Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH2:25][CH2:24]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: Cl
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N2CCCC2=O)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-pyrrolidine-2-one, hydrochloride, preparative HPLC (Method C) (55%, semi-crystaline oil). HPLC-MS m/z=450.1 (M+1), Rt: 3.81 min.
Reaction SMILES: C[N:2](C)C1SC(C2N(C)C([N+]([O-])=O)=CN=2)=NN=1.CNC1SC(C2N(C)C([N+]([O-])=O)=CN=2)=NN=1.[NH2:34][C:35]1[S:36][C:37]([C:40]2[N:41]([CH2:48][CH2:49]O)[C:42]([N+:45]([O-:47])=[O:46])=[CH:43][N:44]=2)=[N:38][N:39]=1>>[NH2:34][C:35]1[S:36][C:37]([C:40]2[N:41]([CH2:48][CH3:49])[C:42]([N+:45]([O-:47])=[O:46])=[CH:43][N:44]=2)=[N:38][N:39]=1.[CH2:48]([N:41]1[C:42]([N+:45]([O-:47])=[O:46])=[CH:43][N:44]=[C:40]1[C:37]([NH:38][NH:39][C:35]([NH2:34])=[S:36])=[NH:2])[CH3:49]
Reactant: CN(C)c1nnc(-c2ncc([N+](=O)[O-])n2C)s1
Reactant: Nc1nnc(-c2ncc([N+](=O)[O-])n2CCO)s1
Agent: CNc1nnc(-c2ncc([N+](=O)[O-])n2C)s1
Product: CCn1c([N+](=O)[O-])cnc1-c1nnc(N)s1
Product: CCn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
In a similar manner, 4,4-dimethyl-1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide, 4-methyl-1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide and 1-(1-[2-hydroxyethyl]-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide yield respectively, 2-(2-dimethylamino-1,3,4-thiadiazol-5-yl)-1-methyl-5-nitroimidazole (VIIIE), 2-(2-methylamino-1,3,4-thiadiazol-5-yl)-1-methyl-5-nitroimidazole (VIIIC) and 2-(2-amino-1,3,4-thiadiazol-5-yl)-1-(2-hydroxyethyl)-5-nitroimidazole (VIIID). According to the above procedure, 2-(2-amino-1,3,4-thiadiazol-5-yl)-1-ethyl-5-nitroimidazole (VIIIE) is obtained from 1-(1-ethyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12](CC3C=CC(OC)=CC=3)[S:11]2(=[O:27])=[O:26])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:15][C:13]1([CH3:16])[NH:12][S:11](=[O:27])(=[O:26])[N:10]([C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:14]1
Reactant: COc1ccc(CN2C(C)(C)CN(c3cc(F)ccc3C#N)S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CN(c2cc(F)ccc2C#N)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 4-fluoro-2-(5-(4-methoxybenzyl)-4,4-dimethyl-1,1′-dioxido-1,2,5-thiadiazolidin-2-yl)benzonitrile (4.6 g, 11.81 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (2.73 mL, 35.4 mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with methanol and the white solid collected by filtration and discarded. The cloudy solution was concentrated and the resulting solid was triturated with methanol and then filtered to give the title compound as a white solid (3.18 g, 100% yield). LCMS (M+H) calcd for C11H13FN3O2S: 270.07; found: 270.00. 1H NMR (300 MHz, CDCl3) δ: 7.66 (0.2H, dd, J=8.8, 5.8 Hz), 7.58 (1H, dd, J=9.5, 2.6 Hz), 7.10-7.04 (1H, m), 4.48 (1H, brs), 3.85 (2H, s), 1.55 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (S)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((S)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (773 mg, 2.95 mmol), 4-nitrobenzoic acid (493 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.55 ml, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for four hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (595 mg, yield: 89%/(S)-1-phenylethyl alcohol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][N:6]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([O-:34])(=[O:33])C.[K+].[CH3:36]O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:31]([O:34][CH3:36])=[O:33])[C:3]=2[CH:4]=[N:5][N:6]=1
Reactant: CO
Reactant: Brc1cccc2cnncc12
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cnncc12
Temperature: 100 °C
Yield: 32 %

Procedure:
To a 140 mL pressure flask was added 5-bromophthaiazine (3.5 g, 17 mmol), palladium (II) acetate (0.98 g, 4.4 mmol), triphenylphosphine (1.3 g, 5.0 mmol), potassium acetate (2.1 g, 21 mmol), MeOH (20 mL) and DMF (20 mL). The flask was sealed and purged with CO (3×). The flask was charged with CO to 40 PSI and stirred at 100° C. 15 hours. The suspension was filtered through Celite, the cake was washed with MeOH, and the filtrate was concentrated. The residue was taken up in DCM and washed with saturated sodium bicarbonate (2×), saturated sodium chloride (2×) and water (2×). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was adsorbed on to a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of EtOAc in hexane to provide methyl phthalazine-5-carboxylate (1.0 g, 32%). LCMS (M+H) 189.2 calc. for C10H9N2O2 189.1. 1H NMR (400 MHz, CDCl3): δ ppm 4.05 (s, 3H) 8.06 (d, J=8.41 Hz, 1H) 8.51-8.56 (m, 1H) 8.71 (d, 1H) 9.64 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].CCN(C(C)C)C(C)C>Cl[Pd]Cl.CN(C)C=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(O)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3-(trifluoromethyl)phenol (5 g, 20.75 mmol, 1.00 equiv), N,N-dimethylformamide (60 mL), ethyl prop-2-enoate (10.5 g, 104.88 mmol, 5.06 equiv), PdCl2 (370 mg, 2.09 mmol, 0.10 equiv), P(tolyl)3 (1.28 g, 4.21 mmol, 0.20 equiv), DIEA (16.25 g). The resulting solution was stirred for overnight at 90° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/8). This resulted in 2.6 g (42%) of ethyl (2E)-3-[4-hydroxy-2-(trifluoromethyl)phenyl]prop-2-enoate as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:43])[O:11][CH2:12][C:13]2([C:32](=[O:42])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:43])[O:11][CH2:12][C:13]2([C:32](=[O:42])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of (S)-(1-(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 0.22 mmol) in CH3OH (1 mL) was added 4M HCl in dioxane (200 μL, 0.8 mmol, 3.6 equiv.), which was stirred for 2 h. The reaction mixture was concentrated to dryness by co-evaporating with toluene to give (S)-(1-(2-amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (130 mg, quant.). LRMS (M+H+) m/z 557.1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24]1(C)[C:25]([S:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14]([S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)=[O:31])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: Cc1ccccc1S(=O)Cl
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CO[C@@H]1C=C[C@@H](S(=O)c2ccccc2)C1)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (0.4 g; 1.6 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. in an icebath under a nitrogen atmosphere. Triethylamine (0.3 g; 2.9 mmol) was then added followed by a solution of toluenesulfinyl chloride (0.4 g, 2.9 mmol)in CH2Cl2 (2 mL). The reaction mixture was stirred at 0° C. for 1 hr. The ice bath was removed and the reaction mixture concentrated in vacuo. The residual oil was purified by flash column chromotography with 2% methanol/98% dichloromethane as eluent. The product(0.54 g; 87%) was isolated as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C1([Li])C=CC=CC=1.[CH3:22][N:23]=[C:24]=[S:25].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:22][NH:23][C:24](=[S:25])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CN=C=S
Reactant: c1ccc(CCN2CCOCC2)nc1
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CNC(=S)C(CN1CCOCC1)c1ccccn1
Reaction time: 0.5 h

Procedure:
N-[2-(2-pyridyl)ethyl]morpholine (12.7 g., 0.07 mole) in 60 ml. of dry benzene is added dropwise to 35 ml. of 2M phenyl lithium (0.07 mole) in benzene/ether with cooling. The mixture is stirred for 30 minutes, then methyl isothiocyanate (5.2 g., 0.07 mole), dissolved in 60 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% hydrochloric acid. The phases are separated, the organic phase is washed with water, and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from ethyl acetate to give N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH2:13])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[F:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH2:30][F:31])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:32])[C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH:13][C:17](=[O:18])[C:16]4[C:20]([F:32])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH2:30][F:31])(=[O:26])=[O:27])[C:15]=4[F:14])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Reactant: Nc1cnc2[nH]nc(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2[nH]nc(C3CC3)c2c1)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
3-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.024 g, 0.138 mmol), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.045 g, 0.151 mmol), EDCI (0.029 g, 0.151 mmol) and HOBt (0.019 g, 0.138 mmol) were dissolved in DMF (0.52 mL) and stirred at room temperature for 16 hours. The reaction mixture was purified by reverse phase HPLC to give N-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(3-fluoropropylsulfonamido)benzamide (0.031 g, 50%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.17 (s, 1H), 11.06 (s, 1H), 9.92 (br s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.60-7.54 (m, 1H), 7.28 (t, 1H), 4.62 (t, 1H), 4.51 (t, 1H), 3.29-3.23 (m, 3H), 2.33-2.26 (m, 1H), 2.19-2.09 (m, 2H), 1.01-0.93 (m, 3H); m/z (ES-MS) 454.2 (100.0%) [M+1].
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH:3]([CH3:5])C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC1C=C[CH:37]=[C:36]([Cl:40])[CH:35]=1>>[Cl:40][C:36]1[CH:35]=[C:2]([CH:3]=[CH:5][CH:37]=1)[CH2:1][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Agent: O=Cc1c(O)ccc2ccccc12
Product: O=Cc1c(OCc2cccc(Cl)c2)ccc2ccccc12

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH:19]([CH3:22])[CH2:18][C:17](=[O:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Reaction time: 0.1 h
Yield: 65.6 %

Procedure:
To a solution of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.41 g, 3.89 mM) in 13 ml dioxane was added 60% sodium hydride in mineral oil (0.36 g, 8.95 mM). The reaction was stirred 6 minutes, then methyl benzenesulfinate (0.81 ml, 6.22 mM) was added. The reaction was stirred an additional 6 hours, then diluted with 20 ml dioxane and 0.51 ml acetic acid. The mixture was refluxed 30 minutes, diluted with ethyl acetate, and extracted with saturated NaHCO3, brine, then water. After drying (NaSO4), evaporation in vacuo afforded 2.30 g. The mixture was purified by column chromatography on silica gel (elution with toluene/methylene chloride) to afford 0.92 g (66%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.05 (d, J=8 HZ, 1H), 6.9 (s, 1H), 6.85 (d, J=8 Hz, 1H), 6.75 (s, 1H), 6.7 (s, 1H), 5.45 (s, 2H), 4.1 (s, 3H), 2.4 (s, 3H), 2.25 (s, 3H). MS (ES) m/e 328, 360.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C-:8]#[N:9].[Na+].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O.CCCCCC>[C:2]([NH:6][NH:7][C:11]1([C:8]#[N:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: [C-]#N
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NNC1(C#N)CCCCC1
Reaction time: 2 h

Procedure:
To a rapidly stirred solution of 62.4 grams (0.50 moles) of t-butylhydrazine hydrochloride and 25.8 grams (0.525 moles) of sodium cyanide in 450 ml of water in a 11/2 liter jacketed resin reactor equipped with a thermometer, mechanical stirrer, condenser and dropping funnel was added 49 grams (0.5 moles) of cyclohexanone. The reaction mixture exothermed to about 35°C. The reaction was then warmed to 45°-50°C by circulating hot water through the jacket. The reaction was stirred 11/2 hours at 45°-50°C and then 100 ml of hexane was added to dissolve the solid hydrazo. The temperature had to be kept at 40°C or above to completely dissolve the hydrazo in the hexane. The aqueous layer was separated into 10% sodium hydroxide and set aside in the hood for detoxicafication by sodium hypochlorite solution. The hexane solution was washed with 400 ml of warm water and the wash separated at 40°C or above. A small sample of the hexane solution was dried, the hexane evaporated and an infrared spectrum run on the resultant solid. The infrared spectrum contained strong NH bands and a cyano band and did not contain any carbonyl or imino bands. Thus, the infrared spectrum was consistent with the structure of the desired product.
Reaction SMILES: C[O-:2].Cl.NO.[CH3:6][C:7]1[CH:8]=[C:9]([C:15]#[N:16])[CH:10]=[N:11][C:12]=1[S:13][CH3:14]>CO>[CH3:6][C:7]1[CH:8]=[C:9]([C:15]([NH2:16])=[O:2])[CH:10]=[N:11][C:12]=1[S:13][CH3:14]
Reactant: CSc1ncc(C#N)cc1C
Reactant: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CSc1ncc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 168 h
Yield: 74.7 %

Procedure:
To a stirred s odiu m methoxide solution (25 wt % in methanol; 10.53 g, 48.7 mmol) diluted in dry methanol (100 mL) at room temperature under a nitrogen atmosphere was added hydroxylamine hydrochloride (3.38 g, 48.7 mmol) and 5-methyl-6-methylthio-3-pyridinecarbonitrile (2.00 g, 12.2 mmol). The white suspension was stirred at room temperature for 7 days, when it was evaporated in vacuo. The crude white solid was chromatographed on silica gel (25% EtOAc/pentane) yielding the desired product (1.66 g, 75%) as a white fluffy powder.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.[N-:20]=[C:21]=O>C(OCC)(=O)C>[CH2:1]([NH:10][C:11]([N:7]1[CH2:6][CH2:5][CH2:4][N:20]([CH3:21])[CH2:8]1)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([N:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH2:15]1)=[O:9]
Reactant: [N-]=C=O
Reactant: CN1CCCNC1
Reactant: O=C=NCCCCCCN=C=O
Solvent: CCOC(C)=O
Product: CN1CCCN(C(=O)NCCCCCCNC(=O)N2CCCN(C)C2)C1

Procedure:
168 g of hexamethylenediisocyanate in 150 ml of ethyl acetate are slowly added to a mixture of 224 g of N-methylhexahydropyrimidine and 150 ml of ethyl acetate cooled to temperatures of from 15° to 20° C. Stirring is continued at room temperature after all the diisocyanate has been added until the isocyanate band in the IR spectrum has disappeared (after about 2 hours). The solvent is removed on a thin layer evaporator at 110° C. under a vacuum produced by a water jet pump. The viscous product preferentially consists of the following bis-hexahydropyrimidine derivative: ##STR18##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[C:6]2=[O:20].C(OC([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=O)(C)(C)C.C([O-])(O)=O.[Na+].CN(C=O)C>C(#N)C.C(OCC)(=O)C>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:3]=[CH:4]3)[CH2:14][CH2:15]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(N2CCNCC2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.69 mmol), N-(tert-butoxycarbonyl)-piperazine (256 mg, 1.38 mmol) and NaHCO3 (259 mg, 14.64 mmol) in ACN (8.6 mL) was heated in a microwave at 120° C. for 20 min. DMF (2 mL) was added to the mixture and the reaction was heated in a microwave at 120° C. for 20 min. Then the reaction was heated in a microwave at 130° C. for 30 min twice. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL). After extraction of the aqueous phase with ethyl acetate (2×30 mL), the organic phases were combined washed with brine, dried with magnesium sulfate, filtrated, and concentrated. The residue was dissolved in TFA (1 mL) and agitated for 1 hour prior to evaporation of the solvent. The residue was dissolved in THF (1 mL) and an aqueous 4M NaOH solution (0.79 mL) and heated in a microwave at 120° C. for 10 min. More aqueous 4M NaOH solution (0.5 mL) was added and the reaction was heated in a microwave at 120° C. for 10 min. The mixture was evaporated and the residue purified by preparative HPLC. The title compound EXAMPLE 34 was obtained after lyophilization (28 mg, 12.5%). High-Res MS: calculated 328.1656 (M+H)+. found 328.1642 (M+H)+.