Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[N:14][C:15]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:14][C:13]=2[N:24]([CH:25]2[CH2:27][CH2:26]2)[C:28]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(N2CCCC2)nc1NC1CC1
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1OCc1ccccc1
Yield: 74.5 %

Procedure:
A solution of N-benzyloxy-2-cyclopropylamino-5-fluoro-6-pyrrolidinyl-3-pyridinecarboxamide (Example I-2, 155 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (CDI) (142 mg, 0.88 mmol) in chloroform (2 mL) was refluxed overnight. The mixture was concentrated and purified by flash chromatography on a silica gel column with dichloromethane as eluent giving 130 mg of the title compound as a solid, mp 184-186° C.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])CCC.[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][NH:13][C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)OCCCC
Reactant: NCC(O)CO
Product: CCCCOC(=O)NCC(O)CO

Procedure:
An equimolar mixture of dibutylcarbonate and 3-amino-1,2-propanediol was allowed to react resulting in formation of butyl 2,3-dihydroxypropylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O

Procedure:
With the exception that N-t-butoxycarbonyl-trans-4-(t-butyldimethylsilyl)oxy-L-prolinol, instead of N-t-butoxycarbonyl-L-prolinol, was used, the same procedure as in Preparation Example 1-1 was repeated to afford the title compound. 9.64 g (66%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][OH:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].N12CCCN=C1CCCCC2>CN(C=O)C>[I:21][C:4]1[CH:5]=[C:6]2[C:11]3=[C:2]([O:14][CH2:13][CH2:12][N:10]3[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20])[CH:3]=1
Reactant: CCOC(=O)c1cn(CCO)c2c(F)cc(I)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A solution of ethyl 8-fluoro-1-(2-hydroxyethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 12, 20 mmol) in DMF (30 mL) was treated with 1.8-diazabicyclo[5.4.0]undec-7-ene (5.6 ml, 40 mmol) and the reaction mixture was stirred at 100° C. for 24 h. The solvent was then removed in vacuo and the residue was chromatographed on silica gel using 0-5% (0.2N ammonia in methanol) in dichloromethane to give 1.4 g (18%) of ethyl 9-iodo-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:16]=[O:17])[C:2]1=2.[CH3:18][Mg]Br.Cl.[OH-].[NH4+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:16]([OH:17])[CH3:18])[C:2]1=2
Reactant: O=Cc1cnccc1-c1cccc2ccsc12
Reactant: C[Mg]Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1cccc2ccsc12
Reaction time: 2 h
Yield: 62 %

Procedure:
Cool a solution of 4-benzo[b]thiophen-7-yl-pyridine-3-carbaldehyde (1.5 g, 6.27 mmol in THF (50 mL) in a 250-mL round bottom flask to 0° C. and add gradually methylmagnesium bromide (2.38 g, 6.90 mmol, 2.30 mL) to the solution. Stir the mixture from 0° C. to RT for 2 h. Hydrolyze the mixture by mixing with 1 N HCl (200 mL). Adjust the pH to 11 with ammonium hydroxide. Extract into chloroform/IPA (3/1, 200 mL). Wash the organic phase with water and saturated aqueous sodium chloride. Dry over sodium sulfate and concentrate in vacuo. Purify by FCC (hexane to 10% ethyl acetate in hexane, then 20% THF in DCM) to give the title compound as a yellow oil (1.00 g, 62%). MS (ES) m/z 256 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>Cl.C(O)(=O)C>[C:5]1([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:4][CH2:3][CH2:2][NH2:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
A solution of 2-aminoethanethiol.HCl 80 (11.4 g, 100 mmol), triphenylmethanol (TrOH, 26.0 g, 100 mmol) in HCl (37%, 44.8 mL) and acetic acid (280 mL) was stirred for 5 h at 40° C. The reaction mixture was concentrated in vacuo and the resulting white solid was washed with ether and dissolved in H2O/CH2Cl2 (1:1). After adjusting the pH of the aqueous layer to ca. 14 with 1 N NaOH, the desired compound was removed by extraction. The combined organic layers were dried (K2CO3), filtered, and concentrated in vacuo to provide a white solid, S-(triphenylmethyl) 2-aminoethanethiol (28.8 g, 90.0 mmol, 90% from 80). Rf =0.50 (1:9 MeOH/CH2Cl2); 1H NMR (DMSO-d6) δ7.35-7.20 (m, 15H), 2.43 (t, J=6.1, 2H), 2.15 (t, J=5.9, 2H). To a solution of S-(triphenylmethyl) 2-aminoethanethiol (3.00 g, 9.40 mmol) and triethylamine (951 mg, 9.40 mmol) in dry CH2Cl2 (30 mL) was added bromoacetyl bromide (1.90 g, 9.40 mmol) over 15-20 min at -20°. The reaction mixture was stirred at -20° for 30 min and at room temperature for 1 h. To this mixture was added an additional equivalent of S-(triphenylmethyl) 2-amninoethanethiol (3.00 g, 9.40 mmol) and triethylamine (951 mg, 9.40 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (1:99 MeOH/CH2Cl2) to give compound 81 as a white foam (4.64 g, 6.95 mmol, 67% from amine 80). Rf 0.60 (1:9 MeOH/CH2Cl2); 1H NMR (DMSO-d6) δ7.77 (t, J=6.1, 1H), 7.35-7.20 (m, 30H), 2.97 (dd, J=6.0, 5.9, 2H), 2.86 (s, 2H), 2.35 (t, J=6.1, 2H), 2.18 (m, 4H). See Photaki et al., J. Chem. Soc. (c) 2683-2687 (1970); Bryson, N. J., Neutral technetium (v) complexes with N,S-donor chelates. Ph.D. thesis, Massachusetts Institute of Technology, Cambridge, Mass. (1988).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 30.2 %

Procedure:
Nitrogen was bubbled through dioxane (100 mL) followed by the addition of 4-bromo-1-(methyloxy)-2-nitrobenzene (5.0 g, 21.55 mmol, Transworld). To the solution were added 3-pyridinylboronic acid (3.16 g, 25.90 mmol, Boron Molecular), dichloro(triphenylphosphine)palladium (0.76 g, 1.08 mmol, Strem) and degassed aqueous Na2CO3 (65 mL, 1 M, 65 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was recrystallized from hexanes/ethyl acetate to afford 3-[4-(methyloxy)-3-nitrophenyl]pyridine (1.5 g, 76%). ESIMS (M+H)+=231.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:31][CH2:32][CH2:33][CH3:34])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=O)=[C:21]([O:29][CH3:30])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:14]([N:18]([CH2:31][CH2:32][CH2:33][CH3:34])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=[CH:5][C:3]#[N:4])=[C:21]([O:29][CH3:30])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC=CC#N)c(OC)c1
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To 200 mg (8.3 mmol) of sodium hydride, 14 ml of tetrahydrofuran was added. To this mixture, 1.47 g (8.3 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling, and the mixture was stirred for 20 minutes. Next, 1.02 g (3.52 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal in tetrahydrofuran was added dropwise. After stirred for 30 minutes, the reaction mixture was poured into 100 ml of water and subjected to extraction with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1.0 g of an orange oily matter (yield: 91.2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1.[OH-].[K+]>CN(C=O)C.O.[Pd]>[CH3:21][C:20]1[N:16]([C:11]2[CH:10]=[C:9]([C:3]3[C:4](=[O:8])[NH:5][N:6]=[CH:7][CH:2]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])[C:17]([CH3:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2c(Cl)cn[nH]c2=O)cc1-n1c(C)ccc1C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccn[nH]c2=O)cc1-n1c(C)ccc1C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a solution of 5-chloro-4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one (0.90 g, 2.87 mmol) and KOH (0.40 g, 7.17 mmol) in DMF (1.2 ml) and water (11 ml) was added 10% Pd/C (0.05 g). The mixture was hydrogenated in a Parr vessel at 4.14 BAR for 18 hours. Aqueous 10% KOH (15 ml) was added and the mixture was filtered. The filtrate was take to pH 1 with conc. HCl and extracted with DCM. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/1:1) gave 0.429 g (54%) of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](NC)=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][CH:21]=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CNC(=S)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](CNC=S)CN1c1ccc(N2CCOCC2)c(F)c1
Reaction time: 1.5 h
Yield: 28.5 %

Procedure:
A stirred mixture of 6 (0.38 g, 0.00118 mol) in dioxane (20 mL), under nitrogen was treated with 4 (0.51 g, 0.00126 mol), warmed to reflux during 30 min and kept at this temperature for 90 min. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH—CH2Cl2 and the slightly impure product was rechromatographed on silica gel with 25% EtOAc—CH2Cl2. The resulting product was crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of 7: mp 150-155° C. (dec); IR (DRIFT) 3322, 1752 cm−1; MS(ES) m/z 340 (M+H+), 362 (M+Na+); 1HNMR [300 MHz, (CD3)2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d,d, 1H), 3.94 (t, 2H), 4.12 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 9.33 (d, 1H), 10.59 (s, 1H). Anal. calcd for C15H18FN3O3S: C, 53.08; H, 5.35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[NH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCCNC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (Example 3, Step A) in 2 mL dichloromethane, triethylamine was added (165 μL), followed by tert-butyl 3-aminopropylcarbamate (76 mg). The reaction was stirred for 2 hours at room temperature. The reaction was diluted with EtOAc, washed with saturated NaHCO3 and brine and dried over Na2SO4. The crude product was purified by flash chromatography on silica using EtOAc:hexane (1:3) as mobile phase to give the titled compound. ESI+ MS: 644 [M+H]+.
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([CH:10]([C:3](=[O:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(Cc1ccccc1)C(=O)OCC
Yield: 38.2 %

Procedure:
Under argon, and at room temperature, 1.7 g (74.18 mmol) of sodium are dissolved in 75 mL of anhydrous EtOH. 13.5 mL (74.2 mmol) of diethyl 3-oxopentanedioate and then 8.8 mL (74.2 mmol) of benzyl bromide are then added dropwise, at room temperature. The medium is then refluxed for 3 hours, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 8.29 g of diethyl 2-benzyl-3-oxopentanedioate are obtained in the form of a translucent oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH:26]3[CH2:28][CH2:27]3)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[I:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].Cl>>[I:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=[C:2]([Cl:1])[N:3]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH:26]2[CH2:28][CH2:27]2)[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(I)c1
Agent: Cl
Product: O[C@@H]1[C@H](O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-cyclopropyl-β-D-ribofuranosyl)-purine (65, 483 mg, 1.08 mmol) and 3-iodobenzylamine.HCl (1.63 mmol, 439 mg). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 435 mg (0.78 mmol, 72%), mp 94–96° C.; Rf 0.49 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.93 (t, 1H, J=6.18 Hz, NH), 8.33 (s, 1H, H-8), 7.73 (s, 1H, CCHCI), 7.59 (d, 1H, J=7.90 Hz, CCHCHCH), 7.34 (d, 1H, J=7.55 Hz, CCHCH), 7.11 (t, 1H, J=7.55 Hz, CCHCH), 5.82 (d, 1H, J=5.14 Hz, H-1′), 5.54 (d, 1H, J=5.84 Hz, OH-2′), 5.30 (d, 1H, J=5.15 Hz, OH-3′), 4.61–4.48 (m, 3H, H-2′, NHCH2), 4.09–3.98 (m, 2H, H-3′,4′), 3.68–3.58 (m, 2H, H-5′), 0.45–0.41 (m, 4H, cyclopropyl); MS m/z 559 (M+H)+; Anal. (C20H21ClIN5O4.0.5 H2O) C, H, N.
Reaction SMILES: [C:1]1([C@@:7]([NH2:19])([CH3:18])[CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[C:28](=[O:30])[NH:19]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(NCC[C@@](C)(N)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N2CCC(C)(c3ccccc3)NC2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of (R)-3-phenyl-N1-m-tolylbutane-1,3-diamine (50 mg, 0.2 mol) and Et3N (60 mg, 0.6 mmol) in CH2Cl2 (3 mL) was added triphosgene (24 mg, 0.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and concentrated. The residue was purified by preparative HPLC to give 4-methyl-4-phenyl-1-m-tolyl-tetrahydro-pyrimidin-2-one (8 mg, 14%). LC-MS Method 1 tR=1.13 min, m/z=281; 1H NMR (CDCl3): 1.65 (s, 3H), 2.15-2.23 (m, 1H), 2.25 (s, 3H), 2.27-2.47 (m, 1H), 3.20-3.22 (t, 1H), 3.37-3.40 (d, 1H), 6.89-6.92 (m, 2H), 6.99-7.01 (m, 1H), 7.15-7.17 (m, 1H), 7.25-7.27 (m, 1H), 7.7.31-7.38 (m, 4H), 7.83 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][NH2:8])[CH3:3].[C:16]([S:19][CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:22](O)=[O:23])(=[O:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][NH:8][C:22](=[O:23])[C@@H:21]([CH2:20][S:19][C:16](=[O:18])[CH3:17])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH3:3]
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Reactant: CCOC(=O)C(CN)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CNC(=O)[C@@H](CSC(C)=O)Cc1ccccc1C)c1ccccc1

Procedure:
Combine α-phenyl-β-alanine ethyl ester, hydrochloride (0.40 g, 1.7 mmol) with 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.44 g, 1.77 mmol), HOBT (0.26 g, 1.7 mmol) and triethylamine (0.25 g, 2.6 mmol) in 15 ml DMF. Add EDC (0.32 g, 1.7 mmol), stir 18 hr., partion with EtOAc-water, and wash with 1N HCl, then NaHCO3. Chromatograph on silica, eluting with 1:1 Et2O-hexane, to obtain the title compound, a 1:1 mixture of diastereomers, as an oil, [α]D26 =-19.9° (EtOH).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8](/[C:11](=[N:15]\[OH:16])/[O:12][CH2:13][CH3:14])[CH2:7][C:6]=2[CH:5]=[C:4]([C:17](=[O:20])[CH2:18][CH3:19])[C:3]=1[OH:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:16]/[N:15]=[C:11](\[CH:8]1[CH2:7][C:6]2[CH:5]=[C:4]([C:17](=[O:20])[CH2:18][CH3:19])[C:3]([OH:21])=[C:2]([Cl:1])[C:10]=2[O:9]1)/[O:12][CH2:13][CH3:14])(=[O:24])[CH3:23]
Reactant: CCO/C(=N/O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1
Reactant: CC(=O)OC(C)=O
Product: CCO/C(=N/OC(C)=O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1
Yield: 89.2 %

Procedure:
5b (3.45 g, 0.011 mol) was stirred in acetic anhydride overnight. Evaporation ad trituration in ethanol gave 89.2% of white crystals, M.P. 140°-142° C. Anal. (C16H18ClNO6) C,H,N.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][CH2:7][CH2:8][OH:9].[I:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(OCC)(=O)C.O>[OH:9][CH2:8][CH2:7][NH:6][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[I:10]
Reactant: NCCO
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of sodium hydrogen carbonate (3.30 g, 39.7 mmol) and 2-aminoethanol (1.80 ml, 29.8 mmol) in ethyl acetate (25 ml) and water (15 ml) was added dropwise the solution of 2-iodobenzoyl chloride in ethyl acetate prepared above under ice-cooling, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, yield 87.6%).
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:5](=[O:8])[CH2:6][Cl:7])[CH:2]=[CH2:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:13][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OCC)OCC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN(CC1OCCCCO1)C(=O)CCl

Procedure:
N-Allyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), butandiol-1,4 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-allyl-N-(1,3-dioxepan-2-ylmethyl)-α-chloroacetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:14]([CH3:24])([CH3:23])[O:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11].O>CN1C(=O)CCC1>[Si:14]([O:15][CH2:16][CH2:17][C:18]1[CH:22]=[N:21][N:20]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH:19]=1)([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:23])[CH3:24]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn[nH]c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
A mixture of 2-chloropyridine-4-carbonitrile (1.38 g, 10 mmol), tert-butyl-dimethyl-[2-(1H-pyrazol-4-yl)ethoxy]silane (2.48 1 g, 11 mmol) in NMP (30 mL) was stirred for 5 hr at 150° C. Then the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate three times. Organic extracts collected and washed with water twice, brine and dried with anhydrous Na2SO4. It was then concentrated and purified by flash column chromatograph to give the title compound (1.2 g, 36%). [M+H] Calc'd for C17H24N4O3Si, 329; Found, 329.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:7][C:8]1[N:13]=[C:12](Cl)[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[F:26])=[C:10]([CH3:27])[N:9]=1>O1CCOCC1>[NH2:7][C:8]1[N:9]=[C:10]([CH3:27])[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[F:26])=[C:12]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:13]=1
Reactant: CCCCCN
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1F
Temperature: 100 °C
Reaction time: 50 h

Procedure:
Pentylamine (5.82 mL) was added to a solution of the product from step (iii) (3.1 g) in dioxane (50 mL). The resulting mixture was stirred at 100° C. for 50 h. The mixture was allowed to cool and then the solvent was evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 2 to 5% MeOH in DCM. to give the subtitle compound as a yellow solid 1.52 g.