Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:18]1([N:15]2[CH2:16][CH2:17][CH:12]([C:10]3[N:11]=[C:7]4[N:8]([C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]5[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=5)=[N:4][C:5]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])=[CH:6]4)[N:9]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)nc1
Temperature: 130 °C

Procedure:
21 mg (0.10 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 40 mg (0.10 mmol) of 6-[(2-aminoethyl)-amino]pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.10 ml (0.57 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (62% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33])[C:2]1C=CC=[CH:4][CH:3]=1.[F:34]C1(CO)CC1>>[F:33][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)[CH:13]=[C:14]([F:15])[C:9]=1[O:8][CH2:1][C:2]1([F:34])[CH2:4][CH2:3]1
Reactant: OCC1(F)CC1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4(F)CC4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: CCNCC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A 25° C. mixture of 500 mg of 2-(5-fluoro-2-nitrophenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 14d, 131 mg of diethylamine, and 329 mg of K2CO3 in 4 mL of DMF was stirred for 16 h and then stirred for an additional 24 h at 60° C. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water, and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give 500 mg of a yellow solid.
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:29])[CH2:27][CH3:28]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:29])[CH2:27][CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC(=O)N(C)OC
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:28])[CH:25](O)[OH:26])[CH2:20][CH2:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:26][CH2:25][CH:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)[CH2:28][O:10]2)[CH2:7][CH2:8]1
Reactant: CCCCC[C@H]1CC[C@H](C(C)C(O)O)CC1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](C2COC([C@H]3CC[C@H](C(F)(F)F)CC3)OC2)CC1

Procedure:
A mixture of 0.02 mol of tras-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-(trans-4-pentylcyclohexyl)propanediol (prepared as in DE 3,227,916), 30 ml of toluene and 0.5 g of pTSOH is heated for 6 hours on a water separator. The product is obtained after customary work-up and crystallization.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4]([N:5]([CH3:20])[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 2.0 g (0.0087 mole) 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, 1.1 ml (0.0174 mole) methyl iodide, anhydrous potassium carbonate (1 gram) and acetone (100 ml) was heated under reflux, with stirring, overnight. After refluxing had continued 21 hours an additional 1 ml of methyl iodide was added and solids removed from the mixture by suction filtration. The filtrate was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate, washed with water, then with brine and dried over MgSO4, filtered and solvent stripped off to give 1.8 g of crude product. Purification by high pressure liquid chromatography gave a solid, mp 79°-82° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15](=[NH:16])[O:18][CH3:17])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: C[O-]
Reactant: N#Cc1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reaction time: 2 h
Yield: 1331.1 %

Procedure:
A mixture of 5-(2-nitrophenyl)-2-furonitrile (92 g, 0.43 mole) and anhydrous methanol (1000 ml) was heated to 55° and sodium methoxide (1.5 g) was added. The steam bath was removed, the solution was stirred for 2 hours and stored overnight at room temperature. The solution was poured into ice water (1000 ml) and stirred for 1 hour. The product was collected by filtration and air dried to yield 91 g (86%) of methyl 5-(2-nitrophenyl)-2-furancarboximidate. A sample was recrystallized from isopropanol, m.p. 107°-108°.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1>CN(C=O)C>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[CH:37][C:38]=1[C:46]([F:47])([F:49])[F:48])(=[O:44])=[O:43]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+ 441)
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])/[CH:18]=[C:19](\[C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)/[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])[CH2:18][C@@:19]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:4][N+:1]([O-:3])=[O:2])[C:20]([F:22])([F:21])[F:23])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 360 h

Procedure:
Alternatively, to a solution of 3-[3,5-bis(trifluoromethyl)anilino]-4-[[(S)-(6-methoxy-4-quinolyl)-[(1S,2S,5S)-5-vinylquinuclidin-2-yl]methyl]amino]cyclobut-3-ene-1,2-dione (13 mg, prepared according to the literature: Org. Lett., 2010, 12 (23), 5450-5453) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 5 days at 50° C. then more catalyst (15 mg) was added. The reaction was heated again for 3 days at 50° C. then allowed to stand at room temperature for 15 days. Water was then added and the resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (26 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.13 minutes (major enantiomer), 7.29 minutes (minor enantiomer) indicated that the reaction proceeded with 61% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:9][CH3:10].C(N(CC)CC)C.[H][H]>O1CCCC1.[C].[Pd]>[N:4]1[CH:5]=[CH:6][C:7]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[CH:2][N:3]=1
Reactant: [H][H]
Reactant: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Yield: 28 %

Procedure:
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione, triethylamine (1.11 mL, 8 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in tetrahydrofuran in a hydrogen atmosphere (1 atm) at room temperature for 4 days. The reaction solution was filtered through celite and concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, and the resulting organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to give the desired product (294 mg, 28% yield, two steps).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O>CO.C1CCCCC1.[Pd]>[NH2:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCCCC1
Product: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a solution of methyl 4-amino-3,5-dinitrobenzoate (D203) (3.0 g, 12.4 mmol, 1 equiv) in MeOH (40 ml) and cyclohexane (80 ml) was added 10% palladium on charcoal (50% wet, 2.0 g, 33% w/w) and the resulting mixture was refluxed for 30 min then cooled to room temperature. The catalyst was filtered off through a pad of celite and washed with DMF. The combined organic phases were concentrated in vacuo and the residue triturated with Et2O/iso-hexane to give methyl 3,4-diamino-5-nitrobenzoate (D204) (2.1 g, 80%) as a red solid which was used in the next step without further purification. [M+H]+=212.2, RT=2.46 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([N:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([N:8]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N+:17]([O-:39])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccncc2)c2cccc(Cl)c2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cc[n+]([O-])cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
330 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-(pyridine-4-ylmethyl)glycinamide was dissolved in 5.0 mL of methylene chloride, and 166 mg of m-chloroperbenzoic acid was added thereto, followed by stirring at room temperature for 4 hours. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, and then extracted with chloroform. The organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1), and the obtained residue was crystallized from hexane/ethyl acetate to obtain 179 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-[(1-oxidopyridine-4-yl)methyl]glycinamide.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH:3]=[CH:2][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C(N2C=CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 0.819 mmol) in DCM (8.2 mL) at 0° C. was added DBU (370 μl, 2.46 mmol), and XtalFluor-E® (562 mg, 2.46 mmol). The mixture was stirred overnight while warming up to rt, and quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1)]+=349
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(Cl)[Cl:21].S(Cl)(Cl)=O>CN(C)C=O>[Cl:21][C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
A solution of 2.50 g. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene in 50 ml. of chloroform, 10 ml. of thionyl chloride and 0.3 ml. of dimethylformamide is stirred for 8 hours, then evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 50 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0° C. After 12 hours the solution is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. A solution of 1.37 g. of the latter compound in 50 ml. of tetrahydrofuran is added to 10 ml. of 0.1 N sulfuric acid containing 0.5 g. of copper powder. The mixture is refluxed for 3 hours and then cooled, filtered and poured into water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene which is recrystallized from chloroform/hexane. A solution of 0.05 g. of cupric acetate monohydrate in 5 ml. of acetic acid is heated to 100° C. and 3.0 g. of granular zinc is added. The mixture is shaken for 3 minutes and the acetic acid is then decanted. The residual zinc-copper couple is washed three times with 5 ml. portions of acetic acid, then three times with 5 ml. portions of ether. It is then refluxed for 4 hours under nitrogen in 20 ml. of ether containing 2.5 ml. of methylene iodide, 1.32 g. of 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene is added, and reflux is continued for a further 4 hours. The mixture is cooled and diluted with 50 ml. of benzene. The liquid phase is decanted and washed with water and aqueous sodium bisulfate, then dried and evaporated. The residue is chromatographed on 50 gm. of silica gel, eluting with ethyl acetate/hexane, to yield 2-(5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)prop-1-en-3-ol.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:22][CH3:23])[C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:22][CH3:23])[C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(Cc1ccccc1)C2
Solvent: ClCCCl
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of (4-benzyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (900 mg, 3.0 mmol) in 1,2-dichloroethane (150 mL) was added benzyl chloroformate (900 mg, 3.0 mmol). The mixture was warmed to reflux for four hours whereupon LCMS indicated completion of reaction. The mixture was cooled to ambient temperature, washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (EtOAc-hexanes) gave 7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (390 mg, 40%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.67 (s, 1H), 7.30 (m, 6H), 5.09 (s, 2H), 4.67 (s, 2H), 3.90 (s, 2H), 3.77 (s, 3H); MS (m/e) 372 (M+1); mp 191° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)C>C(O)C.O1CCCC1>[CH2:26]([N:22]([CH2:23][CH2:24][CH3:25])[C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Using General Procedure I; a solution of ethyl4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NAOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[C:10]([CH3:20])=[N:9]2)=[CH:5][CH:4]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([CH3:20])=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2nc(C)c3cc([N+](=O)[O-])ccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3cc(N)ccc32)cc1
Reaction time: 0.5 h

Procedure:
1-(4-methoxybenzyl)-3-methyl-5-nitro-1H-indazole (275 mg, 0.93 mmol) from Step 1 of this example was dissolved in MeOH (4.6 ml) and EtOAc (10 ml) to give a clear yellow solution. Pd/C (10%, 98 mg) was added, the vessel evacuated and backfilled with hydrogen (3×) and slurry stirred under a hydrogen atmosphere for 30 minutes. The mixture was filtered through CELITE, the filter cake washed with EtOAc (2×40 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.