Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]([Cl:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[ClH:30].[C:22]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Solvent: c1ccncc1
Product: Cl
Product: O=C1CCc2c(cccc2OCCCN2CCN(C(=O)c3ccccc3)CC2)N1
Reaction time: 3 h

Procedure:
2.0 grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril and 1.5 g of benzoyl chloride are mixed with 20 ml of pyridine and stirred at 50°-60° C. for 3 hours. The reaction mixture is concentrated under reduced pressure to dryness. The residue is converted into a hydrochloric acid-salt thereof, then recrystallized from methanol to obtain 5-[3-(4-benzoylpiperazinyl)propoxy]-3,4-dihydrocarbostyril hydrochloride in the form of colorless plate-like crystals with a melting point of 240° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:15])[OH:14])[S:11][C:7]=2[C:6]([CH:16]=[CH2:17])=[CH:5][CH:4]=1.[OH2:18].C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][CH2:17][CH:16]([C:6]1[C:7]2[S:11][C:10]([NH:12][C:13](=[O:14])[OH:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)O)sc12
Solvent: C1CCOC1
Product: COc1ccc(C(O)CBr)c2sc(NC(=O)O)nc12

Procedure:
1.5 g of (4-methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyll ester (0.0057 Mol), dissolved in THF (60 ml) were treated with H2O (6 ml) and 1.0 g of NBS (0.006 Mol) at room temperature for 15 min. Then the solvent was removed, the residue taken up in H2O (30 ml) and extracted four times with ethyl acetate (50 ml). The combined organic phases were washed with brine and dried over MgSO4. After evaporation the crude product was subjected to column chromatography (silicagel, ethyl acetate). The title compound was obtained as a white solid (78%), F.p.: 150-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CC(C)=O.[N:23]#[C:24]Cl.[CH2:26]([N:28](CC)CC)C>O>[O:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:24]#[N:23])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1)[C:26]#[N:28]
Reactant: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: N#CCl
Solvent: O
Solvent: CC(C)=O
Product: N#COc1ccc(C=CC(=O)c2ccc(OC#N)cc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
10 g (41.5 mmol) of 1,3-bis-(4-hydroxyphenyl)-2-propen-1-one were initially charged in a double-walled reactor (250 ml) fitted with stirrer, thermometer, gas inlet tube and a metering pump for liquors. After addition of 110 ml of anhydrous acetone, the solution was cooled to −10° C. Over a period of 10 minutes, 5.63 g (91.5 mmol) of cyanogen chloride were then introduced initially, followed by the metered addition, with vigorous stirring, of 8.55 g (84.5 mmol) of triethylamine at a flow rate of approximately 0.4 ml/min, during which the temperature of the reaction mixture was kept below −10° C. at all times. The reaction mixture was then warmed to 20° C. and stirred at this temperature for 30 minutes. Over a period of 10 minutes, the reaction mixture was subsequently added with vigorous stirring to 200 ml of water which had been cooled to 5° C. beforehand. The suspension was then stirred for 30 minutes, slowly warmed to 15° C. and filtered. The filter cake was washed with water (2×30 ml) and dried in a vacuum drying cabinet at 20 mbar/50° C. for 20 hours. In this manner, 11.03 g (92%) of cyanate having a melting point of 171-173° C. were isolated.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23].O>O1CCCC1>[CH3:25][O:24][C:22](=[O:23])[O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:1])([CH3:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(=O)c1ccc(CO)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)OCc1ccc(C(=O)C(C)(C)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
Under argon gas, 3.0 g (15.5 mmol) of 2-hydroxy-1-(4-hydroxymethyl-phenyl)-2-methyl-propan-1-one and 1.5 g (19 mmol) of pyridine in 50 ml of tetrahydrofuran are introduced into a 100 ml reaction flask. The pale-yellow solution is cooled to 0° C., and 1.6 g (17 mmol) of methyl chloroformate diluted with 5 ml of tetrahydrofuran are added dropwise between 0 and 2° C. over 45 minutes. A whitish-yellow suspension is formed, which is further stirred overnight in an ice bath. After warming up to room temperature, the reaction mixture is poured into 50 ml of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The crude product is purified by means of flash chromatography on silica gel (eluant: mixed hexanes:ethyl acetate 2:1). 2.3 g of carbonic acid 4-(2-hydroxy-2-methyl-propionyl)-benzyl ester methyl ester are obtained as a pale-yellow liquid. The structure is confirmed using a 1H NMR spectrum.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:88])([CH3:87])[CH3:86])[C:69](OCC#N)=[O:70])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[C:60]([O:64][C:65]([NH:67][C@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:86])([CH3:87])[CH3:88])[C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])=[O:66])([CH3:61])([CH3:62])[CH3:63]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (37.9 mg, 0.060 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 53) (103 mg, 0.179 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (11 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 55) (12 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:24][CH2:25][C:26]1[NH:27][C:28](=[O:36])[C:29]2[CH2:35][O:34][CH2:33][CH2:32][C:30]=2[N:31]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:24][CH2:25][C:26]4[NH:27][C:28](=[O:36])[C:29]5[CH2:35][O:34][CH2:33][CH2:32][C:30]=5[N:31]=4)=[O:23])[CH2:18][CH2:19]3)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc(C3CCN(CC(=O)O)CC3)o2)cc1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Solvent: CC#N
Product: COc1ccc(-c2nnc(C3CCN(CC(=O)NCc4nc5c(c(=O)[nH]4)COCC5)CC3)o2)cc1
Yield: 7.3 %

Procedure:
The title compound (10 mg, 0.018 mmol) was prepared following the general procedure of Example 1 from {4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-acetic acid (100 mg, 0.246 mmol, 1.0 eq) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (46.8 mg, 0.258 mmol, 1.05 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H) 8.27 (br s, 1H) 7.92 (d, J=9.03 Hz, 2H) 7.14 (d, J=9.03 Hz, 2H) 4.34 (s, 2H) 4.20 (d, J=5.52 Hz, 2H) 3.73-3.92 (m, 5H) 2.86-3.11 (m, 5H) 2.18-2.36 (m, 2H) 2.01-2.10 (m, 2H) 1.87-1.98 (m, 2H). HR-MS (m/z, MH+): 481.2205, 482.2262. HPLC retention time: 2.69 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([NH:16][OH:17])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]([CH:23]=[O:24])C.C(O)(=O)C.[O-]C#N.[K+]>O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([N:16]([OH:17])[C:23]([NH2:21])=[O:24])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON[C@@H]1COc2cc(OCc3ccccc3)ccc21
Reactant: CN(C)C=O
Agent: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N(O)[C@@H]1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred solution of (S)-N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)hydroxyamine of Example 7(b) above, (10.0 kg, 38.9 moles), DMF (50.0 L), and acetic acid (3.34 L) cooled to 5° C. was added in one portion, a cooled (0° C.) solution of potassium cyanate (4.73 kg, 58.3 moles) in water (9.0 L). This was added at such a rate that the internal temperature did not exceed 10° C. The resultant suspension was stirred for 30 min at room temperature. Water (213 L) was added and the mixture stirred for 1 hour at ambient temperature. The product was collected by centrifugation and the wet cake washed with water (425 L) and 95% ethanol (40 L). The product was isolated an dried at 45°-50° C. under vacuum to afford the crude product (11.4, 97%) as an off white solid. The crude product (11.0 kg) was recrystallized from DMF/TBME (110 L/233 L)) and washed with TBME (89 L) to afford the desired compound (9.1 kg, 83%) as a white solid after drying at 45°-50° C. under vacuum. The product was greater than 99% e.e. as determined by chiral HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.CO/[CH:18]=[CH:19]/[C:20](=O)[CH3:21].[CH3:23]O[Na]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:10]([C:11]([O:13][CH2:14][CH3:23])=[O:12])[C:9]2=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)Nc1ccc(F)cc1
Reactant: CO/C=C/C(C)=O
Reactant: CO[Na]
Solvent: CCO
Product: CCOC(=O)c1ccc(C)n(-c2ccc(F)cc2)c1=O
Yield: 15.9 %

Procedure:
To a solution of methyl 3-(4-fluorophenylamino)-3-oxopropanoate(10.1 g, 48 mmol) in EtOH (100 mL) is added trans-4-methoxy-3-buten-2-one (5.7 g, 57 mmol) and CH3ONa (3.1 g, 57 mmol). The mixture is heated at reflux overnight and then concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAC (from 5:1 to 2:1) to give the product (2.1 g, 16% yield). MS (m/z): 276.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]C(=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The starting material, about 10 mmol of 3-acetyl-trifluoroacetylaminobenzene was gradually added to about 20 ml of concentrated H2SO4 at about −20° C., and then stirred for about 30 minutes. Then, nitric acid was added for about 10 minutes. The solution was stirred for about 2 hours. After the reaction was completed, the solution was poured into ice water. An organic layer was extracted twice from the ice water with about 50 mL ethyl acetate, and was washed with sodium hydrogen carbonate solution. And then the organic layer was dried with sodium sulfate anhydride, and distilled under reduced pressure to remove ethyl acetoacetate. Concentrated NH4OH was added, and the solution was stirred at about 50° C. for about 1 hour. Then, the solution was evaporated using a rotary. Extraction was performed with EtOAc and water. Then, 3-acetyl-4-nitro-aminobenzene was obtained in a form of about 54% brown solid using silica gel column chromatography (Hexane/EtOAc=3/1).
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:15]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:16]=[CH2:17].O([Si](C(C)(C)C)(C)C)S(C(F)(F)F)(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:15]([C:18]1([O:24][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:16]=[CH2:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC1(O)CCCCC1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: C=CCC1(O[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Pyridine (11.7 mL, 145 mmol), 4-dimethylaminopyridine (DMAP, 0.59 g, 4.82 mmol) and tert-butyldimethylsilyl chloride (8.71 g, 57.8 mmol) were added to a solution of 1-allylcyclohexanol (48.2 mmol) in acetonitrile (120 mL). The reaction was heated at reflux overnight, then cooled to rt and concentrated to about 50 mL under reduced pressure. The solution was cooled to 0° C. and tert-butyldimethylsilyl triflate (13.3 mL, 57.8 mmol) was added. After the solution had stirred overnight at rt, additional tert-butyldimethylsilyl triflate (5.00 mL) was added and the solution was stirred for 6 h longer. The reaction was quenched with saturated aqueous sodium bicarbonate (120 mL) and extracted with dichloromethane (100 mL, then 2×75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give a colorless oil that was purified on a on a HORIZON High-Performance Flash Chromatography (HPFC) instrument (available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-5% ethyl acetate/hexanes) to afford [(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane as a colorless oil (11.96 g, 97%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
2.8 g of sodium hydride as a 60% dispersion in oil are added in small portions at RT to a solution of 13.35 g of 3,4-dichlorophenylacetonitrile in 100 ml of THF and the reaction mixture is stirred for 3 hours at RT. It is cooled to -20° C., a solution of 16 g of 2-(3-bromopropoxy)tetrahydropyran in 30 ml of THF is added dropwise and the reaction mixture is stirred for 3 hours while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over MgSo4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 11 g of the expected product.
Reaction SMILES: [CH2:1]([N:5]1[C:9](Cl)=[C:8]([Cl:11])[N:7]=[C:6]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].CN([CH:21]=[O:22])C>C1COCC1>[CH2:1]([N:5]1[C:9]([CH:21]=[O:22])=[C:8]([Cl:11])[NH:7][CH:6]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCn1c(N2CCOCC2)nc(Cl)c1Cl
Solvent: C1CCOC1
Product: CCCCN1C(C=O)=C(Cl)NC1N1CCOCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-BuLi (12.1 mL, 19.3 mmol, 1.6M in hexane) at −78° C. is added to a solution of 4-(1-butyl-4,5-dichloro-1H-imidazol-2-yl)-morpholine (3.48 g, 12.5 mmol) in anhydrous THF (50 mL) over a 30 minute period. After stirring for 2 hours at −78° C., anhydrous DMF (3 mL) is added at −78° C. Then the reaction mixture is allowed to warm to room temperature over a 2 hour period. The reaction is then quenched with water. The reaction mixture is extracted with ethyl acetate and dried over MgSO4. The extract is evaporated in vacuo to dryness and purified by flash column chromatography on silica gel using a mixture of hexane-ethyl acetate (4:1 to 3:1) as eluent to give 1-butyl-4-chloro-2-morpholin-4-yl-3H-imidazole-5-carbaldehyde as a colorless oil. 1HNMR (CDCl3) δ 9.59 (1H, s), 4.06 (2H, t, J=7.1 Hz), 3.78 (4H, t, J=4.6 Hz), 3.15 (4H, t, J=4.6 Hz), 1.60–1.70 (2H, m), 1.19–1.30 (2H, m), 0.90 (3H, t, J=7.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13](O)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22]C1(C)OC(=O)CC(=O)O1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:6]1[O:7][C:8](=[O:9])[C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:12][CH:11]=2)(=[O:14])[CH3:22]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
[Step 1] To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (10.3 g), 2,2-dimethyl-[1,3]dioxane-4,6-dione (4.76 g), dimethylpyridin-4-yl-amine (5.50 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (8.6 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. The mixture was diluted with dichloromethane, washed with 1N hydrochloric acid and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue dissolved in water (200 ml) and acetic acid (100 ml) and the mixture was heated under reflux for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was crystallized from diisopropyl ether to give 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (8.29 g, 81%).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 0.17 h

Procedure:
18 mg of Isoamyl nitrite was added to a mixture of 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine, 63 mg of copper(I) chloride, 129 mg of copper(II) chloride and 1.5 ml acetonitrile dropwise at 0° C. and the mixture was stirred for 10 minutes, then at room temperature for 1 hour. This reaction solution was poured into a mixture of 1N hydrochloric acid and ice, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.12 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl) ethoxy} pyridine (as a mixture of two diastereomerical isomers) [present compound 7-2].
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3OS(C(F)(F)F)(=O)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:29]([O:28][C:26](=[O:27])[NH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:16][C:15]3=[O:17])=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Temperature: 80 °C

Procedure:
Trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl ester [E] (380 mg, 1.0 mmol), 4-(N-Boc-aminomethyl)phenylboronic acid (280 mg, 1.1 mmol, 1.1 eq), potassium carbonate (275 mg, 2.0 mmol, 2 eq) and tetrakis triphenylphosphine palladium (0) (60 mg, 0.05 mmol 0.05 eq) were stirred in dioxane (4 ml) and heated to 80° C. for 4 hours. The cooled reaction was then filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-3% methanol in dichloromethane to afford [4-(2-morpholin-4-yl-4-oxo-4H-chromen-8-yl)-benzyl]-carbamic acid tert-butyl ester [F]. Yield 238 mg, 54%.
Reaction SMILES: BrCCC1C(Cl)=[C:6]([O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14](CCBr)[C:13]=2[Cl:22])[CH:7]=C([Cl:10])C=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[ClH:10].[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[O:11][CH2:6][CH2:7][NH:27][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Clc1cc(CCBr)c(Cl)c(Oc2cc(Cl)cc(CCBr)c2Cl)c1
Product: CC(C)NCCOc1cc(Cl)ccc1Cl
Product: Cl

Procedure:
Following the procedure of Preparation 11, 2-bromoethyl-2,5-dichlorophenyl ether and isopropyl amine (excess) were reacted and the reaction mixture processed to give an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to give the hydrochloride salt, m.p. 152°-155° C. in 63.3% yield.