrahydrofuran (9.6 ml) were added a solution of 8S (1.15 g, 3.84 mmol) and tert-butyl bromoacetate (681 μl, 4.61 mmol) in dry tetrahydrofuran (9.6 ml) at 0° C. After stirring for 18 h at rt, the reaction mixture was concentrated in vacuo. After addition of water, the product was extracted with ethyl acetate twice and the organic layer was dried over anhydrous sulfate. After concentration in vacuo, the residue was purified by silica gel chromatography (eluted with 10:1 hexane:AcOEt) to give 9S (1.17 g, 74%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CN(C)c1ccc(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(4-dimethylamino-phenyl)-urea was prepared starting from intermediate D and 4-(dimethylamino)-phenylisocyanate. MS calcd. for C25H24ClN4O2 [(M+H)+] 447.2, obsd. 447.2.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]=2)[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]23[CH2:2][CH:18]2[CH:19]([OH:22])[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: OC1C=C(c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: OC1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To an Et2Zn solution (1.0M in hexane; 14 mL, 14 mmol) cooled to 0° C., a solution of CH2I2 (1.13 mL, 14 mmol) in CH2Cl2 (10 mL) was added. This was stirred for 5 min, then a solution of 3-(3,4-dichlorophenyl)cyclopent-2-en-1-ol (0.5 g, 2.19 mmol) in CH2Cl2 (50 mL) was added dropwise. The reaction mixture was stirred overnight then quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with CH2Cl2 (3×). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by silica gel chromatography using 10-30% EtOAc/Heptane as the eluting solvent gave the target compound (0.3 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.76-0.85 (m, 1 H) 1.20-1.33 (m, 2 H) 1.65-1.77 (broad, 1 H) 1.83-1.90 (m, 1 H) 1.93-2.17 (m, 3 H) 4.64-4.73 (m, 1 H) 6.93-6.97 (m, 1 H) 7.22 (d, 1 H) 7.29-7.34 (m, 1 H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.C1(C)C=CC=CC=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1.C(O)(C)C>S(=O)(=O)(O)O.O>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:25]2[CH:26]=[CH:27][C:28]([N:31]3[C:1](=[O:7])[CH:2]=[CH:3][C:4]3=[O:6])=[CH:29][CH:30]=2)([CH3:24])[CH3:23])=[CH:20][CH:21]=1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(c1ccc(O)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Reaction time: 0.75 h
Yield: 478.3 %

Procedure:
To a reaction vessel equipped with a stirrer, thermometer and an azeotropic distillation trap, 60 g (0.1 mole) of maleic anhydride, 480 g of toluene and 2.6 g of 95% sulfuric acid were charged and heated to a reflux temperature. A solution containing 114 g (0.5 mole) of 2-(4-hydroxyphenyl)-2-(4-aminophenyl)propane in 160 g of N,N'-dimethylacetamide was dropwise added from a dropping funnel over 4 to 5 hours and reacted for 5 hours at the same temperature. Generated water by the reaction was removed by azeotropic distillation. After completing the reaction, the reaction mixture was cooled to 80° to 90° C. and the solvent was successively removed under reduced pressure. The organic layer thus obtained was mixed with 100 ml of isopropyl alcohol and then 300 ml of water was added and stirred for 0.5 to 1 hour to precipitate crystals. The crystals were filtered and dried to obtain 147 g of 2-(4-hydroxyphenyl)-2-(4-maleimidophenyl)propane as yellow crystals. The yield was 96%.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]O)=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]3[CH:23]=[CH:24][C:8]([Cl:7])=[CH:9][C:10]=3[O:14][C:13]=2[CH:15]=1
Reactant: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
11.9 g (0.15 mole) of pyridine were added to a suspension of 26.2 g (0.1 mole) of 2-(7-chlorodibenzofuran-3-yloxy)-ethanol in 100 ml of dry toluene, and 17.9 g (0.15 mole) of thionyl chloride were then added dropwise at from 3° to 15° C. The mixture was stirred for 1 day at 40° C. and for a further 8 hours at 70° C., after which it was cooled and 150 ml of toluene and 200 ml of ice water were added. The organic layer was washed with 100 ml of water, 50 ml of hydrochloric acid, 50 ml of 1N sodium hydroxide solution and 100 ml of water in succession, and was dried and evaporated down. The solid residue was stirred for 30 minutes with 40 ml of petroleum ether at +3° C. (ice bath), and was then filtered off under suction, washed with a little cold petroleum ether and dried. 22.8 g (81% of theory) of 1-chloro-2-(7-chlorodibenzofuran-3-yloxy)-ethane were obtained at colorless crystals of melting point 105°-107° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][N:5]=2)[CH2:3][CH2:2]1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[CH:1]1([C:4]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: c1cc(C2CC2)n[nH]1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c[nH]nc1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a cooling (0° C.) solution of 3-cyclopropyl-1H-pyrazole (1.5 g, 13.89 mmol) in concentrated H2SO4 (20 mL, 98%) was added concentrated HNO3 (20 mL, 65%) over 2 min. The reaction mixture was stirred over 1 hr at this temperature. It was then diluted with ice-water and extracted with EA (30 mL×4). The organic phase was combined and washed with saturated sodium bicarbonate (50 mL). It was dried over Na2SO4 and concentrated in vacuo to give a crude product (1.5 g, 70%). This crude product was pure enough to be delivered or used to the next step reaction. MS: [M+H]+154. 1H NMR (500 MHz, CDCl3) δ 0.97 (m, 2H), 1.22 (m, 2H), 2.66 (m, 1H), 8.20 (s, 1H), 8.38 (s, 1H).
Reaction SMILES: [Si]([O:8][CH:9]([C:15]1[S:16][C:17]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[NH:29][N:28]=3)[C:23]([Cl:35])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(C(C)(C)C)(C)C.CCN(CC)CC>O1CCCC1.C(OCC)(=O)C>[Cl:35][C:23]1[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)=[N:25][C:20]([C:17]2[S:16][C:15]([CH:9]([OH:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=2)=[N:21][CH:22]=1
Reactant: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 2-(tert-butyldimethylsilyloxy)-2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)acetate (200 mg, 0.37 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added Et3N.3HF (0.2 mL, 1.11 mmol, 3.0 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=1:1) to give Ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-hydroxyacetate (Compound 191) (123 mg, 78.6%). LC-MS (m/z): 420.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.21 (t, J=7.0 Hz, 3H), 1.91-1.98 (m, 1H), 4.14-4.19 (m, 2H), 5.42 (d, J=4.8 Hz, 1H), 6.44 (s, 1H), 6.52 (d, J=5.6 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), 7.67 (d, J=4.0 Hz, 1H), 8.40 (s, 1H), 9.29 (s, 1H), 12.30 (bs, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14](F)[CH:15]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ncc(OCC(F)(F)F)cc1F
Reaction time: 1 h
Yield: 50.6 %

Procedure:
60% sodium hydride (0.219 g, 5.71 mmol) was added to a solution of 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (6 ml) at 0 oC and stirred for 1 hour. Then 3,5-difluoropicolinonitrile (1.0 g, 7.1 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (4 mL) was added to the reaction mixture and stirred at room temperature for 20 hours. Then 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) and 60% sodium hydride (0.22 g, 5.7 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. After reaction, the mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6:1-4:1) to give 398 mg (25% yield) of the title compound as a oily solution:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=1)#N.[OH2:22].C(OCC)(=O)C.[OH2:29]>Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=[C:3]([C:1]([OH:29])=[O:22])[CH:8]=1
Reactant: O
Reactant: COc1cc(C#N)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-cyano-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine (1.0 g, 0.0034 mol) was suspended in about 10 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 2 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)C>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1c(F)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 3-fluorosalicylaldehyde (3.52 g, 25.12 mmol) and cesium carbonate (20.46 g, 62.81 mmol) in N,N-dimethylformamide (30 mL) is treated with iodomethane (3.13 mL, 50.2 mmol) and stirred at room temperature under nitrogen for 2 h. The reaction mixture is diluted with diethyl ether (150 mL) and washed with 0.5 M hydrochloric acid (2×150 mL). The organic portion is dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3.42 g (88%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 1H), 7.32 (dd, 1H), 7.04 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C(OC(=O)C)(=O)C>CN(C)C=O>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 63.7 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), urea (170 mg: 2.8 mmoles) and acetic anhydride (1 ml) in dimethyl-formamide (2 ml) was stirred at 100° C. for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 290 mg (yield: 64%) of 5-trifluoromethyldihydrouracil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 653.3 %

Procedure:
t-Boc-GlyGlyGly (1.359 g, 4.7 mmol) was dissolved in 350 mL of anhydrous methylene chloride at room temperature and to this solution were added DIPC (0.75 mL, 4.7 mmol), DMAP (382 mg, 3.13 mmol) and camptothecin (0.55 g, 1.57 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and left for 16 h. The solution was washed with 0.1 N HCl, dried and evaporated under reduced pressure to yield a white solid, which was recrystallized from methanol to give camptothecin-20-ester of t-Boc-GlyGlyGly: 1H NMR (DMSO-d6) δ 8.40 (s), 8.25 (d), 7.91 (d), 7.78 (m), 7.65 (t), 7.26 (s), 7.05 (br, s), 5.65 (d), 5.40 (d), 5.25 (s), 5.10 (br, s), 3.75-4.42 (m), 2.15-2.35 (m), 1.45 (s), 0.95 (t) Camptothecin-20-ester of t-Boc-GlyGlyGly (1.5 g, 1.06 mmol) was dissolved in a mixture of methylene chloride (10 mL) and TFA (10 mL) and stirred at room temperature for 1 h. Solvent was removed under vacuum and the residue was re-dissolved in methylene chloride. The solution was poured into ether to give instant precipitate (yellow). The precipitate was filtered and washed with cold ether to give 1.31 g of 12. 1H NMR (DMSO-d6) δ 8.79 (s), 7.75-8.61 (m), 7.10 (s), 5.55 (s), 3.90-4.37 (m), 3.86 (s), 3.54 (s), 2.11-2.23 (m), 0.95 (t). ESI/MS (m/z) expected 519. Found 520 (M+H).