Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH3:13].C([Li])CCC.CN(C)[CH:21]=[O:22]>O1CCCC1.[Cl-].[NH4+].C(#N)C>[CH3:13][O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:21]=[O:22])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccnc2ccc(C=O)cc12
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 6-bromo-4-methoxy-quinoline (8.91 g, 37.42 mmol) in THF (tetrahydrofuran) (155 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (16.46 mL, 4.16 mmol, 1.1 equiv.) at −70° C. During the addition, the temperature of the reaction mixture was raised slightly to −60° C. and it gave a very dark brown solution. The resulting colored solution was stirred for 30 min at this temperature. Then, a solution of dimethylformamide (5.78 mL, 74.84 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid. This solid was dissolved in acetonitrile (˜50 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with diethyl ether. After drying in air, 4.47 g (64% yield) of 4-methoxy-quinoline-6-carbaldehyde was isolated as a white solid: EI-HRMS m/e calcd for C11H9NO2 (M+) 187.0633, found 187.0638.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=O)=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(Cl)Cl.CO>[F:22][C:23]([F:31])([F:32])[C:24]1[CH:25]=[C:26]([NH:27][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([CH2:8][C:4]4[CH:3]=[C:2]([OH:1])[N:7]=[CH:6][N:5]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12

Procedure:
Prepared from 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (Step 3.8) and 3-trifluoromethyl-aniline analogously to Ex. 3: MS: [M+1]+=424; TLC (CH2Cl2/MeOH 9:1): Rf=0.26.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:30]([F:33])([F:32])[F:31])[CH:16]=2)=[CH:11][CH:10]=1.O>CN(C=O)C.[Cu]>[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=4)[N:18]=[C:17]([C:30]([F:32])([F:31])[F:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-n3ccnc3)cc2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
To a suspention of sodium hydride (0.04 g:1 mmol) (60% mineral oil dispersion; washed with dry hexane (3 mL)) in DMF(2 mL) was added imidazol (0.068 g) at room temperature and the mixture was stirred 30 minutes. Then, 4-[5-[4-Bromophenyl]-3-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole (0.445 g) and copper powder (0.0063 g) were added and the whole was heated at 150° C. for 3 hours. After cooling, water (30 mL) was added to the reaction mixture and the whole was extracted with CH2Cl2 (30 mL×2), the extract was washed with water and brine, dried over MgSO4,and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/methanol (1/0.03). The resulting solid was recrystallized with dichloroethane-diisopropyl ether to give the title compound (0.07 g).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[NH:3][C:2]1=S.C(Cl)[Cl:12].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:12][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][N:8]=2
Reactant: ClCCl
Reactant: S=c1[nH]c2nccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: Clc1nc2nccnc2s1
Temperature: 40 °C
Yield: 53 %

Procedure:
A mixture of 3H-thiazolo[4,5-b]pyrazine-2-thione (4.36 g, 25.8 mmol) and DCM (60 mL) was sonicated (5 min). The suspension was treated with sulfuryl chloride (99.9 g, 740 mmol, 60 mL) and heated (40° C., 16 h). The reaction mixture was cooled (0° C.) and slowly treated with H2O (250 mL), followed by 4 N NaOH (550 mL). The aqueous mixture was extracted with EtOAc (2×1800 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a solid (2.63 g, 53%). MS (ESI): mass calculated for C5H2ClN3S, 170.9; m/z found, 172.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.84 (d, J=2.5, 1H), 8.75 (d, J=2.5, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.Cl[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19]>C[O-].[Na+].CO.C(#N)C>[C:18]([C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:19]
Reactant: N#Cc1ccncc1Cl
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CSc2cnccc2C#N)cc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 6.2 g (40 mmol) of p-methoxybenzylmercaptan in 9.8 mL of 4.4M sodium methoxide in methanol was added dropwise to a solution of 5.52 g (40 mmol) of 3-chloro-4-cyanopyridine in dry acetonitrile that has been cooled in an ice bath. After addition was complete the solution was allowed to warm to room temperature over 2 hours. The solvent was concentrated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with two portions of dichloromethane and the combined extracts were washed with brine, dried (MgSO4) and concentrated to afford 6.1 g (60%) of a pale yellow crystalline solid, m.p. 80°-81° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24]Br>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 48.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (196 mg, yield: 48.7%).
Reaction SMILES: [Cl:1][C:2]1[C:10](F)=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[Na].[CH3:19][O:20][CH2:21][CH2:22][SH:23]>CN(C=O)C.O>[Cl:1][C:2]1[C:10]([S:23][CH2:22][CH2:21][O:20][CH3:19])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Reactant: COCCS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g (19.8 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid (synthesis described in WO 98/42648) were taken up in 40 ml of DMF. 871 mg (21.8 mmol, purity 60% by weight) of NaH were added. The mixture was stirred at RT for 30 minutes. A reaction mixture containing the sodium salt of 2-methoxyethanethiol (prepared from a solution of 2.19 g (23.7 mmol) of 2-methoxyethanethiol in 10 ml of DMF which had been added dropwise to a suspension of 950 mg (23.7 mmol, purity 60% by weight) of NaH in 30 ml of DMF, followed by stirring at RT for 30 minutes) was then added a little at a time. During the addition, the temperature was kept below 30° C. The reaction mixture was stirred at RT for 16 h, for work-up diluted with water and washed with diethyl ether. The aqueous phase was acidified with 1M HCl and extracted with tert-butyl methyl ether. The organic phase was dried and filtered. The aqueous phase was additionally extracted with EA, and the organic phase was also dried and filtered. The filtrates of the organic phases were combined and freed from the solvent. The residue was dried under reduced pressure and purified chromatographically. This gave 4.8 g of the pure product.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:9]([OH:11])[CH3:10])(C)(C)C.[H-].[Na+].Br[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45]>>[CH2:12]([C@H:8]1[C@H:9]([CH3:10])[O:11][C:6](=[O:19])[N:7]1[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](C)[C@@H]1Cc1ccccc1

Procedure:
tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (Step B, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil, 12 mg, 0.309 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 to afford (4S,5S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.68 (d, J=11.5 Hz, 1 H), 7.66-7.63 (m, 1 H), 7.39-7.36 (m, 1 H), 7.28-7.23 (m, 3 H), 7.07 (d, J=8.5 Hz, 1 H), 6.94 (d, J=6.9 Hz, 2 H), 6.73 (d, J=4.8 Hz, 1 H), 4.81 (d, J=16 Hz, 1 H) 4.38 (d, J=16.1 Hz, 1 H), 4.28-4.23 (m, 1 H), 3.78 (s, 3 H), 3.29-3.17 (m, 2 H), 2.81 (dd, J=13.3, 3.9 Hz, 1H), 2.38-2.28 (m, 1 H), 1.29-1.13 (m, 6 H), 0.98 (d, J=6.2 Hz, 3 H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[CH2:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.CN(C)C=O.[CH:23](OC)(OC)[O:24][CH3:25]>C(OC(=O)C)(=O)C>[CH3:23][O:24]/[CH:25]=[C:9]1/[C:10](=[O:17])[NH:11][C:12](=[O:16])[C:13]2[C:8]/1=[CH:7][C:6]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[CH:15][CH:14]=2
Reactant: O=C1Cc2cc(-n3cccc3)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Temperature: 120 °C
Yield: 39.6 %

Procedure:
6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (0.1 g, 0.442 mmol) is dissolved in acetic anhydride (0.6 mL), N,N-dimethylformamide (0.15 mL) and trimethyl orthoformate (0.1 mL, 0.919 mmol). After heating at 120° C. for 0.5 h, it is cooled and the solid is filtered and washed successively with acetic anhydride, ether and hexane to yield 47 mg (40%) solid of the title compound; mp 272-273° C.; HRMS (ESI) m/z calcd for C15H12N2O3 269.09207. found 269.09210 (M+H)+1.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:25]12[O:30][CH:29]1[CH2:28][O:27][CH2:26]2.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[F:1][C:2]1[C:3]([O:24][C@H:29]2[C@H:25]([OH:30])[CH2:26][O:27][CH2:28]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1OCC2OC12
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@H]1O)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21.2 %

Procedure:
27B (680 mg, 2.034 mmol) was mixed with 3,6-dioxabicyclo[3.1.0]hexane (876 mg, 10.17 mmol), and K2CO3 (1546 mg, 11.19 mmol) in acetonitrile (1 mL) and H2O (1 mL) in a sealed tube. The mixture was stirred at 100° C. for 20 h. The reaction was quenched with H2O then extracted with EtOAc (2×) and concentrated. The residue was purified by flash column chromatography (0-90% EtOAc/hexanes) to give a mixture of diastereomers as yellow oil. The diastereomers were further separated by a prep chiral HPLC equipped with a OJ Column to give the first peak 27C (181 mg, 0.431 mmol, 21.17% yield). The relative stereochemistry of hydroxyether is trans however absolute stereochemistry is undetermined MS (ESI) m/z: 421.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccnc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of quinoline-4-carboxylic acid (301 mg, 1.74 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (357 mg, 1.74 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (8 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-70% EtOAc in heptane) to give a pure product (49) as a pale yellow solid (370 mg, 59%).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:36])[C:22]([OH:35])([C:27]3[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=3)[C:23]([F:26])([F:25])[F:24])=[C:17]([Cl:37])[CH:16]=2)=[N:6][CH:5]=1.[OH-].[Na+].Cl.CCOC(C)=O>O1CCCC1>[Cl:37][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:26])([F:24])[F:25])[O:14][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]([C:3]([OH:38])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2cc(C(F)(F)F)c(C(=O)O)cn2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 6-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-4-trifluoromethyl-nicotinic acid methyl ester (Example 163, 65 mg) in tetrahydrofuran (0.5 ml) was added a 1 M aqueous sodium hydroxide solution (0.23 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. The mixture was cooled in an ice bath. 2 M aqueous HCl (0.12 ml) and EtOAc were added. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:1=>EtOAc=>EtOAc/MeOH 4:1) to give the title compound (61 mg) as a colorless solid. MS (m/e)=551.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[S:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([S:12][C:11]([F:21])([F:10])[F:20])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(SC(F)(F)F)c1
Product: Fc1cnc(Cl)nc1Nc1cccc(SC(F)(F)F)c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline were reacted to provide 2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H), 7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:24][C:25]1[CH:26]=[C:27]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31][OH:32])(=[O:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:24][C:25]1[CH:26]=[C:27]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31][O:32][N:57]1[C:58](=[O:67])[C:59]2=[CH:66][CH:65]=[CH:64][CH:63]=[C:60]2[C:61]1=[O:62])(=[O:23])=[O:22]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
Diethyl azodicarboxylate (67 (L, 0.40 mmol) was added dropwise over 5.5 min to 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (118 mg, 0.33 mmol, prepared in the preceding step), triphenylphosphine (106 mg, 0.40 mmol), and N-hydroxyphthalimide (55 mg, 0.33 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for an additional 20 min then at ambient temperature overnight. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (dichloromethane) to give the title compound (116 mg, 69%) as a colorless resin. 1H-NMR (300 MHz, CDCl3) (7.88-7.73 (m, 5H), 7.61 (ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.10 (d, 1H, J=8.4 Hz), 7.01 (dt, 1H, J=7.7, 0.9 Hz), 6.60 (br s, 1H), 6.56, (br s, 1H), 6.42 (t, 1H, J=2.2 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.09 (t, 2H, J=6.2 Hz), 4.04 (s, 3H), 2.25 (s, 3H), 2.18 (pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H23NO8S: 520.1 (M+Na). Found: 520.2.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[NH2:19][C:20]([NH2:22])=[S:21]>CN(C=O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[N:19]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CCCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Product: Nc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
1-bromo-5-phthalimido-2-pentanone (0.500 g, 1.61 mmol) was dissolved in DMF (3.5 mL) at 0° C. and thiourea (0.135 g, 1.77 mmol) was added drop-wise as a solution in DMF (0.50 mL). The solution was allowed to warm to room temperature and stirring was continued for 2 h at which time the DMF was removed under reduced pressure and the resulting slurry was made alkaline with 10% K2CO3 (100 ML). The aqueous solution was then extracted with EtOAc (3×40 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to obtain 51 (448 mg, 97%) as a fine white powder in its freebase form: 1H NMR (300 MHz, DMSO-d6) δ 7.85 (m, 4H), 6.78 (s, 2H), 6.13 (s, 1H), 3.56 (t, 2H, J=6.9 Hz), 2.42 (t, 2H, J=7.5 Hz), 1.88 (quint., 2H, J=7.5 Hz); 13C NMR (75 MHz, DMSO-d6) δ 168.01, 167.87, 151.20, 134.25, 131.61, 122.89, 100.17, 37.27, 28.70, 27.09; HRMS (ESI) calcd for C14H14N3O2S (MH+) 288.0801, found 288.0799.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>O1CCOCC1>[CH:10]1([NH:16][C:2]2[N:4]=[C:5]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]=[C:8]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:1]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: C1CCC(Nc2nc(NC3CCCCC3)nc(NC3CCCCC3)n2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 400 mL of 1,4-dioxane. The mixture solution was warmed to 50° C. While stirring, the warmed solution was dropwise added with 60.2 g (0.6 mol.) of cyclohexylamine over two hours in such a manner that the reaction temperature did not raise over 50° C. While continuing further stirring, the temperature was raised to 85° C. and 60.2 g (0.61 mol.) of cyclohexylamine by keeping the temperature. Thereafter, the temperature was again raised and the reaction was carried out at the reaction temperature of 95° C. for six hours. 230 g of water were added to the reaction solution so that the temperature did not fall less than 90° C. and then, cooled. to the room temperature while stirring. Product was separated, from the reaction solution through filtration and washed with each 150 mL of water four times. The filtered product was dried at 70° C. for six hours under vacuum to obtain 34.2 g of 2,4,6-tris(cyclohexylamino)-1,3,5-triazine (yield: 225° C.)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+].O>COCCOC>[CH3:1][O:2][CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10]
Reactant: O=S([O-])[O-]
Reactant: COCCCl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COCCS(=O)(=O)[O-]

Procedure:
To a solution of 2-chloroethyl methyl ether (Acros, 68.0 mL) in 1,2-dimethoxyethane (DME) (250 mL) was added sodium sulfite (103 g) and water (250 mL). The reaction mixture was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue was extracted with methanol (500 mL). The solid was removed by filtration and washed with methanol (250 mL). The combined filtrate and washings were evaporated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(Cl)cccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Yield: 103.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2,6-dichlorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (1.5 g, 2.2 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.900 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.84 (s, 3H), 7.62-7.30 (m, 5H), 7.82 (d, J=8.7 Hz, 1H), 12.76 (br s, 1H); MS (m/z): 393.85 (M+H)+.