Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][CH:20]=3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(C)C(S([NH:47][N:48]=[C:49]([CH3:53])[CH:50](Cl)Cl)(=O)=O)=CC=CC=1.CO>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:17][CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:5]3[CH2:4][C@H:3]([CH2:2][N:1]4[CH:50]=[C:49]([CH3:53])[N:48]=[N:47]4)[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:28])[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Reactant: NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3ccc(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Yield: 34 %

Procedure:
(5S)-5-(Aminomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-flurophenyl]-oxazolidin-2-one (Intermediate 57) (13 g, 34 mmol) was reacted with diisopropylethylamine (23 ml, 136 mmol) and 1,1-dichloroacetone toluenesulfonylhydrazone (15.1 g, 51 mmol) as described for Example 3. Chromatography on silica gel with 0-5% methanol in ethyl acetate gave 5.17 g of the title product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 7 °C

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235.2 mmol, Intermediate 2: step a), dichloromethane (493 mL), and N,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After the mixture was cooled to 7° C., diisopropylethylamine (90.263 mL, 517.6 mmol) was added such that the addition temperature did not exceed 16° C. After the addition, the reaction was allowed to warm to room temperature. The reaction was then transferred to a separatory funnel and the organic layer was washed with saturated aqueous NaHCO3 (2×100 mL) followed by water (100 mL) and then dried over sodium sulfate and filtered. Solvent removal afforded the title compound as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C=C(CNC(C)=O)C(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
A solution of 0.42 g (1.57 mmol) of the amine obtained in Step C in 5 ml of anhydrous pyridine is cooled to 0° C.; 0.18 ml (1.97 mmol) of acetic anhydride is then added to the medium. After 30 minutes of stirring under argon, the medium is diluted with dichloromethane and then adjusted to an acid pH with 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained, after evaporation of the solvent in vacuo, is purified on a silica column (eluant:AcOEt/PE:70/30) to yield the title amide in the form of a white solid.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=1.O.CCOC(C)=O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:2]([C:16]1[N:17]([CH3:19])[CH:18]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:5]=3[F:4])=[CH:13][CH:12]=2)[N:15]=1)#[N:1].[C:2]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:5]=3[F:4])=[CH:13][CH:12]=2)[CH2:18][N:17]([CH3:19])[CH:16]=[N:15]1)#[N:1]
Reactant: N#CBr
Reactant: Cn1cnc(-c2ccc(Oc3ccc(F)cc3F)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C=NC(C#N)(c2ccc(Oc3ccc(F)cc3F)cc2)C1
Product: Cn1cc(-c2ccc(Oc3ccc(F)cc3F)cc2)nc1C#N
Temperature: 60 °C

Procedure:
2-Cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole. A mixture of crude 4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole (prepared from 4.14 g of 2-bromo-1-[4-(2,4-difluorophenoxy)phenyl]ethanone and 35 mL of formamide as described above), solid KOH (2.57 g) and MeI (1 mL) was heated at reflux overnight. After filtration, the reaction was concentrated to dryness and the residue was purified by flash chromatography, affording 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid. A solution of 4-(dimethylamino)pyridine (1.34 g, 10.9 mmol) in 30 mL of dry DMF at −10° C. was added cyanogen bromide (5.0 M solution in MeCN; 2.1 mL, 10.5 mmol), giving a pale yellow precipitate. Solid 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole (1.39 g, 4.86 mmol) was added and the reaction was heated at 60° C. overnight. The reaction was allowed to cool to room temperature and added to water and EtOAc. The separated aqueous layer was extracted twice with EtOAc and the pooled organic layers were washed with water (3×), dried (Na2SO4), filtered and concentrated. The oily residue was purified by flash chromatography (gradient from 8.5/2.5 to 7/3 hexane/EtOAc) affording 713 mg of 2-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid, mp 109-110° C. (Rf 0.42, 7/3 hexane/EtOAc) along with 122 mg of 4-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole, mp 169-170° C. (Rf 0.32, 7/3 hexane/EtOAc). 1H NMR (2-cyano; CDCl3): δ 7.65 (d, 2H, J=9.0 Hz), 7.16 (s, 1H), 7.06 (dt, 1H, J=9.3, 5.4 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.98-6.80 (m, 2H), 3.65 (s, 3H). 1H NMR (4-cyano; CDCl3): δ 7.69 (d, 2H, J=8.7 Hz), 7.27 (s, 1H), 7.09 (dt, J=8.7, 5.7 Hz), 6.96 (d, 2H, J=8.7 Hz), 7.00-6.82 (m, 2H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:20])=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:19])=[O:20])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:27]([O-:29])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2ccccc2c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc2c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
An ice-cold, stirred solution of 3-(2-acetoxy-ethyl)-4-bromonaphthalene-1-sulfonyl chloride (17.66 g, 45.1 mmol) in trifluoroacetic acid (150 mL) was treated with 96% sulfuric acid (12.5 mL, 225 mmol) and with 90% nitric acid (2.65 mL, 56.4 mmol) added dropwise over 3 minutes. The reaction mixture was removed from the ice bath, stirred at room temperature for 15 minutes, re-cooled in an ice bath, and treated with water (850 mL) added dropwise. The resulting mixture was filtered through a celite pad to collect the solid which was washed with water (100 mL) and dissolved in methylene chloride (350 mL). The methylene chloride solution was washed with water (500 mL) containing brine (100 mL), dried over magnesium sulfate, and evaporated under vacuum to an oil (21.23 g). This material was shown to be a 42:58 mixture of the 5-NO2 to 8-NO2 products by 1H NMR). The crude product was mixed with ethyl acetate (20 mL) and sonicated to provide a crystalline precipitate. This material was collected, washed with ethyl acetate, and dried under vacuum to afford the title compound (8.11 g, 41% yield) as an off-white solid. The mother liquors yielded an additional 1.47 g of the title compound following flash chromatography on silica gel (eluting with 30-35% ethyl acetate in hexane) and crystallization from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:15][NH:14][C:12](=[O:13])[C:3]=2[N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1nc(C(F)(F)F)ccc1N
Product: O=c1[nH]cnc2ccc(C(F)(F)F)nc12
Yield: 95.37 %

Procedure:
6.8 g (0.0332 mol, 1 eq) of 3-amino-6-trifluoromethyl-pyridine-2-carboxylic acid amide in 170 ml of triethylorthoformate under nitrogen was heated at 145° C. for 8 h. Excess triethylorthoformate was removed under reduced pressure and the solid product obtained was washed with pet-ether and dried under vacuum to get 6.8 g (95.37%) of white solid. 1H NMR (CDCl3, 400 MHz): 8.11 (1H, d), 8.35 (1H, d), 12.28 (1H, bs). MS 216 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27]C4NC(=O)[CH2:32][CH2:31][CH2:30][C:29]=4[CH:36]=3)[CH2:19][CH2:18]2)=[N:9]1.CI>CCCCC>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:3]4[N:4]([CH3:7])[C:5](=[O:6])[CH2:32][CH2:31][CH2:30][C:29]=4[CH:36]=3)[CH2:21][CH2:22]2)=[N:9]1
Reactant: CN(C)C=O
Reactant: O=C1CCCc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CI
Product: CN1C(=O)CCCc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, sodium hydride (20 mg, 0.5 mmol, 60% oil dispersed) was washed free of oil with pentane and layered with 6 ml dimethylformamide. In one portion, 155 mg (0.38 mmol) 7-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (the title compound of Example 54) was added and stirring was continued for 0.5 hours at 25° C. To the solution was then added methyl iodide (162 mg, 1.14 mmol) and stirring was continued overnight. After pouring over 60 ml ice/water, the product was extracted with 40 ml ethyl acetate which was washed with water (2×50 ml), dried with sodium sulfate and concentrated to an oil, 54 mg. Chromatography (32-63 micron silica gel) eluting with 2% methanol in methylene dichloride provided the pure free base, 46 mg (29%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([OH:8])[CH3:7].[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:6]=[CH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:8][C:6]1[CH:11]=[CH:10][C:9]([CH:14]=[CH2:13])=[CH:15][CH:7]=1
Reactant: CCO
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccccc1

Procedure:
The obtained copolymer A was dissolved in an ethanol/toluene solvent (volume ratio 7:3) and was then reacted using sulfuric acid at 65° C. for 90 minutes. After washing this reaction solution with an alkaline solution, the resulting solution was subjected to a reprecipitation process using a methanol/water (volume ratio 1:1) solvent to obtain a reprecipitate, then the reprecipitate was filtered to obtain the retained matter, and the retained matter was air-dried to obtain styrene-p-hydroxystyrene (PHS) copolymer B (yield 87%). The Mw of copolymer B was 216,300 and the ratio Mw/Mn was 1.15.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([NH:37][CH2:38][CH2:39][NH2:40])(=[O:36])[CH3:35]>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:15][CH:16]=2)[C:12](=[O:14])[N:40]([CH2:39][CH2:38][NH:37][C:34](=[O:36])[CH3:35])[C:17]3=[O:19])=[CH:20][CH:21]=1
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: CC(=O)NCCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 10 min and then heated at 50° C. for 15 min. To this mixture was added N-acetylethylenediamine (78 mg, 0.76 mmol) and the resulting mixture heated under reflux for 20 min. After cooling to room temperature, the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 98:2 to 9:1) to afford the title compound (139 mg, 62%) as an off-white solid. MS: m/e=357.3. (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:28]([SiH2:32][O:33][C:34]([CH3:43])([CH3:42])[C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1)([CH3:31])([CH3:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[C:28]([SiH2:32][O:33][C:34]([CH3:43])([CH3:42])[C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[N:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N)nc1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(C(C)(C)O[SiH2]C(C)(C)C)cn2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (2.03 g, 6.61 mmol) was dissolved in DCM (33 mL) with DMF (0.05 mL), and cooled to 0° C. Oxalyl chloride (1.16 mL, 13.22 mmol) was added dropwise and the mixture was allowed to stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove residual oxalyl chloride. The yellow oil was re-dissolved in DCM (33 mL), and 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.71 g, 7.17 mmol) and pyridine (0.86 mL, 10.5 mmol) were added. After 16 hours, the reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (50 mL) and water (50 mL). The organic layer was rinsed with water (30 mL), and then a saturated sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated to brown oil. After chromatography on silica gel with a gradient from 5-30% ethyl acetate-hexanes, N-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.25 g, 36.0% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.25 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.40 (d, J=3.0 Hz, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.60 (s, 1H), 4.65 (s, 2H), 4.60 (m, 1H), 4.15 (t, 2H), 2.95 (t, 2H), 1.05 (s, 3H), 1.0 (s, 3H), 0.85 (s, 9H), 0.00 (s, 6H); LCMS (m/z): 527.3 [C28H38N2O4SSi+H]+.
Reaction SMILES: [CH2:1]1[C:6](=O)N(Br)[C:3](=[O:4])[CH2:2]1.CC1C=C[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH:3]([C:2]1[CH:1]=[CH:6][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1)=[O:4]
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2sccc2c1
Reaction time: 0.25 h
Yield: 297.4 %

Procedure:
Under N2, NBS (6 g, 0.034 mol) was added to a solution of 5-methylbenzo[b]thiophene (30.8 g, 0.21 mol), benzoylperoxide (1.6 g) in CCl4 (300 ml) and was heated at reflux. After 15 minutes, the remainder of the NBS (35 g, 0.2 mol) was added over a period of 5 minutes and heated at reflux for 1.5 hours. The reaction mixture was then cooled, filtered and the filtrate washed with H2O (2x), dried, filtered and concentrated to dryness. The residue was dissolved in CHCl3 (130 ml) and added to a solution of hexamethylenetetramine (33.6 g, 0.24 mol) in CHCl3 (60 ml). After 0.5 hour, the reaction mixture was cooled, filtered and the solid washed with hexane. After drying, the solid was dissolved in acetic acid-H2O (275 ml) and heated at reflux for 2 hours. Then concentrated HCl (55 ml) was added and the mixture refluxed an additional 5 minutes. After cooling, the solution was extracted with ether (3×), and the organic extracts were backwashed with saturated Na2CO3 (2×), dried, filtered, and concentrated to dryness to yield 16.4 g (48%) of product
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:20].Cl[C:22]1C=CC=C(C(OO)=O)C=1.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:32]([CH3:22])(=[O:36])=[O:34])=[N:14][CH:15]=2)[NH:10][C:9]1=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (4.1 g, 12.8 mmol) in 50 mL of chloroform was cooled in ice and treated with 70% 3-chloroperbenzoic acid (9.8 g, 39.8 mmol). The mixture was stirred at room temperature for 2 hours, then treated twice with 100 mL of 10% aqueous sodium thiosulfate and left to stir for 30 minutes. The reaction was diluted with 400 mL dichloromethane and the phases were separated. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and then dried over magnesium sulfate and filtered. Concentration of the filtrate under reduced pressure gave a solid which was stirred with ethyl acetate, then filtered to give 2.6 g of 3-(2-chloro-phenyl)-7-methylsulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (sulfone 11.1) as a white solid. (MH+=364)
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH2:26][OH:27])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.CC(C)=[O:39].OS(O)(=O)=O.O=[Cr](=O)=O.[Na].O>CC(C)=O.C(OCC)(=O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=1[C:26]([OH:39])=[O:27])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: OCc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methanol (225 mg) is dissolved in acetone (5 ml), and thereto is added 1.94M Jones reagent (290 μl) under ice-cooling, and the mixture is stirred for 30 minutes. To the reaction solution are added sodium hydrogenesulfite, water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (181 mg). MS (m/z): 602/604 [M+H]+
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[SH:29][CH:30](O)C.CN(C)[CH:35]=[O:36]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([S:29][CH2:30][CH2:35][OH:36])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: CN(C)C=O
Reactant: CC(O)S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(SCCO)cn2)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of the N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (94 mg, 0.19 mmol), mercaptoethanol (0.031 mL, 0.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.097 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was heated at 120° C. in a sealed tube. After 3 h, the mixture was allowed to cool to 25° C., diluted with water, and then extracted with diethyl ether. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230–400 mesh, 55% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy-ethylsulfanyl)-pyrazin-2-yl]-propionamide (58 mg, 62%) as a light brown foam: mp=78–81° C.; (ES)+-HRMS m/e calcd for C21H27ClN3O4S2 (M+H)+ 484.1126, found 484.1131.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[CH:20]=[C:19]([O:21][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1ccc(O)cc1Cl
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C#N)cc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloro-4-hydroxybenzonitrile.