Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[C:30](F)=[N:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>CS(C)=O>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:30]2[C:29]([Cl:28])=[CH:34][C:33]([C:35]([F:38])([F:36])[F:37])=[CH:32][N:31]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2c2ncc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a vial containing (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.212 g; 0.731 mmol) in dimethylsulfoxide (2 mL) is added N,N-diisopropylethylamine (0.127 mL; 0.731 mmol) and 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.096 mL; 0.731 mmol). The mixture is heated at 100° C. for 1 hour in an oil bath and then cooled to room temperature. The crude mixture is filtered and purified by preparative HPLC chromatography. Product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 433 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)nc2ccccc12
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Cl)c3ccccc3n2)cc1

Procedure:
To a mixture of 15.8 g of 2-(4-chlorophenyl)quinazolin-4(3H)-one and 115 ml of thionyl chloride was added dropwise 4.5 g of dimethylformamide and the mixture was treated as described in Example I to obtain a yellow solid which was recrystallized from cyclohexane to give 13.6 g of light yellow 4-chloro-2-(4-chlorophenyl)quinazoline, m.p. 166°-167°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:28])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=1.CC(O)=O.OP(O)(O)=O>CC#N.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=4)[CH2:15][C:14](=[O:28])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a mixture of 11E (2.6 g, 6.19 mmol) in MeCN (30 mL) was added ZnCl2 (1.27 g, 1.5 eq, 9.3 mmol) at room temperature, followed by AcOH (30 mL) and H3PO4 (30 mL) The reaction mixture was stirred 80° C. overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 1.6 g of crude product, which was purified by column chromatography on silica gel to give 500 mg of pure product (11F).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:5])C.[ClH:15]>>[ClH:15].[CH:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CCC2)cn1
Agent: Cl
Product: O=C(O)c1cn(C2CCC2)cn1
Yield: 88 %

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (WO 2007042545) (45 g, 0.27 mol) was added to cyclobutylamine (50 g, 0.70 mol) and heated to reflux for 2 hours. The solution was then cooled and concentrated. The residue was purified by column chromatography over silica gel (3:1 EtOAc:Heptane). The oily residue was triturated with TBME:heptane (1:1) and the resulting solid was collected and dried, giving 1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 67%, second crop not harvested). 1-Cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 0.21 mol) was dissolved in 6 N HCl (300 mL) and refluxed for 1 day. The solution was concentrated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and then dried under vacuum, giving the title compound 88% yield, 37.2 g, m/z 167 [M+H]+.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[S:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[N+:15]([C:12]1[S:11][C:10]([NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1ncc([N+](=O)[O-])s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCC(=O)Nc1ncc([N+](=O)[O-])s1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2Cl2 (7 mL). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then added and the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mL) and extracted with 1M NaOH (3×30 mL). The combined aqueous layers were washed with EtOAc (20 mL) then acidified with 12M HCl and subsequently extracted with EtOAc (5×20 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (1.13 g, 54%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 1.82 (quint., J=7.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S+H]+260.0336. found 260.0344. Method B with 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (30 mg, 0.12 mmol) afforded the title compound VPC161276 (23 mg, 46%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 2.61 (t, J=7.2 Hz, 4H), 1.97 (quint., J=7.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 162.0, 142.8, 141.5, 34.0, 19.3; HRMS (ESI) calcd for [C11H10N6O6S2+H]+387.0176. found 387.0185.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10](S(C)=O)[C:9]([C:15]([NH2:17])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]1[CH2:25][C@@H:24]([OH:26])[C@H:23]([CH3:27])[CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[N:11]=[C:10]([NH:19][C@@H:20]2[CH2:21][CH2:22][C@@H:23]([CH3:27])[C@H:24]([OH:26])[CH2:25]2)[C:9]([C:15]([NH2:17])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a stirring suspension of 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (0.092 g, 0.359 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (0.065 g, 0.395 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.157 mL, 0.897 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then ice-cold water (20 mL) was added to the residue. The resulting mixture was vigorously stirred for 1 h and then the product was filtered, washed with water and dried under vacuum to afford 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carboxamide (0.074 g, 0.230 mmol, 64.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (br. s., 1H), 8.34 (s, 1H), 6.69 (br. s., 1H), 4.59 (d, J=5.47 Hz, 1H), 3.87 (br. s., 1H), 2.92-3.01 (m, 1H), 2.14 (d, J=10.15 Hz, 1H), 1.91 (d, J=11.71 Hz, 1H), 1.67 (dd, J=13.28, 3.12 Hz, 1H), 1.07-1.24 (m, 3H), 0.91-0.99 (m, 4H). MS (ESI) m/z 322.3 [M+1]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Biphenylcarbonyl chloride (8 g) was suspended in chloroform (30 mL). This was added dropwise to a stirred solution of N,O-dimethyl hydroxylamine hydrochloride (5.2 g) and triethylamine (13.5 mL) in chloroform (80 mL) at 0° C. After addition was complete, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The organic phase was separated, washed with water and dried over MgSO4. Evaporation gave an oil, purified by flash column chromatography (ethyl acetate:light petroleum, 1:1) to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 33.8, 61.1, 126.7, 127.2, 127.9, 128.9, 132.8, 140.2, 143.4 and 169.7. δH (CDCl3, 250 MHz): 3.38 (3H, s), 3.59 (3H, s), 7.37-7.48 (3H, m), 7.61 (4H, m) and 7.77 (2H, d, J 8.5).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:18]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(C#N)c2)c1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
3-Cyanobenzylbromide (542 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) over 1 min. The reaction mixture was then stirred at 56° C. for 24 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated in vacuo to yield the title compound as an off white solid. 411 mg.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:14](=[O:22])[O:15][C:16]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]=2[C:11]2[C@@H:10]([OH:23])[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[C:34]([Si:38](OS(C(F)(F)F)(=O)=O)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[Si:38]([O:23][C@H:10]1[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]2[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]3[C:14](=[O:22])[O:15][C:16]4([CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:12]=3[C:11]1=2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O)CC(C)(C)C2
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.2 g (S)-4-Isopropyl-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 15 ml tetrahydrofurane and 1.31 ml 2,6-lutidine and 2.44 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for 4 hours at room temperature. Then the reaction is absorbed onto silica gel and chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=2)[C:18](=[O:26])[NH:17][C:16]1=[O:27]>CN(C)C=O>[Br:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:26])[NH:17][C:16](=[O:27])[C:15]2=[CH:14][NH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1coc(CN)cc1=O
Solvent: CN(C)C=O
Product: COc1coc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyran-4-one (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a light pink solid, 152 mg, (50%), mp 259-61° C. dec; MS (ES−): m/z 403 (M−H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[H-].[Na+].[CH2:21](Cl)[O:22][CH3:23]>C1COCC1>[CH3:21][O:22][CH2:23][O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6][C:5]2=[O:17]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)O2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Reaction time: 0.08 h

Procedure:
To a solution of 6-Hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (2.2 g) in 20 mL of THF at 0° C. was added sodium hydride (370 mg, 60% in mineral oil). After 5 min, MOM-Cl (0.96 mL) was added slowly to the reaction. After the reaction was complete, the mixture was extracted with ethyl acetate and was washed with water. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 2.0 g of 6-(methoxymethoxy)--5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a yellow paste.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccccn4)cc3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
To a solution of (E)-N-[4-(2-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (350 mg) in tetrahydrofuran (10 ml) and dichloromethane (30 ml) was added 3-chloro-perbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol/ethyl acetate=1:1) concentrated to give crystals, which were recrystallized from ethanol-chloroform to give (E)-N-[4-(1-oxidopyridin-2-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 189) (188 mg) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([NH2:23])=O)[O:3]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:8]=2)[C@@H:4]([C:21]#[N:23])[O:3]1
Reactant: NC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Yield: 68.2 %

Procedure:
To a solution of (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxamide (80 mg, 0.261 mmol) in dichloromethane (2 mL) was added phosphorus oxychloride (0.243 mL, 2.61 mmol). The reaction was heated to reflux for 4 h and sodium bicarbonate (sat) was added until pH 7. The reaction mixture was back extracted with dichloromethane (3×5 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield a yellow wax that was purified by Preparative HPLC Method 6 providing (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonitrile (53 mg, 0.178 mmol, 68.3% yield) 1H NMR (500 MHz, DMSO-d6) δ ppm 5.36 (d, J=4.27 Hz, 1H) 5.63 (d, J=4.27 Hz, 1H) 7.39-7.49 (m, 4H) 7.52 (t, J=7.93 Hz, 1H) 7.56-7.64 (m, 4H) 8.76 (br. s., 1H).
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)[C:7](=[O:9])[N:8]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=4)[C:7](=[O:9])[N:8]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CSc1nc(=O)c(Cc2ccc(=O)[nH]c2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Product: O=c1ccc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Yield: 13.1 %

Procedure:
2-methylsulfanyl-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (20 mg, 0.08 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (40 mg, 0.127 mmol, 1.58 eq) were heated in 300 μl of dry pyridine at 150° C. for 16 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/30% MeOH in DCM solvent system (gradient 5-100% of 30% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (5.4 mg, yield=11.7%, purity=90%). MS: [M+H]+=517.34. 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.81 (t, J=7.032 Hz, 2H), 3.23 (s, 2H), 3.43-3.53 (m, 2H), 6.24(d, J=9.45 Hz, 1H), 6.36 (br.s., 1H), 7.03-7.14 (m, 3H), 7.20-7.37 (m, 4H), 7.41 (d, J=2.55 Hz, 1H), 7.54 (s, 1H), 7.70 (d, J=8.82 Hz, 1H).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][S:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:33]1[CH2:34][CH2:35][N:30]([C:28]([C:26]2[N:27]=[C:23]([N:21]3[CH2:22][CH:19]([OH:18])[CH2:20]3)[S:24][CH:25]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1csc(N2CC(O)C2)n1)N1CCSCC1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)azetidine (1.16 g, 2.10 mmol) (obtained as described in Reference Example 25(1)) in anhydrous tetrahydrofuran (35 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.52 ml, 2.52 mmol), and the reaction mixture was stirred for 30 minutes. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (599 mg, yield 100%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH:28][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2cccc(Oc3ccccc3)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-phenoxyaniline (71 mg, 0.386 mmol) similar to Example 58 and isolated as a pale white solid (33 mg, 42%). 1H NMR (CDCl3): 9.74 (d, J=2.1 Hz, 1H), 8.72-8.66 (m, 2H), 8.52 (bs, 1H), 7.45-7.37 (m, 4H), 7.21-7.10 (m, 5H), 6.97 (s, 1H), 6.93 (dd, J=2.1, 8.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:24]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(C=C2SC(N3CCN(S(C)(=O)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 52 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (50 mg, 92 μmol) (from Example 23) chloroform (5 mL), methyl sulfonyl chloride (3 equiv, 32 μL) and TEA (3 equiv, 40 μL). The reaction was stirred at 60° C. under N2. The reaction solution was diluted with DCM (70 mL), washed with aq NH4Cl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 90:10) to provide the title compound as a white solid (30 mg, 52%). 1H NMR (DMSO-d6) δ 7.99 (2H, s), 7.94 (1H, s), 7.62 (1H, s), 7.18 (1H, s), 7.13 (1H, dd, J1=2.0 Hz, J2=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 5.37 (2H, s), 4.06 (2H, m), 3.88 (3H, s), 3.74 (2H, m), 3.31-3.36 (4H, m), 2.85 (3H, s); MS (ESI) 624 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH:12]=[CH:11][CH2:10]2)=[CH:5][N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:9]1([C:6]2[CH:5]=[N:4][C:3]([CH2:2][Cl:27])=[N:8][CH:7]=2)[CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:15])[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(c2cnc(CO)nc2)CC=CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(c2cnc(CCl)nc2)CC=CC1
Temperature: 25 °C

Procedure:
To a solution of ethyl 1-(2-hydroxymethylpyrimidin-5-yl)cyclopent-3-ene carboxylate (5.0 g, 20.1 mmol), in chloroform (50 ml) was added pyridine (5.1 ml), followed by thionyl chloride (4.4 ml, 60.3 mmol). The reaction mixture was refluxed for 30 minutes, cooled to room temperature and quenched with water (50 ml). The chloroform layer was collected, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic extract was dried over MgSO4 and then evaporated to an oily residue, which was purified by flashe chromatography with hexanes/ethyl acetate (3:1) as eluent.