Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2].[NH2:24][C:25]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:17])([F:16])[F:18])[CH:13]=[N:24][C:25]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:36])[NH:30]3)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Reactant: CCc1c(F)ccc(C(CC)C[C@@](O)(C=O)C(F)(F)F)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CCc1c(F)ccc(C(CC)C[C@@](O)(C=Nc2cc(F)cc3[nH]c(=O)ccc23)C(F)(F)F)c1OC

Procedure:
In the same way as in Example 137, 45 mg (0.13 mmol) of (2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 23 mg (0.13 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.09 ml (0.27 mmol) of titanium tert-butoxide are reacted to give 5-{[(2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-7-fluoroquinolin-2(1H)-one. 80 mg of crude imine are cyclized in the same way as in Example 137 at −30° C. with 1.3 ml (1.3 mmol) of 1 M boron tribromide solution. Purification by column chromatography on silica gel (hexane/isopropanol 16%) and subsequent preparative thin-layer chromatography on an amine phase (Merck NH2F254, ethyl acetate/triethylamine, 2%) yield 7 mg of the title compound and 5 mg of the corresponding (8R)-diastereomer.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:22]1([O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:30][C@H:29]([C:28]([O:27][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CBr)cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)C[C@H](NCc1ccc(CBr)cc1)C(=O)OC1CCCC1
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (0.940 g, 4.72 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (2.40 g, 6.4 mmol) and sodium triacetoxyborohydride (2.53 g, 11.9 mmol). The reaction mixture was stirred for 1 hour then poured into ethyl acetate (300 mL). The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane) to yield the desired product (1.504 g, 83% yield). LC/MS: m/z 382/384 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A slurry of 6.00 g (16.8 mmol) of 6-nitro-4-[(3-trifluoromethylphenyl)amino]quinoline-3-carbonitrile and 18.9 g (83.3 mmol) of SnCl2 dihydrate in 240 mL of ethanol was refluxed under N2 for 1 h. After cooling to 25° C., the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. The product was extracted with chloroform, treated with Darco, dried(magnesium sulfate) and evaporated. The residue was filtered through silica gel (10% methanol in chloroform), evaporated and dried in vacuo (40° C.) to give 4.87 g of brown solid: mass spectrum (electrospray, m/e): M+H 329.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15]([OH:17])=O)[N:7]3[C:6]=2[CH:24]=1.[CH3:25][NH2:26].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:13]([CH2:14][C:15]([NH:26][CH3:25])=[O:17])[N:7]3[C:6]=2[CH:24]=1
Reactant: Cn1c2ccc(Cl)cc2n2c(CC(=O)O)c(-c3ccccc3)nc12
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Reaction time: 18 h

Procedure:
A suspension of 1.5 g (0.044 mol) of 6-chloro-9-methyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.15 g (0.071 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred for 18 h. The solution is then treated with an excess of dry gaseous methylamine and again stirred for 6 h. The solvent is evaporated under reduced pressure. The residue is treated with water, sodium bicarbonate solution and again with water. The insoluble matter is collected by filtration and dried. It is purified by silica gel column chromatography, eluting with a dichloromethane/methanol 97/3 mixture. The product obtained is treated with a hydrochloric acid solution. The precipitate is collected by filtration and treated with excess of ammonium hydroxide. The product obtained is recrystallized from an N,N-dimethylformamide/water 75/25 mixture and then dried at 100° C. under vacuum. 0.8 g of solid is obtained. Melting point: 272°-273.5° C. (decomposition).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:40])[C:29]3[N:33]=[C:32]([C@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[NH:31][C:30]=3[CH:39]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:40][C:28]1[C:29]2[N:33]=[C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[NH:31][C:30]=2[CH:39]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@H]3CCCO3)nc12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c([C@H]3CCCO3)nc12

Procedure:
166 mg (0.65 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 205 mg (0.62 mmol) (R)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 320 μL (1.86 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 50° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]([NH:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2.1 mmol) and benzoic acid (2.1 mmol, 1 equiv.) were dissolved in DMF (10 mL). EDC.HCl (1.5 equiv.), DIPEA (3 equiv.) and HOBT (1.5 equiv.) were added to the reaction mixture and stirred at room temperature for 5 h. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get N′-benzoyl-6-chloro-4-(isopropylamino)nicotinohydrazide.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([O:30][C:31]5[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:40])[NH:38][CH3:39])[CH:32]=5)=[CH:29][C:23]=4[N:22]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][NH:38][C:37]([C:33]1[CH:32]=[C:31]([O:30][C:28]2[CH:27]=[CH:26][C:24]3[NH:25][C:21]([NH:20][C:12]4[CH:11]=[C:10]5[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]5)=[CH:14][CH:13]=4)=[N:22][C:23]=3[CH:29]=2)[CH:36]=[CH:35][N:34]=1)=[O:40]
Reactant: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5(C)C)nc3c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc5c(c4)CNCC5(C)C)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butoxycarbonyl-4,4-dimethyl-7-[5-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-benzimidazol-2-ylamino]-3,4-dihydro-1H-isoquinoline (230 mg) (Example 11) in CH2Cl2 (10 mL) was added TFA (1 mL). The mixture was stirred at RT for 2 h. Solvent was evaporated, aqueous NaHCO3 solution was added, and the mixture was extracted with EtOAc. The organic phase was dried, filtered and evaporated to give the title compound. MS (MH+)=443.2; Calc'd 442.21 for C25H26N6O2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.I[CH3:10]>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[CH3:10][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: CI
Reactant: Cc1cccc(O)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cccc(C)n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 80.8 %

Procedure:
A mixture of 2-hydroxy-6-methylpyridine (6.85 g, 62.8 mmol), silver carbonate (22.5 g, 81.6 mmol), iodomethane (39.1 mL, 628 mmol) and chloroform (200 mL) was stirred at ambient temperature for 40 h in the dark. The reaction mixture was filtered through celite. The collected solid was washed with ether. The combined filtrates were concentrated in vacuo to give a liquid (6.25 g), which was identical to the product from Part A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>N1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([O:8][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:16])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1cc(OC)c(O)cc1Cl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(OC)c(OS(=O)(=O)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2-chloro-4-hydroxy-5-methoxyphenyl)acetate (570 mg, 2.468 mmol) in 10 mL of pyridine was added Tf2O (853 mg, 2.962 mmol) dropwise at 0° C. The resulting mixture was stirred at rt overnight and concentrated to dryness. The residue was dissolved in EtOAc (50 mL), washed with 1 N HCl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give methyl(2-chloro-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyeacetate.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:31](=[O:34])([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]=[O:34])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCNC(=O)OC(C)(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 171.5 %

Procedure:
To a suspension of methyl 2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.04 mmol), 2-formylphenylbononic acid (187 mg, 1.24 mmol) and sodium hydrogen carbonate (345 mg, 4.15 mmol) in 1,2-dimethoxyethane (5 ml) and water (2.5 ml) was added tetrakis(triphenylphosphine)palladium (60.0 mg, 0.05 mmol), and the mixture was stirred at 90° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-3:1) to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (450 mg, yield 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.C([Li])CCC.[CH3:35][N:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:35][N:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][N:6]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]3)([OH:42])[CH2:38][CH2:37]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C3)CC1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Under nitrogen, a solution of 5-bromo-2-trityl-2,3-dihydro-1H-isoindole (2.03 g, 4.6 mmol) in THF (20 mL) was cooled to −78° C. n-Butyllithium solution (2.5M in hexanes, 2.0 mL, 5 mmol) was added over 5 minutes, then after 10 minutes, 1-methyl-4-piperidone was added dropwise. After a further hour, the cooling bath was removed and the reaction quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate then the organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica (gradient elution with 2M methanolic ammonia/dichloromethane, 0% to 5%) to afford 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol as a pink foam (1.25 g, 57%). 1H NMR (MeOH-d4) 7.56 (6H, dd), 7.28 (6H, t), 7.25-7.21 (2H, m), 7.15 (3H, t), 7.03 (1H, d), 3.92 (2H, s), 3.91 (2H, s), 2.70 (2H, d), 2.53 (2H, td), 2.33 (3H, s), 2.06 (2H, td), 1.70 (2H, d). MS: [M+H]+ 475.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)(=[O:41])=[O:40])([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (300 mg, 0.897 mmol) from Step A of Example 256 and triethylamine (0.313 mL, 2.243 mmol) were combined in dichloromethane (20 mL). 2-Nitrobenzene-1-sulfonyl chloride (258 mg, 1.166 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, and the organic layer was separated and concentrated. The resulted crude material was triturated with 50% diethyl ether/hexane, collected by filtration, washed with water then hexane to yield a solid. The crude solid was purified using a 12 g silica gel cartridge with a gradient of 10-100% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.69 (s, 1H), 8.31 (dd, J=6.0, 3.3, 1H), 8.12 (d, J=8.2, 2H), 7.92 (dd, J=8.6, 2.1, 3H), 7.67 (dd, J=5.9, 3.3, 2H), 4.94 (s, 2H), 3.84 (dd, J=15.0, 6.2, 1H), 3.58 (dd, J=10.0, 2.4, 1H), 3.17 (dd, J=9.7, 2.7, 1H), 2.94 (dd, J=10.0, 7.7, 1H), 2.87 (dd, J=9.6, 7.7, 1H), 2.71 (td, J=9.3, 2.4, 1H), 2.60-2.50 (m, 1H), 1.94-1.80 (m, 2H), 1.71-1.58 (m, 1H), 1.23 (tt, J=10.5, 6.5, 1H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[Br-:1].[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH2:2][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 56.3 %

Procedure:
A solution of ethyl 2-bromomethylbenzoate (1.00 g) in tetrahydrofuran (10.0 ml) and triphenylphosphine (1.21 g) was heated under reflux for 8 hours. After being cooled, the resulting precipitates were collected by filtration and washed with tetrahydrofuran to give 2-ethoxycarbonylbenzyltriphenylphosphonium bromide (1.17 g).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH3:9])([CH2:5][OH:6])[CH2:3][OH:4].[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-:20].[Na+]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:4][CH2:3][C:2]([CH3:1])([CH2:7][CH2:8][CH3:9])[CH2:5][O:6][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:11])=[O:20])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCCC(C)(CO)CO
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(C)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1

Procedure:
132 g (1 mol) 2-methyl-2-propyl-1,3-dihydroxypropane, 346.5 g (2.2 mols) 4-nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted in the same manner as was described in Example 1 in 600 ml DMSO.
Reaction SMILES: Cl[CH:2]1[CH2:6][O:5][C:4](=[O:7])[O:3]1.[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O-:21])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9].[K+].[I-].[Na+]>CN(C=O)C>[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O:21][CH:2]2[CH2:6][O:5][C:4](=[O:7])[O:3]2)=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9]
Reactant: O=C1OCC(Cl)O1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC2COC(=O)O2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
4-Chloro-1,3-dioxolan-2-one (1.35 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml). After stirring at 50° C. for 6 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After treatment with magnesium sulfate the solution was finally evaporated to dryness. Yield: 5.6 g. Purity by HPLC: 93%. 1H-NMR (DMSO-d6): delta=1.67 (N (CH3)COCH3); 2.05(NCOCH3); 2.96(NCH3); 4.7; 4.9(CH2); 7.02(CH); 10.14 ppm(NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Br:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-bromo-1H-indazole-3-carbaldehyde (0.0646 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-bromo-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0700 g, 44%).
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[N:6]=[CH:7][C:8]([C:20]#[N:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][N:15]=1>CC(O)C>[NH2:4][C:5]1[N:6]=[CH:7][C:8](/[C:20](=[N:2]/[NH2:3])/[NH2:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:18])([CH3:17])[CH3:19])=[N:14][N:15]=1
Reactant: CC(C)(C)c1nnc(-c2nc(C#N)cnc2N)o1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
Hydrazine hydrate (82 mL, 1.69 mol) was added to 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile (55 g, 225.18 mmol) in IPA (200 mL) and the mixture was heated at 50° C. under nitrogen for 16 hours. The mixture was cooled in an ice bath. The resulting precipitate was collected by filtration, washed with IPA and diethyl ether and dried to a constant weight to afford (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (49.2 g, 79%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.45 (9H, s), 5.26 (2H, s), 5.58 (2H, s), 7.56 (2H, s), 8.75 (1H, s); Mass Spectrum [M+H]+=277.