Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:2]([C:13]([NH:15][C@@H:16]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH:27]=[O:28])[CH:19]=1)=[O:14])[CH2:3][CH2:4][C:5](=[O:12])[O:6]CC(Cl)(Cl)Cl>CC(O)=O.[Zn]>[NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:2]([C:13]([NH:15][C@@H:16]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH:27]=[O:28])[CH:19]=1)=[O:14])[CH2:3][CH2:4][C:5](=[O:6])[OH:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCC(Cl)(Cl)Cl)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a solution of Boc-Glu(OTce)-D-Trp(CHO)-Phe-OBzl (0.40 g) in 90% AcOH (10 ml), was added zinc (0.20 g). The mixture was stirred for four and half an hour at room temperature. After filtration and evaporation, the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and dried over magnesium sulfate. The evaporated residue was subjected to column chromatography on silica gel (20 g) and eluted with a mixture of chloroform and methanol (30:1 to 9:1, gradient elution). The fractions containing the object compound were combined and evaporated. The residue was pulverized with n-hexane, filtered and dried to give Boc-Glu-D-Trp(CHO)-Phe-OBzl (0.27 g).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: BrCc1nc2ccccc2o1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])Cc1nc2ccccc2o1
Temperature: 60 °C
Reaction time: 6 h
Yield: 135.2 %

Procedure:
To a solution of 3.0 g of 2-bromomethylbenzoxazole [prepared according to the procedures described in Belgian Pat. No. 624,463] in 40 ml of methanol was added a solution of 1.9 g of sodium sulfite in 40 ml of water. The mixture was heated with stirring at 60° C. for 6 hours and concentrated under reduced pressure to give crude sodium benzoxazole-2-methanesulfonate (4.5 g). To the sodium salt was added 15 ml of phosphorus oxychloride and the mixture was heated under reflux for one hour. The removal of the remaining phosphorus oxychloride by distillation under reduced pressure gave the desired product as an oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1.BrC1C=C(C2C(=O)N(C)C(Cl)=NC=2C2C=CN=CC=2)C=CC=1>ClCCl>[CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC[C@H]1CCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.186 g, 0.86 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.3 mL diisopropylethylamine (1.71 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.2 g, 0.57 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. (This naphthyl chloro-intermediate was synthesized by a similar procedure as that of 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.) The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.21 g as pale yellow solid. MS (ES+): 454 (M+H)+; (ES−): 452 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28](=[O:39])OC2C=CC([N+]([O-])=O)=CC=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.ClCCCl.Br.[F:45][C:46]1([F:51])[CH2:50][CH2:49][NH:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28]([N:48]2[CH2:49][CH2:50][C:46]([F:51])([F:45])[CH2:47]2)=[O:39])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC1(F)CCNC1
Agent: Br
Solvent: ClCCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a crude solution of (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate in DCE (1 mL) (67 mg, 0.13 mmol) was added 3,3-difluoropyrrolidine hydrobromide (24 mg, 0. 12 mmol). The reaction mixture was stirred at room temperature for 2 h and the solution turned yellow. The solution was concentrated, dissolved in MeOH (1.5 mL), filtered and purified by reverse phase prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate. (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3,3-difluoropyrrolidine-1-carboxamide (0.011 g, 17% yield) eluted at a retention time of 11.2 mins and was isolated as colorless oil. LCMS: 2.15 min [M+1] 528.2 (2 min gradient, MeOH/H2O 0.1% TFA) 1H NMR (CDCl3, 400 MHz): 8.20 (d, J=2.0 Hz, 1H), 7.60 (dd, J=2 Hz, J=8 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=8 Hz, 1H), 7.15 (m, 2H), 7.05 (m, 1H), 7.03 (m, 3H), 6.44, (d, J=8 Hz, 1H), 4.37, (d, J=12 Hz, 1H), 3.74, (q, J=12 Hz, 1H), 3.54, (m, 1H), 3.44, (m, 2H), 3.32, (q, J=8 Hz, 1H), 2.32, (m, 2H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.N.[F:10][C:11](I)([F:13])[F:12].C(OCC)C>O>[F:10][C:11]([F:13])([F:12])[S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=1
Reactant: FC(F)(F)I
Reactant: Cc1ccc(S)cc1
Agent: N
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(SC(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
p-Toluenethiol (8 g.) was added to liquid ammonia (60 ml.) at -30°. Trifluoromethyl iodide (18 g.) was added and the mixture was irradiated with uv light (297nm.) for 30 minutes. Dry diethyl ether (35 ml.) was added and irradiation was continued for 1 hour. The mixture was allowed to warm to 20° C. and water was added. The mixture was extracted with diethyl ether and the ethereal extracts were washed with sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Distillation gave 4-trifluoromethylthiotoluene as a mobile yellow-brown liquid (b.p. 78°-80° C., 16 mm.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([F:50])([F:49])[F:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]([F:50])([F:49])[F:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC(F)(F)F)c3=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (98 mg, 0.19 mmol) in dry DMF (2 ml) was added potassium carbonate (79 mg, 0.57 mmol) and 2-bromo-1,1,1-trifluoroethane (94 mg, 0.57 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at 80° C. Water was added and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 27% EtOAc in cyclohexane) to give the title compound (45 mg, 40%). 1H NMR (500 MHz, CDCl3): 8.47 (1H, s), 7.26-7.20 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.38 (2H, q), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28])#[N:18].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[F:28][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=2)[CH:23]=[CH:24][C:19]=1[C:17]#[N:18]
Reactant: CNc1nc(Cl)cc(N2CCOC[C@H]2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Temperature: 140 °C
Yield: 109 %

Procedure:
To a 5-mL microwave vial was added 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (200 mg, 0.824 mmol), (4-cyano-3-fluorophenyl)boronic acid (177 mg, 1.071 mmol), PdCl2(dppf).CH2Cl2 adduct (33.6 mg, 0.041 mmol), K2CO3 (1.236 mL, 2.472 mmol), and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 10 minutes in a microwave reactor. The 1,4-dioxane was removed, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in hexanes, 12 g column) to afford the title compound (294 mg) as a yellow oil. LC-MS (ES) m/z=328 [M+H]+.
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1Br)[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C-]#N.[Na+]>O>[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1[C:1]#[N:2])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Reactant: N#CCCSCCC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
Into a solution composed of 6.8 parts of cuprous bromide in 300 parts by volume of bis(β-cyanoethyl) sulfide, there are introduced 26 parts of 3-cinnamoylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline. The mixture is heated to 100° C. and, during several minutes, a solution of 2.6 parts of sodium cyanide in 16 parts of water is allowed to flow in. Stirring is continued for 1 to 2 hours more, at 115° C. After cooling to 30° C., the 3-cinnamoylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline formed is separated, under the same conditions as in example 1. The yield is 85.5%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1F)[C:32]#[N:33]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=2[Cl:28])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To 1.2 g (4.23 mmol) of 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester, dissolved in 10 ml of DMF, potassium carbonate 1.17 g (8.46 mmol) was added and stirred for 30 min at RT. 1.31 g (8.46 mmol) of 3-chloro-4-fluoro-benzonitrile, dissolved in 5 ml of DMF, was added dropwise to the reaction mixture during 15 min and final contents were stirred at 80° C. overnight. The reaction mixture was concentrated, residue was dissolved in 200 ml of ethyl acetate and partitioned with water. The organic layer was washed with brine followed by of water. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was subjected to column chromatography, using silica-gel and eluted with hexane:ethyl acetate (8:2) to afford 1.4 g of pure product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 7.2-7.36 (4H, m), 7.44 (2H, dd), 7.88 (3H, m), 8.26 (1H, d).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]([CH3:38])[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[C:28](I)[CH:27]=2)=[C:14]([O:39][CH3:40])[CH:13]=1.CS([O-])(=O)=O.[Na+].[NH4+].[Cl-:48]>CS(C)=O.[Cu]I.CCOC(C)=O>[Cl:48][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=1)[C:25]([N:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[O:39][CH3:40])[CH3:38])=[O:37]
Reactant: [Cl-]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(I)cc(S(C)(=O)=O)c1
Agent: [Cu]I
Agent: CS(=O)(=O)[O-]
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of L-proline (27.8 mg, 242 μmol) in DMSO (3 ml) was added sodium hydride (9.66 mg, 242 μmol, 60% dispersion in mineral oil). The mixture was stirred at room temperature for 30 minutes then copper(I)iodide (46.0 mg, 242 μmol) and N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-iodo-5-methanesulfonyl-N-methyl-benzamide (150 mg, 302 μmol) and sodium methanesulfonate (247 mg, 2.42 mmol) were added. The reaction mixture was stirred for 4 hours at 120° C. The reaction mixture was poured on 30 mL 10% aqueous NH4Cl solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (121 mg, 89.3%). MS (ESI): m/z=449.071 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=2[CH:17]=1.CN1CCOCC1.[CH3:25][NH:26][C:27]1[N:32]=[C:31]([CH2:33][CH2:34]O)[CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:25][NH:26][C:27]1[N:32]=[C:31]([CH2:33][CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=3[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CNc1cccc(CCO)n1
Reactant: CCOC(=O)CCc1csc2cc(O)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)CCc1csc2cc(OCCc3cccc(NC)n3)ccc12
Reaction time: 0.08 h
Yield: 19.5 %

Procedure:
Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (100 mg, 0.4 mmol) and 4-methylmorpholine (0.05 ml, 0.44 mmol) were dissolved in THF (5 ml) and stirred for 5 minutes. 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (91 mg, 0.6 mmol), triphenylphosphine (210 mg, 0.8 mmol) and diisopropyl azodicarboxylate (0.16 ml, 0.8 mmol) were added to the mixture sequentially. After stirring overnight under argon, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum. The crude product was chromatographed over silica gel to yield 30 mg (19%) of Ethyl 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoate.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][NH:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22].C(O)(=O)C>O>[Cl:17][CH2:18][C:19]1[NH:12][C:11]2[N:10]([N:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21](=[O:22])[CH:20]=1
Reactant: Nc1[nH]nc(C(F)(F)F)c1-c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CCl)[nH]c2c(-c3ccccc3)c(C(F)(F)F)nn12
Yield: 11.6 %

Procedure:
Referring to the process as shown in FIG. 2 of the drawings, provide and place 0.227 g of the intermediate 4-phenyl-3-trifluoromethyl-5-amino-1H-pyrazole (1 mmol), 0.130 g of ethyl 4-chloro-3-oxobutanoate and 3 ml of acetic acid (anhydrous acetic acid) into a parallel synthesis instrument (Buchi, Switzerland), allow reflux reaction for 4 hours, stop heating, filling cold water into the low temperature module of the synthesis instrument for precipitation of solid substance, wash with acetic acid, then wash with water until the solid substance is neutral, obtain 30 mg of 5-chloromethyl-3-phenyl-2-trifluoromethylpyrazolo[1,5-a]pyrimidin-7(4H)-one, which is a white solid. The purity is greater than 98% (HPLC-UV by area normalization); ESI-Ms(m/z): 328 (M+1)+; 1HNMR (500 MHz, CD3OD): 7.56 (d, 2H), 7.42 (m, 2H), 7.33 (m, 1H), 6.12 (s, 1H), 4.57 (s, 2H).
Reaction SMILES: [CH2:1]([S:4]([OH:7])(=[O:6])=[O:5])[CH2:2][CH3:3].BrCCCS([O-])(=O)=O.[Na+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]1[C:23]([OH:25])=[O:24]>[OH-].[Na+]>[C:23]([CH:18]1[CH2:19][N:20]([CH2:3][CH2:2][CH2:1][S:4]([OH:7])(=[O:6])=[O:5])[CH2:21][CH2:22][NH:17]1)([OH:25])=[O:24]
Reactant: O=C(O)C1CNCCN1
Reactant: CCCS(=O)(=O)O
Agent: O=S(=O)([O-])CCCBr
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(CCCS(=O)(=O)O)CCN1

Procedure:
Synthesis of 3-(±)-2-carboxypiperazin-4-yl)-propane-1-sulphonic acid. (CPS) ##STR9## Sodium 3-bromo-propane-1-sulphonate (2.25 g, 0.01 mole) was added to a solution of piperazine-2-carboxylic acid (1.3 g, 0.01 mole) in aqueous sodium hydroxide (0.9 g NaOH/30 ml H2O). The resulting solution was maintained at 60°-65° for 12 h. The product, 3((±)-2-carboxypiperazin-4-yl)-propane-1-sulphonic acid, was isolated by passage of the reaction mixture through Dowex-AG-1-acetate resin. Evaporation of the column filtrate and aqueous washings and recrystallization of the crude product from a 50% aqueous ethanol solution yielded 3-((±)-2-carboxy-piperazin-4-yl)-propane-1-sulphonic acid (500 mg) as a white crystalline solid, m.p. 190°-191°.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:1][C:2]2[C:3]([O:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)C(C)Oc1nc(C)ncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 1 hour at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine.
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[C:2]1C=CC=C[CH:3]=1.C(O)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O1CCOCC1>[CH2:2]([O:1][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[CH3:3]
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CC(C)NC(N)=O

Procedure:
Phenoxycarbonylpropyleneurea of 1 g (4.5 mmol) and ethanol of 10 g (21.7 mmol) were dissolved in dioxane of 20 ml by heating. Dibutyltin dilaurate of 10 mg (1%) was added to the resulting solution and the resulting mixture was heated for 5 hours with stirring. After confirming the completion of the reaction by the thin layer chromatography, the reaction product was concentrated and the resulting crude crystals were washed with ether to obtain the aimed substance of 567 mg (80%).