Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]([CH3:18])[CH:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.CN(C=O)C.[H-].[Na+].[C:31]([Si:35](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]>CCOC(C)=O>[CH3:34][C:31]([Si:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:1][C:2]1[C:7]2[CH:8]([CH3:18])[CH:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1)([CH3:32])[CH3:33]
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)C2C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCCO)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of 3.17 g (8.78 mmol) of rac-3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol in 60 mL of anhy. DMF (Aldrich) was added to a suspension of 383 mg (1 eq) of sodium hydride (Aldrich) in 20 mL of anhy. DMF (Aldrich) and the mixture stirred at RT under argon for 0.5 hr. 2.28 mL (1 eq.) of tert-butylchlorodiphenylsilane (Aldrich) was then added by syringe. After stirring for 2 hr at RT the reaction was diluted with EtOAc, washed with 0.1N aq. HCl, water, sat. aq. NaCl, dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 30% EtOAc-hexane. The fractions containing the product were combined and evaporated under reduced pressure to give 2.23 g (45%) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as a pale yellow oil. HR EI MS: Calc M+, 558.3530; Observed, 558.3516.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C@@H:26]([O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:25][C:24]4=[O:47])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:48])[O:11]1)[Si](C(C)(C)C)(C)C.B(Cl)(Cl)Cl.ClCCl>C1COCC1>[O:29]([C@@H:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:14]3[N:13]4[C:12](=[O:48])[O:11][C@@H:10]([CH2:9][OH:1])[C@@H:18]4[CH2:17][O:16][C:15]=3[CH:19]=2)[C:24](=[O:47])[CH2:25]1)[Si:30]([C:43]([CH3:45])([CH3:44])[CH3:46])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CC[C@@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4=O)cc3OC[C@@H]12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CO)OC(=O)N32)C(=O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
Compound (3R,3 aS)-3-((t-butyldimethylsiloxy)methyl)-7-((R)-4-(t-butyldiphenylsiloxy)-2-oxopiperidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (0.78 g, 1.135 mmol) was dissolved in THF. A solution of BCl3 in dichloromethane (1M, 6.81 ml, 6.81 mmol) was added, stirred at room temperature for 24 h, and dried by spinning. Column chromatography afforded pale yellow solid 0.56 g, yield 86.0%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][CH2:30]Cl>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][O:18][CH2:28][O:29][CH3:30])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1csc([N+](=O)[O-])c1SCc1ccccc1

Procedure:
[4-(benzylthio)-5-nitrothien-3-yl]methanol (3.9 g, 13.9 mmol) in dichloromethane (8 mL) was reacted with diisopropylethylamine (7.42 mL, 3 equivalents) and methoxymethyl chloride (2.38 mL, 2.25 equivalents) at 25° C. 16 hours. The reaction was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel using a Biotage-40m column eluting with dichloromethane to give 3-(benzylthio)-4-[(methoxymethoxy)methyl]-2-nitrothiophene as a yellowish oil, (4.32 g, 94%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-:18])=[O:17])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C1COCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 2-(benzylthio)-4,6-dichloro-5-nitropyrimidine (WO 01/58906 A1) (9 g, 28.5 mmol) in THF (60 mL) and DIEA (9.9 mL, 7.36 g, 57 mmol, 2 equiv.) was added drop wise a solution of 4-aminotetrahydropyran (2.77 g, 27.4 mmol, 0.96 equiv.) in THF (20 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to afford, after evaporation and drying, the desired product as a yellow solid (7.59 g, 70% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 7.86 (br d, J=6.8 Hz, 1H), 7.42-7.36 (m, 2H), 7.36-7.27 (m, 3H), 4.38 (s, 2H), 4.31-4.20 (m, 1H), 3.96 (dt, J=11.7, 3.5 Hz, 2H), 3.47 (ddd, J=11.7, 11.3, 2.2 Hz, 2H), 1.92 (br dd, J=12.4, 2.2 Hz, 2H), 1.66-1.52 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][NH:31][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccccc1F
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]4-(2-fluorophenyl)butanoic acid (0.69 g; 2.34 mmol) and 7-nitro-1,2,3,4 tetrahydroisoquinoline (0.50 g; 2.34 mmol) were treated with EDC (0.54 g, 2.8 mmol), HOBt (0.38 g, 2.8 mmol) and N,N-diisopropylethylamine (0.60 g, 4.67 mmol) essentially following the procedure outlined in Example 1, Step A. Purification by flash chromatography (silica gel; 35% ethyl acetate/hexanes as eluant) afforded the title compound. LC/MS: 358.1 (M+1-BOC)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ccncc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccncc2)s1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 4-mercaptopyridine (3.4 g) and potassium carbonate in N,N-dimethylformamide (50 ml) was heated at 120° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-pyridylthio)thiazole (6.3 g, yield: 83.7%). IR (Nujol): 3150, 1680, 1580, 1300 cm-1
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:13][NH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)[CH2:2][CH3:3]
Reactant: CCCc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CNc2ccccc2N1
Temperature: 40 °C
Reaction time: 28 h
Yield: 96.8 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (1.6 mg, 1.4 μmol) and KO(t-Bu) (8.0 mg, 0.071 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (1.4 mL) solution containing 2-(1-propyl)quinoxaline (238.5 mg, 1.38 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 28 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (ethyl acetate) to obtain (S)-1,2,3,4-tetrahydro-2-(1-propyl)quinoxaline (235.4 mg, 96%). A result of an analysis conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=80:20, 1 mL/min) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25]>CN(C=O)C>[OH:25][CH2:24][C:23]1[CH:22]=[C:21]([NH:20][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(CO)c1
Reactant: COCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
0.76 g (7.31 mmol) 3-methoxypropionic acid in 10 ml dry DMF were treated with 1.25 g (7.71 mmol) 1,1′-carbonyl-diimidazole and stirred for 1 hr at room temperature. 1.00 g 3-aminobenzylalcohol were added and stirring was continued over night. The solvent was removed and the residue chromatographed on silica in ethyl acetate, yielding 1.26 g N-(3-Hydroxymethyl-phenyl)-3-methoxy-propionamide.
Reaction SMILES: CN(C)[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH3:17]>>[N+:5]([CH:4]=[CH:3][C:25]1[C:24]2[C:28](=[CH:29][C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:22][CH:23]=2)[NH:27][CH:26]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (1.93 g, 16.58 mmol) and TFA (110.0 ml) and stir until dissolved. Add 6-ethoxycarbonyl-1H-indole (3.14 g, 16.58 mmol) and stir at ambient temperature. After 1 hour, pour the reaction mixture into ice/water, extract with ethyl acetate, then evaporate to residue. Stir the residue in warm ethanol, cool to ambient temperature, then filter and dry to give the title compound as a dark yellow powder: mp 241° C. MS (ACPI): m/e 261.1 (M+1). Analysis for C13H12N2O4: Calcd: C, 60.00; H, 4.65; N, 10.76. found: C, 59.99; H, 4.63; N, 10.59.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=O.N1CCC[C@H]1C(O)=O>CCO>[C:4]([C:3]([C:2](=[O:1])[CH2:6][CH3:7])=[CH:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)#[N:5]
Reactant: CCC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a 1000 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 3-oxopentanenitrile (23) (21.8 g, 135 mmol, 60%) of, 4-formylbenzonitrile (17.7 g, 135 mmol), L-proline (3.65 g, 27 mmol, 0.2 eq) and 200 ml of EtOH. The mixture was stirred at 22° C. for 16 hours and concentrated to a volume of approximately 120 ml. 100 ml of MTBE was added and the mixture was stirred at 22° C. for about 30 min. The precipitate was collected by vacuum filtration. The solid was washed with 50 ml of MTBE. It was dried in a vacuum oven at 50° C. to give the product 24 as a off white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 8.10 (d, 2H), 7.81 (d, 2H), 3.00 (m, 2H), 1.28 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:30][CH2:29][CH2:28][C:10]2([O:14][CH2:13][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:30][CH2:29][CH2:28][C:10]2([O:14][CH2:13][C:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[CH:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC2(CCCN(Cc3ccccc3)C2)OC1
Reactant: COc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1=CC2(CCCN(Cc3ccccc3)C2)OC1

Procedure:
A mixture of 7-benzyl-3-tributylstannyl-1-oxa-7-azaspiro[4,5]dec-3-ene (Desc. 3; 1.68 g, 3.24 mmol), 2-bromoanisole (0.80 ml, 6.42 mmol), lithium chloride (0.94 g, 22 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in toluene (40 ml) was degassed then heated at reflux overnight (17 hours). The mixture was allowed to cool, filtered and concentrated in vacuo. The residue was dissolved in ether (100 ml) and extracted with 2M hydrochloric acid (100 ml then 25 ml). The aqueous phases were washed with more ether (100 ml), combined, basified with 4 M sodium hydroxide (70 ml) and extracted with ethyl acetate (2×50 ml). The organic phases were washed with brine (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:2 then 1:1), to give 7-benzyl-3-(2-methoxyphenyl)-1-oxa-7-azaspiro[4,5]dec-3-ene (0.67 g, 62%. This oil was dissolved in isopropanol and treated with excess ethereal hydrogen chloride. The mixture was concentrated in vacuo and recrystallised from isopropanol/diethyl ether to afford the title compound, m.p. 198°-201° C.; (Found: C, 69.61; H, 6.85; N, 3.62. C22H26ClNO2 0.4H2O requires C, 69.70; H, 7.13; N, 3.69%); δH (360MHz, D2O) 1.78-2.22 (4H, m), 2.98-3.26(3H, m), 3.58 (1H, m), 3.89 (3H, s, ArOCH3), 4.29 (1H, br d, NCHAHBPh), 4.43 (1H, d, J 13.1Hz, NCHAHBPh), 5.00 (2H, m, 2-CH2), 6.33 (1H, br, s, 4-H), 7.02 (1H, t, J 7.5Hz, ArH), 7.11 (1H, d, J 8.4Hz, ArH), 7.16 (1H, m, ArH), 7.39 (1H, m, ArH), 7.53 (5H, m, PhH); m/z (ES+) 336 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10].[H-].[Na+]>C1COCC1>[O:6]=[C:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC1=O

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of cyclopentanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclopentanecarboxylate. Reaction of ethyl 2-oxocyclopentanecarboxy late with urea at 175-185° C. produced 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Reaction of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Reaction of 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine with methyl 3-(bromomethyl)benzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: ClCC1COc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CCl)CO2
Reaction time: 2 h

Procedure:
92 g of 2-chloromethyl 2,3-dihydro [4H] 1,4-benzodioxin are dissolved in 675 ml acetic acid. In this solution it is added a mixture of 500 ml acetic acid and 250 ml nitric acid while keeping the temperature below 20°. The mixture is kept at room temperature for 2 hours then heated at 90° for 1 hour. It is thereafter poured in water and extracted with methylene chloride. 102 g of the nitroderivative are obtained. It is in the form of yellow crystalls which melt at 60°-62°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].[OH:32]O>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=[O:32])=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reactant: OO
Solvent: CCO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1c1ccc(C(N)=O)c(F)c1

Procedure:
To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamide (Compound (MII)) (1.48 g, 3.4 mmol) in ethanol (60 mL) was added 30% aqueous H2O2 (30 mL) at room temperature. The solution was heated to reflux for 1 h. After removal of ethanol, brine (100 mL) was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product that was purified by silica gel chromatography. MS (m/z): 435 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 6 min, hold for 10 min, 90% to 10% B in 4 min, Retention time, 9.548 min, HPLC Purity, 98.08%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.18 (s, 1H), 8.2 (d, 1H), 7.96 (d, 1H), 7.25 (m, 2H), 6.65 (bd, 1H), 5.9 (bs, 1H) 1.65 (s, 6H).
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:42])([CH3:41])[C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[O:29][C@@H:21](OCC[Si](C)(C)C)[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:51])([Cl:50])[Cl:49])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:87]>C(Cl)(Cl)Cl.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:41])([CH3:42])[C:37]([Cl:38])([Cl:40])[Cl:39])=[O:34])[O:29][C@H:21]([Cl:87])[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:50])([Cl:49])[Cl:51])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H](OCC[Si](C)(C)C)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](Cl)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of the compound 8 (6.5 g, 4.84 mmol) and dichloromethyl methyl ether (2.18 ml, 24.2 mmol) in CHCl3 (60 ml) at 0°C. was treated with ZnCl2 (1.0 M in ether; 2.41 ml, 2.41 mmol) and then allowed to warm slowly and stir at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aq. NaHCO3, dried (Na2SO4) and then concentrated. The light yellow oil obtained was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 5.4 g (88%) of 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl chloride (compound 9) as an amorphous solid: 1H NMR (CDCl3) δ 0.88 (~t, 6H), 1.1-1.6 (m, 42H), 1.78 (s, 3H), 1.88 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.34-2.52 (m, 2H), 4.2-4.4 (m, 4H), 4.70 (d, 1H, J=12 Hz), 4.73 (d, 1H J=12 Hz), 4.83 (~q, 1H, J=9 Hz), 5.09 (m, 1H), 5.51 (~t, 1H, J=10 Hz), 5.79 (d, 1H, J=8.0 Hz), 6.26 (d, 1H, J=3.6 Hz), 7.1-7.4 (m, 10H).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[CH:32])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1CCN(Cc2ccc(I)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)4-methylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 50 mg (27% of theory); C28H27ClN2O (M=442.99); calc.: molecular ion peak (M+H)+: 443/445; found: molecular ion peak (M+H)+: 443/445; Rf value: 0.45 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1>CC(C)=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([N:8]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
N-(para-carboxyphenyl)maleimide was prepared as follows. Maleic anhydride (45.2 grams (g)) was dissolved in from 300-400 milliliters (ml) of acetone. To this solution, an equimolar amount of para-aminobenzoic acid (63.2 g) was added with rapid stirring. The reaction mixture solidified within a few seconds. Excess solvent was removed by evaporation to yield the amic acid intermediate which was then dried overnight at 65° C. under vacuum.