Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:61][C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH2:74])[CH2:70][CH2:69]1)=[O:67])([CH3:64])[CH3:63]>ClCCl.CN(C)C=O>[C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:7]4[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]=4[N:19]=3)=[CH:22][CH:23]=2)[CH2:70][CH2:69]1)=[O:67])([CH3:61])([CH3:63])[CH3:64]
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A mixture of 0.093 g (0.23 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.093 g (0.92 mmole) of triethylamine, 0.133 g (0.35 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.070 g (0.35 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.075 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[C:42]([OH:46])(=[O:45])[CH:43]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:43][C:42]([OH:46])=[O:45])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=CC(=O)O
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CN1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.25 mmol; see Example 88) in methanol (1 mL) was added glyoxylic acid (0.5 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (0.6 mmol), and the stirring was continued at RT for 10 h. To the reaction mixture was then added a few drops of glacial acetic acid, and the mixture was stirred for 30 min. The volatiles were then removed in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford {4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}acetic acid as a white solid. MS: m/z 579 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH2:28][NH2:29])[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:36](OC(=O)C)(=[O:38])[CH3:37]>O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH2:28][NH:29][C:36](=[O:38])[CH3:37])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1nc(CN)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1nc(CNC(C)=O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 92.9 mg (0.22 mmol) sample of 5-[4′-[(5-butyl-3-methylamine-1H-1,2,4-triazol-1-yl)methyl]-(1,1′-biphenyl-2-yl]-1H-tetrazole hydrochloride from Example 27 was dissolved in 5 ml of water and the pH was adjusted to 9 with 1M potassium carbonate (K2CO3). The solution was cooled to 0° C. and 0.22 ml of 1M K2CO3 was added followed by 0.22 mmol of acetic anhydride. Additional K2CO3 was added as needed to maintain a pH of 9. At 30 min intervals, this addition was repeated until analytical reverse phase chromatography showed that all starting material has been consumed. The pH was adjusted to three with 1N HCl and extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the product lyophilized from acetonitrile/water providing 36 mg (39%) of N-[[5-butyl-1-[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]acetamide as a colorless solid: NMR (CDCl3) δ0.80 (t, J=8 Hz, 3H), 1.18–1.37 (m, 2H), 1.47–1.64 (m, 2H), 1.94 (s, 3H), 2.63 (t, J=8 Hz, 2H), 4.22 (d, J=8 Hz, 2H), 5.18 (s, 2H), 6.95 (d, J=8 Hz, 2H), 7.04–7.21 (m, 2H), 7.44 (d, J=8 Hz, 1H), 7.50–7.66 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 431 (42), 207 (100); HRMS. Calc'd for M+H: 431.2308. Found: 431.2271.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:55][CH2:56][C:57]1[C:58](=[O:65])[NH:59][C:60]([CH3:64])=[CH:61][C:62]=1[CH3:63]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:55][CH2:56][C:57]1[C:58](=[O:65])[NH:59][C:60]([CH3:64])=[CH:61][C:62]=1[CH3:63])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCOCC1
Yield: 63.1 %

Procedure:
To a solution of 5-chloro-2-ethyl-3-[ethyl(oxan-4-yl)amino]benzoic acid (100 mg, 0.32 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (146 mg, 0.38 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (84 μl, 0.48 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 60.3 mg, 0.35 mmol). After stirring for 3 hours at room EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% EtOAc to 97:3 EtOAc:MeOH) to give 90 mg (63%) of the title compound as a white solid. LC-MS 97%, m/z=446.1/448.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.93 (s, 1H), 7.14 (t, J=5.7 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.30 (td, J=11.3, 3.6 Hz, 2H), 3.01 (q, J=7.0 Hz, 2H), 2.93 (ddd, J=15.3, 10.0, 5.3 Hz, 1H), 2.83 (q, J=7.4 Hz, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.71-1.63 (m, 4H), 1.02 (t, J=7.5 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:29]([O-])=O.[Na+]>Cl.O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=4)[N:10]=3)=[CH:3][C:2]=2[N:1]=[N:29]1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N3CCC[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of (S)-methyl 2-(3,4-diaminophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (600 mg, crude) in HCl (60 mL, 2N) was added sodium nitrite (164.7 mg, 2.39 mmol) in water (1 mL) dropwise at 0-5° C. The resulting solution was stirred for 15 min at 0° C., then diluted with water (150 mL), extracted with dichloromethane (3×80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1.25% methanol in dichloromethane) to afford (S)-methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (130 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][Cl:3])=[CH:30][CH:29]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: ClCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.27 mL, 0.0037 mol) and N,N-dimethylformamide (0.1 mL) are added to a stirred solution of {4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]phenyl}methanol (0.45 g, 0.0012 mol) in dichloromethane (10 mL) at 0° C. The reaction mixture is heated at 40-45° C. and is stirred at this temperature for 1 hr. It is then cooled to 0-5° C. temperature, treated with demineralized water (3 mL) and is neutralized with 4N sodium hydroxide solution at 0-5° C. to adjust the pH 8-9. Finally it is extracted with dichloromethane (2×10 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives 5-(3-chloro-4-cyclohexylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 83 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 160 mg of 4-(2-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (55)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:13]=[O:14].C(N(CC)CC)C.[Na+].[Cl-].Cl.[O:25]1CCOC[CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([N+:10]([O-:12])=[O:11])([CH2:13][OH:14])[CH2:26][OH:25])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C1COCCO1
Reactant: C=O
Reactant: O=[N+]([O-])Cc1cc(Br)cnc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C(CO)(CO)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitromethyl-pyridine (286 mg, 1.14 mmol) in dioxane (2.3 ml) was added 35% aq. formaldehyde (215 mg, 2.50 mmol), triethylamine (0.079 ml, 0.57 mmol) and the reaction mixture was stirred at room temperature for 2 h, to the mixture was added a mixture of saturated aq. NaCl and 12N HCl (0.05 ml, 0.6 mmol). Then the mixture was extracted with TBME the combined organic layers were washed with saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:1) to provide the title compound as colorless solid. M.p. 162-163° C. HPLC: RtH4=0.69 min; ESIMS [M+H]+=311.0, 313.0; 1H NMR (600 MHz, DMSO-d6): 8.64 (d, 1H), 8.11 (d, 1H), 5.60 (t, 2H), 4.34 (dd, 2H), 4.19 (dd, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[I:12][C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[I:12][C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cc(I)nc2C)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (7.9 g), 4-iodo-2-methylimidazole (9.0 g) and sodium carbonate (4.5 g) was heated with stirring in dimethylformamide (50 cm3) at 120° for 16 hours under nitrogen. The mixture was poured into water (50 cm3) and extracted with chloroform (3×100 cm3). The combined and dried (MgSO4) organic extracts were concentrated in vacuo to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:toluene, 1:5 by volume. Combination and evaporation of appropriate fractions afforded a solid which was recrystallised from dichloromethane-hexane to give the title compound, m.p. 146°-8°, (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[N:16]=2)C(O)=O)[CH:7]=1.P([N:35]=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(CC)CC)C.CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[CH:9]=[C:10]([NH2:35])[CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(-c2cc(Cl)ccc2F)n1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cc(N)cc(-c2cc(Cl)ccc2F)n1

Procedure:
2-(5-Chloro-2-fluorophenyl)-6-methylisonicotinic acid (1.1 g, 4.14 mmol), diphenyl phosphorazidate (0.895 ml, 4.14 mmol), triethylamine (0.873 ml, 6.21 mmol), 2-methylpropan-2-ol (0.466 ml, 4.97 mmol) were combined in toluene (12.5 mL) and heated at reflux for 30 minutes, then cooled and concentrated to give a residue. The residue was purified by silica chromatography eluted using a step gradient (0-25% ethyl acetate/hexanes) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (s, 9H) 2.46 (s, 3H) 7.34-7.42 (m, 2H) 7.49-7.56 (m, 1H) 7.76 (s, 1H) 7.94 (dd, J=6.82, 2.78 Hz, 1H) 9.90 (s, 1H). ESI-MS: m/z 337.2 (M+H).
Reaction SMILES: [131I][131I].[CH3:3][C:4]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][NH:7][N:8]=1.[CH3:14][O:15][CH2:16][CH2:17]Br>>[CH3:14][O:15][CH2:16][CH2:17][N:7]1[N:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([CH3:3])=[N:8]1
Reactant: CCOC(=O)c1n[nH]nc1C
Reactant: COCCBr
Agent: [131I][131I]
Product: CCOC(=O)c1nn(CCOC)nc1C
Yield: 54 %

Procedure:
The title compound was synthesized as described for Intermediate example I-131 in 54% yield starting from ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate and 2-bromoethyl methyl ether; 1H NMR (400 MHz, CDCl3) δ ppm 4.58 (t, 2 H), 4.42 (q, 2 H), 3.90 (t, 2 H), 3.35 (s, 3 H), 2.49-2.56 (m, 3 H), 1.34-1.46 (m, 3 H); MS (ESI) m/z 214[M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1)=[O:4].CCCCCCC.C(O)C.C(NCC)C>>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][C@@H:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1)=[O:4]
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2n1C)CCC(c1ccccc1)O3
Solvent: CCNCC
Solvent: CCO
Solvent: CCCCCCC
Product: Cc1nc2c3c(c(C(=O)N(C)C)cc2n1C)CC[C@@H](c1ccccc1)O3

Procedure:
Resolution of racemic 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid dimethylamide (0.5 g, 1.4 mmol) was achieved by preparative chromatography using a 275×110 mm CHIRALPAK® AS-V 20 μm column. The mobile phase consisted of a n-heptan/ethanol/diethylamine mixture [95/5/0.1 (v/v/v)]. The separation was performed at room temperature with a flow rate of 1 ml/min. The products were detected at a wavelength of 225 nm. The separation afforded 0.19 g (39%; ee 98.9%) of the title compound ((8S)-enantiomer) as a white solid. m.p. 227°-228° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][O:19][C:15]4=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31]N1C(=O)CCC1=O.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:31][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]3[O:19][CH2:20][CH2:21][NH:22][CH2:23][C:14]3=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 15 mg, 0.035 mmol) was dissolved in CHCl3 (2 mL) and N-chlorosuccinimide (7.0 mg, 0.053 mmol) was added. The mixture was heated at 70° C. overnight. The mixture was cooled to room temperature, TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a light yellow solid (4.1 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])(=[O:13])=[O:12])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:28])[S:11]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])(=[O:13])=[O:12])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a suspension of sodium hydride (65%, 0.05 g (1.36 mmol)) in DMF (3.0 ml), N-(4-chloro-2-nitrophenyl)-3,5-dimethyl-4-isoxazolesulfonamide (0.30 g (0.90 mmol)) was added with stirring at room temperature. To the mixture, after stirring for one hour at room temperature, dimethyl sulfate (0.13 ml (1.36 mmol)) was added dropwise, and the mixture was stirred for 16 hours. Water (20.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with acetone-hexane (1:4) as eluent, to give 0.11 g (35%) of the title compound as white crystals.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1(N2CCNCC2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][N:22]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:23][CH2:24]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCN(c5ccccc5)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 1-phenylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 2.80 (4H, br), 3.11 (1H, m), 3.80 (1H, dd, J=11.44, 2.75 Hz), 4.39 (1H, J=11.53 Hz), 4.41 (1H, J=11.53 Hz), 7.14 (1H, tt, J=7.42, 1.09 Hz), 7.36 (6H, m), 7.52 (2H, m), 7.83 (1H, d, J=9.34 Hz), 8.16 (2H, m), 8.54 (1H, s). m/z 423.5 (MH+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: Nc1ccccc1Cl
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.38 g, 1.37 mmol) and 2-chloroaniline (0.23 mL, 2.2 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Recrystalized from ethylacetate and hexanes, 203 mg (41%) of 3-(2-chloroanilino)-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione was obtained. LCMS(H+) 360.
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClN(Cl)C([O:17][CH2:18][CH3:19])=O.[CH:21]1C=CC=CC=1>CCOCC.CCCCCC>[CH3:21][CH2:19][C:18](=[O:17])[CH2:1][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: c1ccccc1
Reactant: C1=CCCCCCCCCCC1
Reactant: CCOC(=O)N(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCC(=O)CC

Procedure:
A solution of 15.7 g cyclododecene and 15.8 g dichlorourethane in 125 ml of benzene was refluxed for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with 100 ml of ether and then washed repeatedly with saturated sodiumbisulfite solution. After washing with brine the organic layer was dried and concentrated to give 19.5 g of crudechlorourethane. This was heated at 100°-120° C. for 6 hours. The resulting thick dark oil was diluted with hexane and allowed to stand in the freezer overnight. The solid was filtered and recrystallized from hexane/dichloromethane to give 5.66 g of white crystals, m.p. 84°-86° C. The mother liquor was concentrated to give 5.23 g of thick oil which after flash chromatography (silica gel; ethyl acetate/hexane) gave additional 1.23 g of white crystals, m.p. 85° C. and 0.96 g of a clear oil, which slowly solidified. Recrystallization from hexane gave 0.25 g of crystals, m.p. 72°-74° C.