Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:11]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: COC(=O)c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1cccc1C(=O)OC
Temperature: 80 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of methylpyrrole-2-carboxylate (1.01 g, 8.07 mmol) in N,N-dimethylformamide (12 ml) were added 1-bromohexane (1.36 ml, 9.69 mmol) and potassium carbonate (1.474 g, 10.7 mmol), and the mixture was stirred at 80° C. for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 1-hexylpyrrole-2-carboxylate (0.980 g, 4.68 mmol, yield 58%). This was dissolved in methanol (8 ml), 1N-aqueous sodium hydroxide solution (8 ml) was added at room temperature, and the mixture was stirred at 60° C. for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 1-hexylpyrrole-2-carboxylic acid (0.877 g, 4.49 mmol, yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (157.4 mg, 0.36 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (71.1 mg, 1.78 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 36 mg (23%) of 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
9.6 g (34.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate and 34.5 ml (233 mmol) of (trifluoromethyl)-trimethylsilane in 343 ml of DMF are mixed with 46.9 g of cesium carbonate at 0° C. It is stirred for 2 hours at 0° C. and then the reaction mixture is added to-water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 10.4 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 297 ml of diethyl ether at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride, and it is stirred for 1 more hour at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-50%), 5.6 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained. 12.4 ml (89 mmol) of triethylamine is added to 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO, and 11 g (70 mmol) of pyridine/SO3 complex is added in portions over 10 minutes. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after-chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 5.9 g of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[N:6][N:5]([CH2:13][C:14](=O)[CH3:15])[CH:4]=2.[Si](OC(C)[CH2:26][N:27]1C=C2C(C(Cl)=C(Cl)C=C2Cl)=N1)(C(C)(C)C)(C)C.[Si:40]([O:47][CH:48]([CH3:64])[CH2:49][NH:50][CH2:51][C:52]1[C:57]([Cl:58])=[CH:56][C:55]([Cl:59])=[C:54]([Cl:60])[C:53]=1[N+:61]([O-:63])=[O:62])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].[N+](C1C(Cl)=C(Cl)C=C(Cl)C=1C=O)([O-])=O>>[NH2:50][C:14]([CH3:15])([CH2:13][N:5]1[CH:4]=[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:2]2[Cl:1])=[N:6]1)[C:26]#[N:27].[Cl:58][C:57]1[C:52]2[C:53]([C:54]([Cl:60])=[C:55]([Cl:59])[CH:56]=1)=[N:61][N:50]([CH2:49][C:48](=[O:47])[CH3:64])[CH:51]=2.[Si:40]([O:47][CH:48]([CH3:64])[CH2:49][NH:50][CH2:51][C:52]1[C:57]([Cl:58])=[CH:56][C:55]([Cl:59])=[C:54]([Cl:60])[C:53]=1[N+:61]([O-:63])=[O:62])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Agent: CC(CNCc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-])O[Si](C)(C)C(C)(C)C
Agent: O=Cc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-]
Product: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Yield: 60 %

Procedure:
2-Amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.16 g, 60%) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(4,6,7-trichloro-2H-indazol-2-yl) propan-2-one (0.25 g). 1-(4,6,7-Trichloro-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part c and d except starting from 2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6,7-trichloro-2H-indazole (1.4 g, 69%) that was prepared using a procedure similar to that described in Example 132 part a except starting from [2-(tert-butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine (2.2 g). [2-(tert-Butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine (2.2 g, 44%) was prepared using a procedure similar to that described in Example 105 part a except starting from 2-nitro-3,4,6-trichlorobenzaldehyde (3 g) that was prepared as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C@@:9]([OH:19])([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]2[NH:6][C:20](=[O:21])[O:19][C@:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:12])([F:13])[F:11])[C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1

Procedure:
A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O>[N+:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.3 %

Procedure:
Pyrrolidine ((983 μl, 12.0 mmol, commercially available product) was added at 0° C. to a N,N-dimethylformamide (DMF; 4 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.02 g, 4.89 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 4.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=5/1). Thus, 1-[2-nitro-4-(trifluoromethyl)phenyl]pyrrolidine (1.26 g, 99.3%) was yielded as an orange-colored solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH3:28])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CCCI
Reactant: OC1(c2ccc(F)c(C(F)(F)F)c2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
Preparation according to Example 2: 4-[4-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.4 g, 1.52 mmol), acetonitrile (20 ml), potassium carbonate (0.42 g, 3.0 mmol), iodopropane (0.18 ml, 1.82 mmol). Yield: 0.31 g, 67%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 179-181° C. MS m/z (relative intensity, 70 eV) 305 (M+, 5), 276 (bp), 258 (52), 256 (23), 185 (50).
Reaction SMILES: [F:1][C:2]([F:13])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[CH2:3][OH:4].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)([F:13])[F:1]
Reactant: COc1cccc(C(F)(F)CO)c1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(F)(F)COCCCCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of Intermediate 68 (3.19 g, 16.95 mmol) in dimethylformamide (20 mL) was added 60% sodium hydride (1.36 g, 33.9 mmol) and 1,6-dibromohexane (5.2 mL, 33.9 mmol). The mixture was stirred at room temperature for 2 hours. The crude was diluted with methylene chloride (50 mL) and washed with water (3×50 mL), dried (MgSO4) and concentrated. The excess of 1,6-dibromohexane was eliminated by distillation at reduced pressure (P=0.15-0.18 mmHg, T=60-65° C.) and the crude was purified by column chromatography with silica gel using methylene chloride as eluent. The title compound was obtained (3.41 g, 57%) as oil.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28].ClC1N=NC=C(C2C=CC(Cl)=CC=2)C=1NN>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NNc1c(-c2ccc(Cl)cc2)cnnc1Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirring solution of triphosgene (17.5 g, 59.0 mmol) in THF (150 mL) was cooled to 0° C. under argon and a mixture of 1-(4-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine and 1-(3-chloro-5-(4-chlorophenyl)pyridazin-4-yl)hydrazine, as prepared in Example 361E, (3.0 g gross) was added over 3 min. The reaction mixture was then allowed to warm to RT gradually and then was stirred for 16 h. The solvent was removed under vacuum to reduce the reaction mixture to half its original volume, and the resulting suspension was cooled in an ice bath. Ice water (300 mL) was added, followed by stirring for 30 min. The product was collected by filtration and washed with 0.5 N aqueous HCl (20 mL×2), then H2O (20 mL×2). After drying under vacuum at room temperature for 16 h, the title compound, 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2.1 g) was obtained as a yellow solid. MS [M+H]+ 281; HPLC retention time=2.71 min.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc[nH]c(=O)c1C#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 316.2 %

Procedure:
14 g (104 mmol) of 3-cyano-4-methylpyridone was slowly added to a mixture of 6.52 g (31.3 mmol) of phosphorus pentachloride and 30 ml (48 g, 313 mmol) of phosphorus oxychloride, followed by stirring at room temperature for 70 minutes and then under reflux with heating for 2 hours. After the reaction mixture was left to stand to cool, it was poured into ice water (400 ml) so that the surplus reagent was decomposed, followed by extraction with 100 ml of dichloromethane three times. The dichloromethane solution was washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.1 g of crude crystals of 2-chloro-3-cyano-4-methylpyridine. 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.86 (s, 3H), 7.89 (d, J=5.6 Hz, 1H) 8.86 (d, J=5.6 Hz, 1H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH2:12]=O>>[S:1]1[C:2]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Reactant: C=O
Product: O=C(O)C1Cc2sccc2CN1
Temperature: 60 °C

Procedure:
A suspension of (D,L) 3-(2-thienyl)-alanine (302 mg, 1.77 mmol) in 37% aq. HCHO (4 mL) was heated at 60° C. for 2 h. The suspension became clear. It was concentrated in vacuo to give the titled compound (323 mg), which was used in the next step without further purification. MS 184.3 (M+H)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[C:42]([Cl:44])[C:16]([C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=3[CH3:37])=[CH:27][CH:26]=2)[C:21]([OH:23])=[O:22])=[O:18])=[C:15]([Cl:45])[CH:14]=1.O=C1CCC(=O)N1[O:53][C:54](=O)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]1[C:77](=[O:78])[CH:76]=[CH:75][C:74]1=[O:79].CCN(C(C)C)C(C)C>>[Cl:45][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:54](=[O:53])[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]2[C:77](=[O:78])[CH:76]=[CH:75][C:74]2=[O:79])[CH:43]=[C:42]([Cl:44])[C:16]=1[C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=2[CH3:37])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:18]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCN)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid trifluoroacetate salt (203 mg, 0.3 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (154 mg, 0.3 mmol), and DIPEA (194 mg, 261 uL, 1.5 mmol), and after HPLC purification, resulted in an amorphous white solid (175 mg, 61%). ES(+)-HRMS m/e calcd. for C44H54Cl2N6O14 (M+H)+ 961.3148, obsd. 961.3156.
Reaction SMILES: [CH2:1]1[CH:6]([NH2:7])[CH2:5][CH2:4][CH:3]([NH2:8])[CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:7][C@H:6]3[CH2:5][CH2:4][C@H:3]([NH2:8])[CH2:2][CH2:1]3)[N:28]=2)=[CH:19]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NC1CCC(N)CC1
Product: N[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1

Procedure:
Using the procedure of example 1, trans-1,4-cyclohexyldiamine (277 mg) was reacted with compound 1f (300 mg) to provide compound 42 (86 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.90 (d, J=8.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.22 (m, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.85 (m, 1H), 2.78 (m, 1H), 2.18 (m, 2H), 2.20 (m, 2H), 1.40 (m, 4H). MS (ESI) m/z: 309 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:8]2[N:13]([C:14]=1[Br:15])[N:12]=[CH:11][N:10]=[C:9]2[NH2:16])=[O:5])[CH3:2].O.O.[Sn](Cl)Cl>CCO>[NH2:16][C:9]1[C:8]2=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([Br:15])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnn2c1Br
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(N)cc2)c2c(N)ncnn2c1Br
Yield: 78.6 %

Procedure:
Ethyl-4-amino-7-bromo-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.06 g, 5.07 mmol) was suspended in EtOH (30 mL) and treated with tin(II)chloride dihydrate (3.66 g. 16.2 mmol). The mixture was heated to reflux for 18 h. The mixture was concentrated then diluted with EtOAc and saturated NaHCO3 solution. The emulsion was filtered and the filtrate was transferred to a separatory funnel. The organic layer was washed with water and saturated NaCl solution, dried then (MgSO4) and concentrated to afford 1.5 g of the desired product as tan solid (79%). 1H-NMR (DMSO-d6) δ 8.00 (s, 1H), 7.00 (d, J=8.6, 1H), 6.62 (d, J=9.2, 3H), 5.40 (bd, 2H), 5.19 (bs, 2H), 4.05 (q, J=7.0, 2H), 1.03 (t, J=7.0, 3H); MS [M+H]+=376.0, 378.0; LCMS RT=2.02.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10](N)[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:26])[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(-c2cc(N)cc([N+](=O)[O-])c2)ccn1
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2cc(O)cc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To 0° C. flask charged with 65.B (2.85 g, 11.7 mmol) was added a solution of BBr3/CH2Cl2 (1.0 M, 25 mL). The solution was allowed to warm to rt and stirred for 45 mins. The resulting mixture was treated with MeOH (7 mL), neutralized with solid NaHCO3 to PH=7 and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-10% of MeOH/CH2Cl2 for elution gave the title product 65.C as solid (1.83 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1
Reactant: COc1cccc(Cl)n1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: COc1cccc(-c2cc([N+](=O)[O-])ccc2F)n1

Procedure:
2-Chloro-6-methoxypyridine (1.26 g, 8.81 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3 g, 11.45 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)-6-methoxypyridine as a white solid: δH (400 MHz, CDCl3) 4.05 (3H, s), 6.81 (1H, d, J 8), 7.30 (1H, dd, J 10 and 9), 7.48-7.51 (1H, m), 7.69 (1H, t, J 8), 8.22-8.26 (1H, m), 9.08 (1H, dd, J 7 and 3).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:1][C:4]1[N:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1cnc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 109.2 %

Procedure:
A solution of N-(5-nitro-pyrazin-2-yl)-methanesulfonamide (583.9 mg, 2.67 mmol) in methanol (26.8 mL) was treated with a solution of ammonium chloride (300.6 mg, 5.62 mmol) in water (2 mL). This solution was stirred at 25° C. for 5 min. At this time, the reaction was treated with zinc dust (1.71 g, 26.2 mmol). The resulting mixture was heated under reflux for 2 h. At this time, the reaction was cooled to 25° C. and was filtered through a pad of silica gel (9/1 methylene chloride/methanol wash). The filtrate was concentrated in vacuo to afford N-(5-amino-pyrazin-2-yl)-methanesulfonamide (548.8 mg, 100%) as a dark-brown gum: EI-HRMS m/e calcd for C5H8N4O2S (M+H)+ 189.0441, found 189.0442.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH2:22][CH:23]([CH3:27])[C:24]([NH2:26])=[O:25]>CO.C(Cl)Cl>[C:24]([CH:23]([NH:22][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:27])(=[O:25])[NH2:26]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CC(N)C(N)=O
Solvent: CO
Solvent: ClCCl
Product: CC(NCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1)C(N)=O

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-aminopropionamide (62.3 mg, 0.50 mmol) as described in General Procedure X to afford Iaf (39 mg, 62.9%) as an ivory colored solid, tlc Rf=0.5 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=369 (M+1).