Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]([OH:37])[C:33]([F:34])([F:35])[F:36])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:34])([F:35])[F:36])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: Cc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(Cc2ccccc2)C(=O)C(F)(F)F)cc1
Product: Cc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(Cc2ccccc2)C(O)C(F)(F)F)cc1

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 4, 3.00 g, 7.63 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.76 g, 8.03 mmol), WSCI hydrochloride (1.76 g, 9.18 mmol) and HOBT (2.06 g, 15.2 mmol) in DMF (25 mL) to give 4.23 g (93%) of the target compound as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[ClH:10].[C:11]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[NH:12][NH2:13]>C(O)C>[ClH:10].[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:13][NH:12][C:11]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH3:2])=[CH:5][CH:6]=1
Reactant: NNC(=O)Oc1ccccc1
Reactant: CC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=O)Oc1ccccc1)c1ccncc1
Yield: 96.4 %

Procedure:
A mixture of 12.11 gm (0.1 mole) of 4-acetylpyridine, 18.85 gm (0.1 mole) of phenyl carbazate hydrochloride and 250 ml of absolute ethanol is refluxed 6 hr and cooled. The reaction mixture is evaporated to dryness in vacuo to give a rose-colored solid. The crude product is crystallized from absolute ethanol to yield 28.13 gm (97%) of the title compound having a melting point of 159.1° C.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](O)=[O:13].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12]([Cl:25])=[O:13]
Reactant: C#CCOc1c(F)cc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Temperature: 25 °C

Procedure:
To 17 ml of toluene were added 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid, 1 ml of thionyl chloride and 10 mg of DMF, and the resulting mixture was heated to reflux for 4 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was concentrated under reduced pressure, and 1.9 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: CC(C)COC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.N1C=CC=CC=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[SH:33].BrBr>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6][C:7]2[N:12]=[C:11]([OH:13])[C:10]([S:33][C:29]3[S:28][CH:32]=[N:31][N:30]=3)=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Reactant: Sc1nncs1
Agent: BrBr
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1Sc1nncs1
Reaction time: 1 h

Procedure:
The product of Example 3 (0.12 g), pyridine (50 μl) and 1,3,4-thiadiazole-2-thiol (0.18 g) were dissolved in DMF (3 ml) and bromine (18 μl) added dropwise. The reaction mixture was stirred for 1 h before being purified directly by reverse phase HPLC (95-75% 0.02M ammonium hydroxide/acetonitrile) to yield the title product as a white solid. Yield 0.15 g.
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CNC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25 can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O.CC(C)=O>C(Cl)(Cl)Cl>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
To a suspension of 3a in chloroform were added 4 equivalents of oxalyl chloride followed by 0.1 equiv. of dimethylformamide. The solution was refluxed for 3 hours and was quenched with 5 M sodium hydroxide solution at 4° C. The chloroform layer was collected, washed with 100 mL water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Product was obtained by recrystallization using acetone. 1H-NMR (CDCl3) δ (ppm): 1.48 (3H, t, J=7.08 Hz), 4.55 (2H, q, J=7.08 Hz), 8.31 (1H, d, J=9.27 Hz), 8.62 (1H, m), 9.36 (2H, m). m/z 281.7 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH3:2].C1COCC1>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc(/C=C/C(=O)O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc(CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (2E)-3-{3-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]phenyl}acrylic acid (10.40 g) in a mixed solvent(THF:EtOAc=150 mL:100 mL) was added 10% Palladium on activated carbon (50% wet, 1.6 g) at ambient temperature. The reaction mixture was stirred under hydrogen atmosphere at ambient temperature for 5 hours and was filtered through celite. The filtrate was evaporated in vacuo to afford 3-[3-(3-ethoxy-3-oxopropyl)phenyl]propanoic acid (10.57 g) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][C:21]([OH:23])=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.S(O)(O)(=O)=O.[NH2:41][C:42]([NH2:44])=[NH:43].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][C:21]([NH:43][C:42]([NH2:44])=[NH:41])=[O:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)N
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC(=O)CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid (0.30 grams, 0.80 mmole) and carbonyl diimidazole (0.13 gms, 0.90 mmole) in 30 mL DMF was stirred for three hours at room temperature. Guanidine sulfate (90 mg) was added, followed by 0.1 ml diisopropylethylamine, and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and the resulting white crystals were collected by filtration, washed with water, and dried under vacuum to afford 190 mg of N-[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-guanidine, M+H=372.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].Cl[CH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[O:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].N[C@H:28](C(O)=O)[CH2:29]C1C=C2C(C=CC=C2)=CC=1>CC#N>[CH2:28]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([O:1][CH2:14][C:15]2[CH:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH:3]=1)[CH3:29]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Cc1cc(CCl)no1
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OC)c(OCc2cc(C)on2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxy-4-methoxy-benzoic acid (2.00 g, 10.2 mmol), 3-(chloromethyl)-5-methylisoxazole (1.61 g, 12.2 mmol; commercially available from Maybridge, SPB01262DA), anhydrous K2CO3 (2.11 g, 15.3 mmol) and Nal (0.31 g, 2.04 mmol) in MeCN (35 mL) is refluxed overnight. After cooling to room temperature, the mixture is filtered, the filtrate is diluted with CH2Cl2 and the organics are washed with aqueous 0.5M NaOH, water and brine. Drying over Na2SO4 and evaporation to dryness affords the crude title compound as oil. MS: 292.0 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.14 min. 1H-NMR (CDCl3): δ 1.39 (t, 3H), 2.45 (s, 3H), 3.93 (s, 3H), 4.35 (q, 2H), 5.20 (s, 2H), 6.15 (s, 1H), 6.15 (dd, 1H), 6.90 (d, 1H), 7.70 (dd, 1H) ppm.
Reaction SMILES: [C:1]([OH:6])(CC)(C)C.NC1C=CN=CC=1.[CH3:14][O:15][CH2:16][C@H:17]1[O:19][CH2:18]1.[C]=O.[CH3:22][OH:23]>>[CH3:22][O:23][C:1](=[O:6])[CH2:18][C@H:17]([OH:19])[CH2:16][O:15][CH3:14]
Reactant: CCC(C)(C)O
Reactant: CO
Reactant: COC[C@@H]1CO1
Agent: Nc1ccncc1
Agent: [C]=O
Product: COC[C@@H](O)CC(=O)OC
Temperature: 25 °C
Yield: 92 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated methanol (10 mL) and t-amyl alcohol (10 mL), and thereto were added 4-aminopyridine (47 mg, 0.5 mmol) and (S)-methylglycidyl ether (1.8 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (1 MPa) was introduced therein and the mixture was reacted at 40° C. for 8 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (S)-4-methoxy-3-hydroxybutanoic acid methyl ester (2.7 g, 92%, >99% ee) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].O.[H][H]>C(O)(=O)C>[CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([CH:7]2[NH:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21

Procedure:
A solution of 1.2 g 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione in 75 ml acetic acid and 10 ml water containing 100 mg 5% palladium on carbon is shaken in an atmosphere of hydrogen at a pressure of 10 psi and room temperature. One equivalent of hydrogen is absorbed in 75 minutes. The mixture is filtered, and the filtrate concentrated under reduced pressure. To the residue is added toluene which is then removed in vacuo. This is repeated. To the gummy residue is added a small volume of acetonitrile to give the desired 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione as a crystalline solid identical to that prepared in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 69.5 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)ethanol (0.134 g, 0.89 mmol) and 4M HCl in dioxane (0.222 mL, 0.89 mmol) in EtOH was heated for 2.5 h at 85° C. After this time, the mixture was neutralized with NaHCO3 at 0° C. and purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.145 g, 70%) as a yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 9.53 (s, 1H), 8.33-8.28 (m, 2H), 7.62-7.55 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 4.62 (t, J=5.2 Hz, 1H), 3.63-3.59 (m, 2H), 2.72-2.64 (m, 4H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 354 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1ccccc1N1CCN(CCNc2ccccc2[N+](=O)[O-])CC1
Reaction time: 32 h
Yield: 32.1 %

Procedure:
A mixture of 3.03 g of 2-chloronitrobenzene, 4.52 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine, and 3.18 g of anhydrous potassium carbonate in 30 mL of n-butanol was stirred for 32 h at reflux. After cooling, the mixture was poured into H2O, then extracted with EtOAc and the organic phase dried on Na2SO4. The crude obtained by evaporating the solvent was purified by flash chromatography (EtOAc-petrolium ether 4:6) and the residue obtained after evaporation of the solvents was taken up with Et2O, stirred and filtered giving 2.2 g (31%) of the title compound. Melting point: 117-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.[CH3:23][O:24][NH:25][CH3:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:19]([N:25]([O:24][CH3:23])[CH3:26])=[O:21])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)N(C)OC)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (1 g, 3.171 mmol), N-methoxymethanamine hydrochloride (371.2 mg, 3.805 mmol) and triethylamine (705.9 mg, 972.3 μL 6.976 mmol) were dissolved in DMF (10 mL) and treated with TBTU (1.527 g, 4.756 mmol). The mixture was allowed to stir at ambient temperature for 1 hour. The reaction was treated with water, extracted with EtOAc (4×), and the organics separated, dried (MgSO4) and concentrated. The resultant residue was purified on silica gel by flash column chromatography (0-100% EtOAc/Petrol) to afford the title compound as a yellow solid (864 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 1.21 (t, 3H), 3.10 (q, 2H), 3.27-3.30 (m, 4H), 3.34 (s, 3H), 3.38-3.40 (m, 4H), 3.68 (s, 3H), 5.87 (br s, 2H) and 7.99 (s, 1H) ppm; MS (ES+) 359.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:28]2[CH2:34][CH:31]([CH2:32][CH:33]=1)[CH2:30][CH2:29]2)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH:28]3[CH2:34][CH:31]([CH2:32][CH:33]=2)[CH2:30][CH2:29]3)=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: O=S(=O)(OC1=CCC2CCC1C2)C(F)(F)F
Product: COC(=O)c1ccc(C2=CCC3CCC2C3)c(C)c1
Yield: 57.6 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (0.300 g, 1.09 mmol) and bicyclo[3.2.1]oct-2-en-2-yl trifluoromethanesulfonate (0.336 g, 1.31 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 5% ethyl acetate in hexane, afforded the title compound (0.161 g) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[CH:12][C:11]=2[CH3:17])[CH2:4][O:3]1.[SH:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[OH-].[Na+].[CH3:31]O>>[CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:11]([CH3:17])=[CH:12][N:13]=[C:14]([CH2:31][S:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:15]=2[CH3:16])[CH2:4][O:3]1
Reactant: Cc1cncc(C)c1OCC1COC(C)(C)OC1
Reactant: CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 84.9 %

Procedure:
To a mixture of 2-(chloromethyl)-(4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridine (837 mg, 2.79 mmol), 2-mercaptobenzimidazole (419 mg, 2.79 mmol) and sodium hydroxide (223 mg, 5.58 mmol), methanol (20 ml) was added and the mixture was stirred at room temperature for 12 hours and 55 minutes. The reaction mixture was concentrated under reduced pressure. Toluene and a 0.1N aqueous sodium hydroxide solution were added to the residue and insoluble substance was removed by filtration, and then, the organic layer was taken out. The aqueous layer was extracted again with toluene. The organic layers were combined and washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (980 mg, 84.9%) as a white foam.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C(#N)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][C:13]=1[O:12][CH2:8][CH2:9][CH2:10][O:4][CH3:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(CO)ccc1OC

Procedure:
Potassium carbonate (272.3 g) and 1,3-dibromopropane (1.34 liters) are added to a solution of 3-hydroxy-4-methoxy-benzaldehyde (200 g) in acetonitrile and the white suspension is stirred under reflux for 19 hours. After cooling, the mixture is filtered, the solvent and excess 1,3-dibromopropane are removed under reduced pressure and the residue is purified by FC on silica gel (ethyl acetatelhexane 1:3). The title compound is obtained in the form of a white solid (334 g): Rf (ethyl acetate/hexane 1:1)=0.50. Anal. C11H13BrO3 (273.13): calc. C, 48.37; H, 4.80; Br, 29.26; found C, 48.61; H, 4.84; Br, 29.19.
Reaction SMILES: Cl.[NH2:2][OH:3].ClC(Cl)(Cl)C([O:8][CH2:9][CH3:10])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>O.Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:9](=[O:8])[CH:10]=[N:2][OH:3])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: NO
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(F)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
Hydroxylamine hydrochloride (22.24 g, 320 mmol) in water (50 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (23.21 g, 120 mmol) and sodium sulfate (128 g, 900 mmol) in water (150 mL) and 2N HCl (100 mL). The mixture was stirred at 60° C. for 20 min. 3-Chloro-4-fluoroaniline (14.56 g, 100 mmol) in 2N HCl (100 mL) was added, and the mixture was heated to 90° C. for 2 h. The mixture was cooled to room temperature. The solid was collected by filtration, washed with water, and air dried to afford N-(3-chloro-4-fluorophenyl)-2-(hydroxyimino)ethanamide (19.45 g, 90% yield). This material was used in the next step without further purification.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.O.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[N:1]#[N:2].[C:31]1([CH3:41])[CH:32]=[CH:33][C:34]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[CH2:41]([O:28][C:27](=[O:29])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])[NH:18][S:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCc3ccccc3)cc2c1
Yield: 94 %

Procedure:
A mixture of 1.0 gram of N2 -(7-methoxy-2-naphthalenesulfonyl) -L-arginine, 1.0 gram of p-toluenesulfonic acid monohydrate in 5 ml of benzyl alcohol and 30 ml of benzene was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue, giving a cystalline mass of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine benzyl ester p-toluenesulfonate in 94% yield; mp. 115° - 117°C.