Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH:18]([CH3:17])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
A 22 g quantity of 4-benzyloxybenzyl chloride was treated with diethyl methylmalonate anion following the procedure in Example 8. The alkylated methylmalonate was saponified and decarboxylated following the same procedure to obtain 18.06 g of 2-(4-benzyloxybenzyl)propionic acid, m p. 93°-95° C. A 3.6 g quantity of this acid was treated with 5,6-diamino-1,3-dipropyluracil to obtain the amide and was cyclized following the procedure in Example 7 to obtain 1.46 g of material which was recrystallized from 5% ethyl ether in hexane to yield 0.72 g of 3,7-dihydro-8-[methyl-2-(4-benzyloxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione, m.p. 124°-126° C. A 260 mg quantity of 3,7-dihydro-8-[methyl-2-(4-benzyloxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione was dissolved in 20 ml of methyl alcohol and treated with a catalytic amount of 5% palladium on charcoal. This was placed under an atmosphere of hydrogen for 2 hours with stirring. It was then filtered through Celite and the filtrate concentrated under vacuum. The residue was purified by radial chromatography (50% ethyl acetate in hexane, 4 mm plate) to yield 182 mg of material which was triturated with 5% ethyl ether in hexane to yield, after drying under high vacuum at 39° C. for 3 hours, 162 mg of 3,7-dihydro-8-[methyl-2-(4-hydroxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione, m.p. 218°-220° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].C(O)(=O)C>CN(C=O)C>[NH2:24][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17])=[O:23]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccccc3C(N)=O)c2cc1OC
Temperature: 100 °C
Yield: 41.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 2-aminobenzamide (0.029 g, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 6 h. After cooling the reaction mixture was evaporated. The residue was dissolved in a mixture of MeCN and water (1:3) containing 0.1% trifluoroacetic acid and the turbid solution was filtered through a plug of glass wool. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 an absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and then water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol. After evaporation, the residue was crystallized from ethanol to give the title compound (26 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>C(O)C>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1cccc(Br)n1
Solvent: CCO
Product: FC(F)(F)c1cn2c(Br)cccc2n1
Yield: 84.6 %

Procedure:
6-Bromopyridin-2-amine (20.0 g, 116 mmol) and 3-bromo-1,1,1-trifluoroacetone (24.0 mL, 231 mmol) were dissolved in ethanol (200 mL), and the mixture was heated under reflux for 4 days. The precipitated solid was collected by filtration and dissolved in dichloromethane. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (26.0 g, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Br:11]Br.N>CC(O)=O>[Br:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc2nc[nH]c2c1
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-aminobenzimidazole (0.3 g, 2.3 mmol) in 30 ml of AcOH was added bromine, (0.055 ml, 1.1 mmol) in a portion and resulting reaction mixture was stirred for 0.5 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a dark brown solid which was subjected to silica gel column chromatography (NH3 saturated 10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].[Li]CCCC.CCCCCC.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:15])=[CH:7][CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:10]=1[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCOc1ccc(C)c(OCOC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(OCOC)ccc(C)c1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (Intermediate 150, 5.5 g, 25.94 mmol) in dry tetrahydrofuran (50 ml) at room temperature BuLi 1.6M in hexane (19.45 ml, 31.13 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chlorooxoacetate (4.35 ml, 38.9 mmol) in dry tetrahydrofuran (30 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with water (20 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound (4.65 g) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:11]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:12]=3[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C1CCCC1c1cc(F)c(F)c(F)c1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)c(F)c(F)c1)CC2
Temperature: 130 °C
Yield: 46.4 %

Procedure:
A mixture of 2-(3,4,5-trifluorophenyl)cyclopentanone (2 g, 9.34 mmol) and carbonisocyanatidic chloride (1.773 g, 16.81 mmol) was heated at 58° C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.227 g, 4.33 mmol, 46.4% yield). LC-MS (M+H)+=284.0.
Reaction SMILES: CN(C)CCCC(NC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:19][N:20]([CH3:36])[CH2:21][CH2:22][N:23]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)[C:24](=[O:26])[CH3:25]>>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH3:36])[C:24](=[O:26])[CH3:25])=[CH:28][CH:29]=1
Reactant: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)CCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N(CCN(C)C)c1ccc(N)cc1

Procedure:
Prepared analogously to Example 141b starting from -(2-dimethylamino-ethyl)-N-(4-nitro-phenyl)-acetamide) (142a).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([CH3:16])[C:11]([C:12]#[N:13])=[C:10]([CH3:17])[CH:9]=1.Br[CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CC(C)=O>[CH:22]1([C:20](=[O:21])[CH2:19][O:7][C:8]2[CH:9]=[C:10]([CH3:17])[C:11]([C:12]#[N:13])=[C:14]([CH3:16])[CH:15]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(O)cc(C)c1C#N
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)C2CC2)cc(C)c1C#N
Yield: 94.1 %

Procedure:
Cesium carbonate (30.7 g, 111.16 mmol) was added to a solution of 4-hydroxy-2,6-dimethylbenzonitrile (15.27 g, 101.89 mmol), in acetone (377 ml). Then 2-bromo-1-cyclopropylethanone (15.1 g, 62.6 mmol), in acetone (100 ml), was added dropwise, over 5 minutes, to the suspension and the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between a saturated aqueous solution of potassium carbonate (300 ml) and dichloromethane (300 ml). The organic layer was separated and washed with brine (250 ml), dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:pentane (50:50 to 80:20, by volume) to provide the title compound (13.5 g, 64%) as a solid. 1H-NMR (400 MHz, CDCl3): δ=0.97-1.01 (m, 2H), 1.12-1.15 (m, 2H), 2.19 (m, 1H), 2.47 (s, 6H), 4.71 (s, 2H), 6.61 (s, 2H); LRMS: APCl+: 230 [MH+]
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(S[C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)C>C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CCSc1nc2ccccc2c(=O)[nH]1
Reactant: C=CCN1CCNCC1
Solvent: CCOC(C)=O
Product: C=CCN1CCN(c2nc3ccccc3c(=O)[nH]2)CC1
Reaction time: 5 h
Yield: 89 %

Procedure:
N-allylpiperazine (37 g) was added to 30 g of 2-ethylthio-4(3H)-quinazolinone [J. Med. Chem., 11, 392 (1968)], and the mixture was stirred at 140° to 160° C. for 5 hours in a stream of nitrogen. After cooling, the reaction mixture was suspended in ethyl acetate and filtered. The resulting crude crystals were recrystallized from ethanol/ethyl acetate to give 35 g of 2-(4-allyl-l-piperazinyl)-4(3H)-quinazolinone.
Reaction SMILES: C1COCC1.[OH:6][C@@H:7]1[C@@:14]([CH3:29])([CH2:15][CH2:16][CH2:17][C:18]([CH3:28])([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:19])[C@@H:13]2[C@:30]([OH:33])(OC)[C@@:9]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])([C:10]([O:35][CH3:36])=[CH:11][C:12]2=[O:34])[CH2:8]1.C([Li])CCC.[CH:47]1[CH:52]=[CH:51][C:50]([O:53][C:54](Cl)=[S:55])=[CH:49][CH:48]=1>CCOC(C)=O.CCCCCC>[C:54](=[S:55])([O:53][C:50]1[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=1)[O:6][C@H:7]1[CH2:8][C@@:9]2([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:30](=[O:33])[C@H:13]([C:12](=[O:34])[CH:11]=[C:10]2[O:35][CH3:36])[C@:14]1([CH3:29])[CH2:15][CH2:16][CH2:17][C:18]([CH3:19])([O:20][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:26][CH3:27])[CH3:28]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)[C@@]2(O)OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1OC(=S)Oc1ccccc1)C2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
A THF (2 mL) solution of 39 (71 mg, 0.14 mmol, 1 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and a hexane solution of n-butyllithium (2.02 M, 141 μL, 0.28 mmol, 2.1 equiv.) was added dropwise over 5 min. After stirring the solution at −78° C. for 20 min, O-phenyl chlorothionoformate (39 μL, 0.28 mmol, 2.1 equiv.) was added in one portion. The resulting yellow solution was allowed to slowly warm to room temperature over 90 min and was subsequently quenched at room temperature with saturated aqueous NaHCO3. The mixture was extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an orange oil. Flash column chromatography (50 mL SiO2, 95:5 hexane:EtOAc) afforded 51 mg (81 μmol, 60% yield) of 40 as a colorless oil. TLC Rf 0.58 (7:3 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 7.41 (dd, J=8.4, 7.6 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 7.08-7.06 (m, 2H), 5.74 (s, 1H), 5.53 (dd, J=11.5, 5.4 Hz, 1H), 4.99 (t, J=7.0 Hz, 1H), 3.80 (s, 3H), 3.25 (s, 1H), 2.56-2.53 (m, 2H), 2.44 (dd, J=14.6, 7.4 Hz, 1H), 1.86 (dd, J=12.9, 11.7 Hz, 1H), 1.69-1.65 (m, 7H), 1.58-1.56 (m, 1H), 1.47-1.41 (m, 2H), 1.37 (m, 2H), 1.23 (s, 3H), 1.23 (s, 3H), 1.03 (s, 3H), 0.95 (t, J=7.9 Hz, 9H), 0.58 (q, J=7.8 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 204.2, 194.6, 192.2, 177.0, 153.4, 134.9, 129.8, 126.9, 122.0, 118.6, 106.3, 84.6, 73.5, 69.8, 57.3, 55.7, 45.65, 45.58, 38.1, 34.3, 30.5, 29.7, 29.3, 26.1, 18.2, 17.8, 17.5, 7.4, 7.0. HRMS-ESI (m/z): [M+Na]+ calculated for C35H52O6SSi, 651.3152. found, 651.3130.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.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.Cl.[CH3:67][N:68]([CH:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:79]3[CH2:78][CH2:77][CH:76]([N:68]([CH3:67])[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:81][CH2:80]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CCOC(=O)CCN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added HATU (123 mg, 0.32 mmol), DIEA (83 mg, 0.64 mmol), and ethyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (200 mg). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting mixture was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (82 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. 20.3 mg product was obtained. This resulted in 20.3 mg (13%) of the formic acid salt of ethyl 3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]methyl)amino]propanoate as an off-white solid. LCMS (Method 28) [M+H]+=659.2, RT=0.90 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.03 (t, 1H, J=73.2 Hz), 5.36-5.15 (m, 2H), 4.48-4.33 (m, 1H), 4.02 (q, 2H, J=7.2 Hz), 4.00-3.96 (m, 1H), 3.18-3.00 (m, 1H), 2.89-2.80 (m, 3H), 2.68-2.54 (m, 3H), 2.31 (s, 3H), 1.85-1.76 (m, 2H), 1.61-1.25 (m, 2H), 1.19 (t, 3H, J=6.9 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22].C(Cl)(=O)C(Cl)=O.O[C:31]1[N:35]([CH2:36][CH3:37])[N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23][C:31]1[N:35]([CH2:36][CH3:37])[N:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: CCn1nccc1O
Reactant: O=C(O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1nccc1OC(=O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-2-phenyl-1-(phenylmethyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 2, Step C) (1.20 g, 3.92 mmol) in dichloromethane (30 mL) was added oxalyl chloride (998 mg, 7.84 mmol) at 0° C. followed by a catalytic amount (4-drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was then concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL) and 5-hydroxy-1-ethyl-1H-pyrazole, (572 mg, 4.7 mmol), followed by triethylamine (1.18 g, 11.8 mmol), and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 70% ethyl acetate in hexanes to afford the title product as a white solid (700 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][C:32]([N:34]([CH:42]([CH3:44])[CH3:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33]>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH:42]([CH3:43])[CH3:44])=[O:33]
Reactant: CC(C)N(C(=O)CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C(=O)CCN(C)C)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-dimethylamino-ethyl)-carbonyl)-N-isopropyl-p-phenylenediamine Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C31H34N4O4
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[N:10]=[C:9]([C:11]2[CH:25]=[CH:24][C:14]3[N:15]([CH3:23])[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:8][S:7][C:6]1=[O:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.C1COCC1>C(N(CC)CC)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[N:10]=[C:9]([C:11]3[CH:25]=[CH:24][C:14]4[N:15]([CH3:23])[C:16]([C:18]5[O:19][CH:20]=[CH:21][CH:22]=5)=[N:17][C:13]=4[CH:12]=3)[CH2:8][S:7][C:6]2=[O:26])=[O:36])=[CH:30][CH:29]=1
Reactant: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCN)C(=O)SC3)ccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCNC(=O)Nc4ccc(Cl)cc4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
120 mg (0.30 mM) of 3-(3-aminopropyl)-5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 50.1 mg (0.33 mM) of 1-chloro-4-isocyanatobenzene are added to 2 ml of THF and 164.33 μl (1.33 mM) of triethylamine. The mixture is stirred at room temperature for 20 hours. The solid is filtered off and washed with water and then with isopropanol to give, after drying, 106 mg of N-(4-chlorophenyl)-N′-{3-[5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]propyl}urea.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C@@H:6]([NH:11]C(=O)OC(C)(C)C)[C:7]([CH3:10])([CH3:9])[CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:11][C@@H:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCCO)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)NCCO

Procedure:
(S)-tert-Butyl 1-(2-hydroxyethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate was treated overnight with trifluoroacetic acid in methylene chloride. The solution was concentrated to give the title compound without further purification.
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH:1]1([C:7]2([O:20][CH3:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-cyclohexyl-4-hydroxy-1-piperidinecarboxylate (7.26 g) in DMF (70 ml) was added sodium hydride (60% in oil) (2.05 g) with stirring under ice-cooling. The mixture was stirred at ambient temperature for 1 hour. To the suspension was added methyl iodide (4.79 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into ice-water (300 ml) and extracted three times with ethyl acetate (200 ml). The extracts were collected, washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (4:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-cyclohexyl-4-methoxy-1-piperidinecarboxylate (6.77 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Yield: 98 %

Procedure:
The product from Example 4a (1 g, 3.51 mmol) was reacted with N-(4-mercapto-phenyl)-acetamide (0.65 g, 351 mmol) for 18 h following the procedure from Example 4b giving the title compound (1.04 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1.[ClH:18]>O>[Cl:18][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: Cl
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a mixture of 7 (7.9 g, 0.033 mol), H2O (60 ml) and concentrated HCl (150 ml) stirred at room temperature was added dropwise a solution of KClO3 (1.5 g, 0.012 mol) in H2O (65 ml). After 41/2 hours, the suspension was filtered and the solid washed with H2O and dried in vacuo to yield 8.1 g (89%) of 55, m.p. 208-210.