Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:25][CH:24]([OH:26])[CH2:23]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=[O:39]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][C:24]([OH:39])([OH:26])[CH2:25]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)C3)ccc21
Reactant: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)(O)C3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 75 in dry DMSO (3 mL) containing triethylamine (0.35 mL) is treated with pyridine-sulfar trioxide complex (0.25 gm). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ethyl acetate and washed with water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by recrysrallization from acetonitrile to afford 0.06 gm of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[BrH:16].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:9]([Br:16])[CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)=[O:20]
Reactant: Br
Reactant: Cc1cccc(C(=O)CBr)n1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(C)n2)c(N)c2cc(Br)c(Cl)cc21

Procedure:
The title compounds were prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni, and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).
Reaction SMILES: [OH:1][C@@H:2]([C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:12][CH2:11]1)=[O:9])[CH2:3][C:4]([O:6]C)=[O:5].O[Li].O>C1COCC1.O>[OH:1][C@@H:2]([C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:14][CH2:15]1)=[O:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(=O)O)CC3)nc(-c3ccccc3O)nc2c1
Yield: 85.9 %

Procedure:
(R)-Methyl 3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate (88 mg, 0.20 mmol) and LiOH.H2O (33 mg, 0.78 mmol) were stirred in THF:H2O 1:1 at room temperature for 3 h. After acidification with 1 M HCl and extraction with EtOAc, the organic extracts were washed with water, dried over Na2SO4, and concentrated. The crude material was then purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 to obtain (R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoic acid (75 mg, 88%). LC/MS: m/z 437.3 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([Cl:27])[CH:18]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:30]1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([NH:16][C:1]([N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH:31]3[CH2:32][CH2:33][CH2:34][N:29]([CH3:28])[CH2:30]3)[CH2:37][CH2:38]2)=[O:2])[CH:22]=[CH:21][C:20]=1[C:23]([F:24])([F:25])[F:26]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN1CCCC(CN2CCN(C(=O)Nc3ccc(C(F)(F)F)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.7 %

Procedure:
To a solution of di-tert-butyl dicarbonate (114.6 mg) in chloroform (2 ml) was added 4-dimethylaminopyridine (6 mg). A solution of 4-amino-2-chlorobenzotrifluoride (98.1 mg) in chloroform (2 ml) was added and the reaction mixture stirred for 20 minutes at room temperature. A solution of 1-[(1-methylpiperidin-3-yl)methyl]piperazine (98.5 mg) in chloroform (2 ml) was added and the resulting solution was stirred at reflux for 18 hours. The reaction mixture was purified by column chromatography on silica gel (20 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (14 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1noc2cc(OCc3ccccc3)ccc12
Temperature: 56 °C
Reaction time: 5 h

Procedure:
To a solution of 0.98 g (4.73 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] in 100 ml acetone, 545 μl (4.73 mMol) benzylchloride, 3.08 g (9.46 mMol) Cs2CO3 und 10 mg NaI are added. Then the mixture is stirred for 2 h at rt and 5 h at 56° C. The reaction mixture is diluted with EtOAc and water, the aq. phase separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated after addition of 10 g SiO2. The resulting powder is put on top of a chromatography column (SiO2) and the title compound eluated with hexan/EtOAc 9:1→8:2→7:3: MS: [M+1]+=298; TLC(hexane/EtOAc 3:1): Rf=0.54.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[F:14][C:15]1[CH:16]=[C:17](N)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:14][C:15]1[CH:16]=[C:17]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-fluoro-4-trifluoromethyl-phenylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12](N)=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(F)c(S(C)(=O)=O)cc1F
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas. The solution of (4-amino-2,5-difluorobenzyl)-carbamic acid t-butyl ester (0.43 g, 1.66 mmol) in methylenechloride was put into the flask and then cooled to 0° C. To the solution were added methanesulfonylchloride (1.2 eq, 1.99 mmol, 0.16 ml) and pyridine (excess, 0.5 ml) slowly, the mixture solution was refluxed for 12 hours. After confirming the completion of the reaction with TLC, the reaction solution was acidified by 10% HCl, extracted with methylenechloride, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=2/1) to yield a white solid (0.41 g, 73.5%).
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])SC)[C:4]([O:6]C)=[O:5])#[N:2].C[OH:19].[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[C:13]([C:12]1[NH:2][C:1](=[O:19])[C:3]([C:4]([OH:6])=[O:5])=[C:8]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C(C#N)=C(NC(=O)C(C)(C)C)SC
Reactant: CO
Reactant: COCCCN
Product: COCCCNc1nc(C(C)(C)C)[nH]c(=O)c1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 2-cyano-3-[(2,2-dimethylpropanoyl)amino]-3-(methylsulfanyl)prop-2-enoate (2.0 g) was dissolved in 3-methoxypropan-1-amine (1.4 g), and the mixture was stirred at 80° C. for 1 hr. Methanol (10 ml) was added to the reaction mixture, and the mixture was refluxed overnight. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (0:10→6:4) was concentrated under reduced pressure, and the fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue (1.0 g) was dissolved in methanol (10 ml), lithium hydroxide (0.42 g) and water (2 ml) were added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, acidified with 6 N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (0.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[Cl:12].C1COCC1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH2:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)c(Cl)cc1N
Temperature: 100 °C
Yield: 98.9 %

Procedure:
To a partial suspension of 1,2-dichloro-4-methyl-5-nitrobenzene (2.0 g, 9.71 mmol) in MeOH (25 ml), water (25 ml), and THF (10 ml) was added NH4Cl (5.19 g, 97.1 mmol) followed by iron powder (2.71 g, 48.5 mmol). The heterogeneous reaction mixture was heated at 100° C. for 3 h then cooled to room temperature and filtered over a Buchner funnel, rinsing with MeOH. The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 1.69 g (99%) of 4,5-dichloro-2-methylaniline as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.10 (s, 1H), 6.75 (s, 1H), 3.74 (br. s., 2H), 2.12 (s, 3H).
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:25])[CH2:19][C:20](OCC)=[O:21])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:25])[CH2:19][C:20]([NH2:1])=[O:21])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.5 %

Procedure:
Into 40 ml of methanol saturated with gaseous ammonia was dissolved 1.69 g (5 mmoles) of ethyl 8-benzyloxycarbonylamino-3-hydroxyoctanoate. The solution was stirred for 3 days at room temperature, and the reaction mixture was evaporated to dryness. The residue was crystallized from ethanol to yield 1.18 g (72.5% yield) of 8-benzyloxycarbonylamino-3-hydroxyoctanamide having a melting point of 100°-101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:35](OC(OCC)OCC)C>[Pt].C1(C)C=CC=CC=1>[N:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:35]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C(NCCCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A catalytic amount of platinum on carbon was added to a suspension of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (5 g, 13.2 mmol) in toluene (250 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After about 2 hours an oily ball had formed in the bottom of the Parr bottle. Magnesium sulfate and additional catalyst were added and the hydrogenation was continued overnight. The reaction mixture was filtered to remove the catalyst. The residue in the Parr bottle was combined with isopropyl alcohol (150 mL), heated on a steam bath and then filtered. HPLC analysis indicated that both filtrates contained product so they were combined and concentrated under vacuum to provide crude N1-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material was combined with toluene (250 mL). Triethylorthoformate (4 g, 26.4 mmol) was added and the reaction mixture was heated at reflux with a Vigreux column for 2 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 3.4 g of N1-[5-(1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as a solid, m.p. 171.5-172.5° C. 1H NMR (500 MHz, DMSO-d6) δ9.22 (s, 1H), 8.43 (t, J=6.0 Hz, 2H), 8.38 (m, 1H), 8.18 (m, 1H), 7.80 (d, J=7.0 Hz, 2H), 7.73 (m, 2H), 7.51 (t, J=7.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 2H), 4.72 (t, J=7.5 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.94 (quintet, J=7.5 Hz, 2H), 1.58 (quintet, J=7.5 Hz, 2H), 1.40 (quintet, J=8.5 Hz, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].Cl>ClCCCl.O>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc2ccccc2c1Br
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc2cc(C(C)=O)ccc2c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 43 g of anhydrous AlCl3 and 24.6 g (0.313 mole) of acetyl chloride in 200 ml of 1,2-dichloroethane at 10° C. was cooled to 0° C. and added dropwise under stirring with a solution of 59.25 g (0.250 mole) of 1-bromo-2-methoxy-naphthalene in 150 ml of 1,2-dichloroethane. The resulting solution was stirred for 15 minutes then poured into a cold solution of 300 ml of water and 100 ml of 2 N hydrochloric acid. The organic phase was separated, washed first with 100 ml of 1 N hydrochloric acid and then with 100 ml of water, dried under vacuum and the obtained residue was crystallized from 2-butanol. Yield 68.11 g (98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1
Reaction time: 18 h

Procedure:
To an ambient slurry of p-hydroxyacetophenone (20 g, 147 mmol) and K2CO3 (30.4 g, 220 mmol) in acetone (150 mL) was added ethyl bromoacetate (17.2 mL, 154 mmol). The slurry was stirred for 18 h and was quenched by the addition of H2O (150 mL) and Et2O (75 mL). The layers were separated, and the aqueous was extracted with additional Et2O (3×75 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give an oil that was used without further purification. MS (ESI) m/e 223 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.12 Hz, 3H), 2.52 (s, 3H), 4.18 (q, J=7.12 Hz, 2H), 4.90 (s, 2H), 7.04 (m, 2H), 7.92 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2S,3R)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol (120 mg, 0.701 mmol), triethylamine (0.1 mL, 1.4 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (220 mg, 0.841 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction was allowed to attain 25° C. overnight. Additional methylene chloride (15 mL) was added and the reaction mixture was poured into saturated sodium bicarbonate solution (25 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (0.36 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-4 as eluent. This provided the title compound 5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophenfe-2-sulfonamide as an oil (125 mg, 53%). The oil (125 mg) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-ipa (1 mL/min)] to obtain 5-chloro-N-[(1 S, 2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (0.15 mg, 6.4%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 364 (M−H)−.
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]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]Br>>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][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: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 45 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (226 mg, yield: 45.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+].[CH3:34][C:35](C)=[O:36]>>[C:35]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=1)(=[O:36])[CH3:34]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCc2ccccc2)c1

Procedure:
A solution of 3′-hydroxy4′-benzyloxyacetophenone (3.5 g, 14.4 mmol), t-butyl bromoacetate (2.8 mL, 17.0 mmol), and K2CO3 (2.3 g, 17.0 mmol) in 100 mL acetone is refluxed 18 hours. After cooling, the mixture is filtered, and the acetone is removed in vacuo. The residue is then dissolved in EtOAc (50 mL) and washed with H2O (1×50 mL) and brine (1×50 mL), dried over MgSO4, and the solvent is removed in vacuo. Chromatography (silica, 5:1 hexane/EtOAc) yields t-butyl (4-acetyl-2-benzyloxyphenoxy)-acetate.
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C.N1C=CC=CC=1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][OH:2])[CH2:5]2)[N:11]=1
Reactant: Fc1cccc2c1CCN2
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
0.975 g of the sodium salt of (±)-[4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 25b, step 6b), 0.534 g of 4-fluoroindoline, 0.57 ml of pyridine and 15 ml of DMF are placed in a three-necked flask. 0.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added and the mixture is stirred at ambient temperature (20° C.) for 72 hours. The reaction mixture is poured into 50 ml of water, with stirring, and then the insoluble material is filtered off through a VF filter, and washed 3 times with approximately 15 ml of water and then with 10 ml of ethyl acetate and twice approximately 5 ml of diisopropyl ether. The solid is air-dried under a hood. 2-[2-(4-Fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-hydroxymethylmorpholin-4-yl)-3H-pyrimidin-4-one is isolated (0.82 g) and characterized in the form of a pinkish solid, yield 60%.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28]>CN(C=O)C.CCO>[CH3:26][N:27]([CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:10]2[N:9]=[C:8]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=[CH:12][N:11]=2)=[CH:20][CH:19]=1)[CH3:28]
Reactant: c1ccc(Nc2ccnc(Nc3ccc(OCC4CO4)cc3)n2)cc1
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1ccc(Nc2nccc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
4-Anilino-2-(4-(2,3-epoxypropoxy)anilino)pyrimidine (Reference Example I-1, 0.61 g, 1.84 mmol) was dissolved in DMF (2 ml) and treated with dimethylamine (6 mmol, 3 ml of a 2M solution in EtOH). After stirring overnight at ambient temperature the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water, dried over MgSO4 and evaporated at reduced pressure. The residue was purified by chromatography (0.1%NH3 (aq), 3–10% MeOH in DCM as eluent). Upon evaporation of the fractions, an oily product was obtained,this was triturated with ether to give the title product as a white solid (0.126 g, 18%). NMR (300 MHz): 2.2 (s, 6H), 2.3–2.8 (m, 2H), 3.75–3.95 (m, 3H(, 4.82 (brs, 1H), 6.17 (d, 1H), 6.82 (d, 2H), 6.97 (t, 1H), 7.27 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 7.95 (d, 1H), 8.95 (s, 1H), 9.25 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[I:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([I:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([I:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: SCc1ccc(I)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(I)cc2)c2ccc(I)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-iodobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form Z-4-fluorostyryl 4-iodobenzylsulfide. The title compound is obtained following oxidation.