Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:18]2[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
4-(Trifluoromethyl)benzoyl chloride (1.5 ml, 9.89 mmol) was added to a solution of 4-hydroxypiperidine (1 g, 9.89 mmol) and triethylamine (1.7 ml, 11.9 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, saturated sodium bicarbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-(4-trifluoromethylbenzoyl)-4-hydroxypiperidine (2.07 g, yield 77%) as a colorless crystalline powder.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1CCN2C(=NCCC2)CC1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[CH2:13]([O:12][C:10]([N:1]1[CH2:9][CH:7]([O:8][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:6][CH:2]1[C:3]([OH:5])=[O:4])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC(C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 140.6 %

Procedure:
A solution of Z-Hyp-OH (1, 300 g, 1.13 mol), TEA (395 mL, 2.83 mol), and DBU (17.2 g, 1.13 mol) in DMF (1.25 L) was stirred in a cold water bath while a suspension of TBS-Cl (188 g, 1.24 mol) in DMF (270 mL) was added slowly at 21-26° C. [Note: moderately exothermic]. The resulting thin suspension was stirred for 22 h at ambient temperature. The reaction mixture was cooled to 2° C. and quenched with water (1.54 L) at ≦26° C. [Note: the pH of the aqueous layer was 8.5-9.0]. MTBE (3 L) was added and the mixture was acidified to pH 3-4 with conc. HCl (168 g) at 17-19° C. The organic layer was separated and washed with water (2×1.5 L). The organic layer was concentrated in vacuo and dried by additional MTBE distillation. Toluene (2×500 mL) was added and distilled to remove moisture to provide 603 g of 2 as a light yellow-colored oil [Note: the water content by KF analysis was 508 ppm]. Based on drying a small sample of 2 to a solid, the contained weight of 2 was 412 g (96% yield, not corrected for purity). 1H NMR (300 MHz, CDCl3): δ7.34 (m, 3H), 7.29 (m, 2H), 5.24-5.11 (m, 2H), 4.52 (m, 1H), 4.43 (m, 1H), 3.64-3.42 (m, 2H), 2.27-2.09 (m, 2H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (75 MHz, d6-DMSO), mixture of rotomers: δ178.7, 178.4, 159.3, 158.9, 141.9, 141.8, 133.4, 133.3, 132.8, 132.6, 132.3, 131.9, 75.3, 74.6, 71.0, 71.0, 62.8, 62.3, 60.1, 59.7, 44.4, 43.4, 30.6, 30.6, 22.6, 22.6, 0.1, 0.0 ppm. Mass spectrum (ESI), m/z 379.5 [(M)+; calcd for C19H29NO5Si: 379.5].
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].[C:38]([NH:45][C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:18][C:15]1([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]2[CH:27]=[C:8]([C:6]([N:5]([CH:2]([CH3:3])[CH3:4])[C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:50]([C@@H:46]([NH:45][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH:47]([CH3:49])[CH3:48])=[O:51])[CH2:33]3)=[O:7])[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]=2[O:16]1
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.1 %

Procedure:
To N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (300 mg) were added N-Boc valine (158 mg), WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml) and chloroform (5 ml), and the mixture was stirred at room temperature overnight. After the reaction is completed, the solvent was concentrated, and the obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the desired title compound (440 mg) as white amorphous.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15]([N:18]3[CH2:23][CH2:22][CH:21](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][CH2:19]3)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1.[CH3:35][NH2:36]>CO>[Cl:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15]([N:18]3[CH2:23][CH2:22][CH:21]([NH:36][CH3:35])[CH2:20][CH2:19]3)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3cccc4c(Cl)nccc34)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(S(=O)(=O)c2cccc3c(Cl)nccc23)CC1
Temperature: 70 °C
Yield: 71 %

Procedure:
To 50 ml of dichloromethane were added 4.0 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-4-p-toluenesulfonyloxypiperidine and 1 ml of a 40% methylamine solution in methanol. The mixture was heated at 70° C. for 6 hours in a sealed vessel. Then, the dichloromethane was removed under reduced pressure to obtain an oily residue. The thus obtained oily residue was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: a 5% methanol solution in chloroform) to obtain 2.28 g of 1-(1-chloro-5-isoquinolinesulfonyl)-4-methylaminopiperidine [Compound (94)] in a yield of 71%. Compound (94) was analyzed to give the following data.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([N:3]1[CH2:4][C@@H:5]([CH3:8])[NH:6][CH2:7][C@@H:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50 g trans-2,5 dimethylpiperazine was dissolved in 300 mL ethanol and treated with 26.36 mL (½ equivalents) benzylbromide. The mixture was stirred at room temperature for 12 hours and concentrated. The residue was taken up in ethyl acetate and washed with 10% aqueous sodium bicarbonate and saturated sodium chloride; dried over anhydrous magnesium sulfate and concentrated to give crude 1-benzyl-trans-2,5-dimethylpiperazine, as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][O:8][C:9]2[C:17]3[C:16]4[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=4[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=3[N:12]=[CH:11][CH:10]=2)[CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(Cl)Cl.CO>[CH3:34][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][O:8][C:9]2[C:17]3[C:16]4[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=4[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=3[N:12]=[CH:11][CH:10]=2)[CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@@H]3CCCNC3)ccnc21
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H](COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-4-(piperidin-3-ylmethoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.1 mmol) in acetonitrile (0.5 mL) and water (0.1 mL) was added Formalin (0.024 mL, 0.3 mmol) followed by sodium triacetoxyborohydride (48 mg, 0.2 mmol). The reaction mixture was stirred for 20 minutes at ambient temperature and then basified by the addition of saturated aqueous sodium carbonate solution (1 mL), diluted with methylene chloride (50 mL) and methanol (5 mL), and washed with saturated aqueous sodium bicarbonate solution (2×15 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford a pale yellow solid, which was used in the next step without any further purification (45 mg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35](O)=[O:36])[N:27]=[C:28]([C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:21]=12.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35]([N:15]3[CH2:14][CH2:13][N:12]([C:7]4[CH:8]=[C:9]([O:10][CH3:11])[C:4]([Cl:3])=[CH:5][C:6]=4[F:18])[CH2:17][CH2:16]3)=[O:36])[N:27]=[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:21]=12
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazine dihydrochloride salt (65.2 mg, 0.206 mmol, 1 equiv), [4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid (50 mg, 1 equiv), BOP reagent (109 mg, 1.7 equiv) and N,N-diisopropylethylamine (0.165 mL, 5 equiv) in DMF (0.5 mL) was stirred at room temperature overnight. Reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) purification gave 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazin-1-yl]ethanone. MS (ES) m/z 486.5 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(CCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(R)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (169) (100 mg) was dissolved in a mixture of TFA-CH2Cl2 (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CH2Cl2, washed with sat. K2CO3, dried (Na2SO4), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1 ml). Then K2CO3 (125 mg, 3 eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70° C. for 12 hr. After cooling to room temperature, the mixture was diluted with sat. NaHCO3 (5 ml), extracted with CH2Cl2 (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel chromatography (100% CH2Cl2, 2%-4%MeOH in CH2Cl2) to give 170 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), 0.20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C22H28N2O2)+ 336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 cm−1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]([OH:16])[CH2:13][CH:14]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:22]CC1.I([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]([OH:16])[CH2:13][CH:14]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@@H](O)CNC(=O)OCc1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=CC[C@@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 133 %

Procedure:
A mixture of ((R)-2-hydroxy-pent-4-enyl)-carbamic acid benzyl ester (690 mg, 2.35 mmol), osmium(VIII) oxide (4% solution in water, 0.22 mL, 35 μmol), and 4-methyl-morpholine-4-oxide (50% solution in water, 0.27 mL, 1.29 mmol) in acetone/THF/water 6:2:1 (6 mL) was stirred for 45 min at RT, then sodium metaperiodate (1.51 g, 7.04 mmol) was added, then after 16 h 10% aq. sodium sulfite solution (5.5 mL) was added. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (407 mg, 73%) as a brown gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1
Reactant: CC1(C)OB(c2cncc(O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1-c1cncc(O)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.31 mmol) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol (102 mg, 0.46 mmol), (1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 25 mg, 0.03 mmol) and a 2M aqueous solution of cesium carbonate in dioxane (462 μl). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 56 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[C:36](Cl)=[O:37]>CCOC(C)=O>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[C:3]1[S:4][C:35](=[O:39])[C:36](=[O:37])[N:5]=1
Reactant: CN(C(N)=S)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C1=NC(=O)C(=O)S1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
To a flask containing EtOAc (30 mL) was added 1-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)thiourea (0.600 g, 1.52 mmol) and triethylamine (510 μl, 3.66 mmol). A solution of oxalyl chloride (467 mL, 5.34 mmol) in EtOAc (24 mL) was added and the solution was stirred at ambient temperature for 15 min Evaporation of solvent in vacuo left a white-yellow solid which was dissolved in 50 mL of dichloromethane and washed with water (3×25 mL). The organic layer was dried (MgSO4) and concentrated to furnish 2-(methyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)thiazole-4,5-dione as an orange solid (632 mg, 92%): mp 114-118° C.; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.36 (d, J=8.7 Hz, 2H), 7.82 (d, J=9.1 Hz, 2H), 7.50-7.34 (m, 4H), 3.82 (s, 3H); ESIMS m/z 448 ([M+H]+).
Reaction SMILES: [CH3:1][N:2](N=O)/[C:3](/[NH2:8])=[N:4]/[N+:5]([O-:7])=[O:6].NC[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:1][NH:2][C:3]([NH:4][N+:5]([O-:7])=[O:6])=[NH:8])[CH2:19][CH2:18]2)=[CH:28][CH:29]=1
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: CCO
Product: N=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 1.5 parts of N-methyl-N'-nitro-N-nitrosoquanidine, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine and 80 parts of ethanol 50% was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried overnight at 110° C., yielding 1.5 parts (33%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-nitroguanidine; mp. 146.7° C. (compound 23).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)C>Cl.O>[CH:17]1([N:7]2[CH2:8][CH:9]([CH2:15][CH3:16])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC1CN(C2CCCC2)c2nc(Cl)ncc2N(CC)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(CC)C1=O
Yield: 62.8 %

Procedure:
A mixture of 0.042 g (0.00013 mole) of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5-ethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-14), 0.026 g (0.00016 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.037 g of (rac)-4-(9-cyclopentyl-5,7-diethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-14) as an off-white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3=[N:30][N:31]=[C:32]([S:33][CH3:34])[N:22]3[N:21]=2)=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3=[N:30][N:31]=[C:32]([S:33]([CH3:34])=[O:9])[N:22]3[N:21]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2nn3c(SC)nnc3c3ccccc23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(S(C)=O)nnc3c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Chloroperbenzoic acid (2.2 g) is added to a solution of 6-(4-methoxyphenyl)-3-(methylthio)-1,2,4-triazolo[3,4-a]phthalazine (4 g) in methylene chloride (120 ml) and the obtained mixture is stirred at room temperature for 5 hours. The solution is washed with sodium metabisulfite first and then with sodium bicarbonate. The organic solution is then dried over MgSO4 and concentrated to dryness by evaporating off the solvent. The residue thus obtained is crystallized from ethanol yielding 4 g of the compound of the title. M.p. 201°-03° C.
Reaction SMILES: [Na+].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([S:20]([O-:23])(=O)=[O:21])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:4])[CH3:3].S(Cl)([Cl:26])=O>CN(C=O)C>[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([S:20]([Cl:26])(=[O:23])=[O:21])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 14.4 g. (0.0416 mole) of 2,3-diacetoxy-7-naphthalenesulfonic acid sodium salt, 150 ml. of thionyl chloride and 1 ml. of DMF was stirred 1 hr. at room temperature and 1 hr. at reflux, cooled to room temperature and poured into 1 l. of petroleum ether. The solid was collected, washed with petroleum ether and dried to give 11.3 g. (79.9%) of cream-colored product, m.p. 158°-167° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH2:67])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]>O.CN(C=O)C>[NH:52]1[CH:53]=[CH:54][N:50]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[N:65]=[C:64]([NH:67][C:13]([C:12]3[CH:11]=[N:10][CH:9]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:16]=3)=[O:15])[NH:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cncc(Oc2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(Oc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
0.07 g (0.30 mmol) of 5-phenoxy-nicotinic acid and 0.12 g (0.32 mmol) of HBTU were combined in a flask charged with 2 mL of DMF and 0.25 mL of DIEA. The reaction mixture was then treated with 0.05 g (0.20 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg (11%) of 2-[(5-phenoxy-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 441 (M+1)+.