Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].Cl>>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:25][CH3:26]
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: CCCNCCC
Agent: Cl
Product: CCCN(CCC)CCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Yield: 30 %

Procedure:
The procedure of Example 18 was followed starting with (D) of Example 18 (2.5 g, 7.6 mmol) and using dipropylamine in place of dibutylamine to produce 0.90 g (30% yield) of the named compound as the HCl salt, mp 150°-152° C. IR(KBR): 1600 cm-1. MS: 393(MH+). 1H NMR (CDCl3): δ 8.09-6.87 (m, 10H), 4.01 (t, J=5.4 Hz, 2H), 3.02 (m, 6H), 1.95 (m, 8H), 0.99 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH: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)[CH2:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[OH-].[Na+].[K+].[Br-]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:23][C:22]([CH3:25])([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH:3]=3)[NH:8][C:7]2=[O:12])[CH2:14][CH2:15]1)=[O:20])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cc(Br)ccc3NC2=O)CC1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc3c(c2)CN(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N3)CC1

Procedure:
A mixture of 10.0 g (24.372 mmol) of 6-bromo-3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-2(1H)-quinazolinone, 2.5 g (24.96 mol) of 1-methylpiperazine, 4.81 g (50.05 mmol) of sodium tert-butoxide, 285 mg (0.4766 mmol) of bis(dibenzylideneacetone)palladium, 305 mg (1.002 mmol) of tris(o-tolyl)phosphine, and 100 mL of toluene was refluxed for 14 hours. After the addition of further equal amounts of 1-methylpiperazine, sodium tert-butoxide, bis(dibenzylideneacetone)palladium, and tris(o-tolyl)phosphine the mixture was refluxed for another 48 hours. The mixture was filtered through activated charcoal and the filtrate was evaporated down in vacuo. The residue was divided between dichloromethane and water. The organic phase was extracted twice with dilute aqueous citric acid solution. The acidic extracts thus obtained were made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined dichloromethane extracts were evaporated down in vacuo, the residue was purified by column chromatography on silica gel (30-60 μm) using dichloromethane to start with, then methanol/concentrated ammonia 9/1 v/v as eluant. After conventional working up of the appropriate eluates 1.1 g (11% of theoretical) of a colorless substance was obtained. IR (KBr): 1670 (C═O) cm−1; MS: M+=429.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:28](=[O:30])[NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:32]>C(O)C>[Na+:32].[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]([O-:26])=[O:25])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:28](=[O:30])[NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)[O-])c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Yield: 56 %

Procedure:
A solution of the {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (83.5 mg, 0.207 mM) and 1.0 mL (2.0 mM) of 2 N NaOH in 10 mL of ethanol was stirred for 45 minutes at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 48 mg (56%) of the {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid sodium salt as a white powder. MS (ES) m/e 314, 372, 389, 411. The filtrate was acidified with 1N HCl to pH=1. After cooling to 5° C., the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 24 mg (29%) {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ11.2 (bs, 1H), 7.8 (bs, 1H), 7.6 (d, J=8 Hz, 1H), 7.45 (bs, 1H), 7.4-7.05 (m, 8H), 6.45 (s, 1H), 5.65 (s, 2H), 4.9 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 314, 372, 389.
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([OH:20])[CH:16]=1)[CH:24]=[O:25]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=Cc1cc(O)cc(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at −10° C. n-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at −10° C. for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at −10° C. over a period of 35 min. After stirring at −10° C. for a further 30 min, the reaction mixture was cooled to −40° C. before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to rt and allowed to stir at rt for 1 h. The reaction was carefully quenched at 0° C. with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recrystallization of the crude product in ether/hexane afforded the title compound as a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1Br.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)c(F)c2)cc1
Yield: 63.4 %

Procedure:
33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene, 1.2 mmol of copper iodide and 1.2 mmol of dichlorobistriphenylphosphine palladium were dissolved in 100 ml of diethylamine and the solution was stirred under an argon stream. To the reaction solution were added dropwise 20 ml of a diethylamine solution of 50 mmol of trimethylsilylacetylene and the solution was stirred at room -temperature for 5 hours. After completion of the agitation, water was added to the reaction solution which was extracted with heptane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. This product was isolated and purified by a silica gel column chromatography to afford 7 g of 1-[2-fluoro-4-[2-(4-propylphenyl)ethynyl]phenyl]-2-trimethylsilylacetylene as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:6]([CH3:9])([Cl:8])[CH3:7])[C:3](=[O:5])[CH3:4].[Br:11]Br>CO>[Br:11][CH2:4][C:3](=[O:5])[C:2]([CH3:10])([CH3:1])[C:6]([Cl:8])([CH3:9])[CH3:7]
Reactant: CC(=O)C(C)(C)C(C)(C)Cl
Reactant: BrBr
Solvent: CO
Product: CC(C)(Cl)C(C)(C)C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.2 Grams of 3,3,4-trimethyl-4-chloro-2-pentanone was dissolved in 15 ml of methanol, and 2.50 g (1.2 times by mole) of bromine was added dropwise at 20° C. After stirring for 1 hour, the reaction solution was poured into ice water and extracted twice with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated to obtain 3.1 g of the desired 1-bromo-4-chloro-3,3,4-trimethyl-2-pentanone (a halogeno-ketone compound of the foregoing formula (II) wherein a substituent X is a bromine atom) (yield, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.C(N(CC)CC)C.[N:27]1([CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:42][CH:41]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: NCc1ccc(OCCN2CCCC2)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCc2ccc(OCCN3CCCC3)cc2)c(OC)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a cooled suspension of 1.82 g of 2,4-dimethoxybenzoic acid in 10 ml of tetrahydrofuran was added 1.09 g of ethyl chloroformate and 1.01 g of triethylamine. After stirring for 15 minutes, to the mixture was added a solution of 2.00 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 15 minutes and the solvent was evaporated. To the residue was added 10% hydrochloric acid, and the solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 3.31 g of the title compound as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.N1([O:15][C:16]([N:20](C)C)=[N+:17]([CH3:19])[CH3:18])C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][N:17]([C:16]([N:20]=[N:20][C:16]([N:17]([CH3:18])[CH3:19])=[O:15])=[O:15])[CH3:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)N=NC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Neat CDI (49 mg, 0.302 mmol) was added to stirred solution of mono acid (92 mg, 0.200 mmol) in an. THF (1 ml) and the mixture was heated at 50° C. for 30 min and then allowed to cool to rt. Then N-cyclopropyl-N-methylsulfamide (45.1 mg, 0.300 mmol) and DBU (0.060 ml, 0.400 mmol) were added consecutively. The mixture sonicated for 1-2 hand then stirred overnight at rt. Reaction was quenched with MeOH (0.5 ml) and then acidified with 1N HCl and extracted with EtOAc (2×25 mL), washed with water, brine and dried (Na2SO4). Crude product (123 mg) was purified by silica gel flash chromatography (5% MeOH in DCM) to afford amide-ester as an off-white solid (101 mg). 1N NaOH (2 mL, 2.000 mmol) was added to stirred solution of the amide ester (98 mg, 0.166 mmol) in THF-MeOH under nitrogen. The mixture was stirred at rt for 2 h and then acidified with 1N HCl (3 ml), extracted with EtOAc (2×25 ml), washed with water, brine and dried (MgSO4). Evaporation of solvents afforded amide-acid as an off-white solid (94 mg). Neat 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (53.5 mg, 0.167 mmol) was added to a stirred mixture of the amide-acid (74 mg, 0.128 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (26.4 mg, 0.128 mmol) and TEA (0.071 ml, 0.512 mmol) in DCM (2 ml) under nitrogen. The mixture was stirred at rt for 1 h and quenched with MeOH (0.5 ml) and then evaporated to dryness and purified by reverse-phase HPLC to afford diamide and isolated in mono TFA salt form (61.3 mg) as a beige solid. LC/MS: Retention time: 1.857 min; m/e 686 (MH+). The product was observed to exist as inter-converting rotamers by 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.72-0.84 (m, J=1.83 Hz, 2H), 0.85-0.96 (m, J=2.44 Hz, 2H), 1.19-1.31 (m, 1H), 1.33-1.48 (m, 2H), 1.50-1.62 (m, 1H), 1.69-1.89 (m, 8H), 1.92-2.23 (m, 10H), 2.56-2.69 (m, 2H), 2.77-2.90 (m, 1H), 2.90-3.02 (m, 1H), 3.04-3.14 (m, 4H), 3.11-3.54 (m, 1H), 3.60-3.71 (m, J=15.26 Hz, 1H), 3.82-3.96 (m, 3H), 5.06-5.22 (m, 1H), 6.92-7.01 (m, J=8.55, 2.44 Hz, 1H), 7.07-7.14 (m, J=2.14 Hz, 1H), 7.27-7.33 (m, J=8.55 Hz, 1H), 7.40-7.49 (m, 1H), 7.86-7.94 (m, J=8.24 Hz, 1H), 7.98-8.06 (m, 1H).
Reaction SMILES: C(=O)C(C)C.O.NN.C=CC=C.[CH:13]([CH:16]1[CH2:27][CH:26]=[CH:25][CH2:24][CH2:23][CH:22]=[CH:21][CH2:20][CH:19]([CH:28]([CH3:30])[CH3:29])[N:18]=[N:17]1)([CH3:15])[CH3:14].[H][H]>C(O)(C)(C)C.[Rh].[Ni]>[NH2:17][CH:16]([CH:13]([CH3:15])[CH3:14])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([NH2:18])[CH:28]([CH3:29])[CH3:30]
Reactant: [H][H]
Reactant: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Agent: [Ni]
Agent: [Rh]
Agent: C=CC=C
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(N)C(C)C
Yield: 83 %

Procedure:
Isobutgraldazine is prepared by causing isobutyraldehyde to react with hydrazine hydrate according to the operating conditions described in Example 1. One then carries out the cyclooligomerization reaction of the azine with the butadiene by using a molar ratio of 1/3 and by operating as in Example 1 (1 at. g of Ni for 20 moles of azine). In 100 ml of tert. butanol, 14 g of 3,12-diisopropyl-1,2-diaza-1,5,9 cyclododecatriene are hydrogenated in a 300-ml autoclave, in the presence of 1.4 g of rhodium catalyst deposited at 5% on alumina. The reaction is allowed to take place for 30 minutes under 100 bars of hydrogen at 30° C., then one maintains a temperature level of 160° C. under 200 bars of hydrogen for 25 hours. 12 g of the 1,10-diamino-1,10-diisopropyl decane thus obtained are chlorhydrated and phosgenated in the same manner as in Example 1. One recovers 13.2 g of 1,10 -diisopropyl-1,10-diisocyanate (phosgenation yield: 92% with respect to the amine) having an NCO group content of 1.85 equivalents per mole and presenting the following N.M.R. characteristics of the 13C atom (chemical shifts expressed in relation to CDCl3 at 77 ppm): ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C(N(CC)CC)C.Cl>ClCCl.C(OCC)(=O)C>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])=[O:13]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloroaniline (5.15 g, 40.37 mmol) in dichloromethane (50 mL) was added 2,4-dichlorobenzoyl chloride 1 (8.88 g, 42.39 mmol) and then triethylamine (6.1 mL, 44 mmol). The reaction mixture was stirred overnight at ambient temperature and ethyl acetate (150 mL) was added followed by 1N HCl (50 mL). The organic phase was washed with water and brine, dried, and concentrated under reduced pressure to yield a light yellow solid. 2,4-dichloro-N-(2-chlorophenyl)benzamide 2 was used for the next step without further purification. Yield: 11 g, 90%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:21]1[CH2:26][CH2:25]O[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.N1CCCC1>C1COCC1>[O:19]=[C:17]([N:21]1[CH2:26][CH2:25][CH2:23][CH2:22]1)[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of N-Boc-(2S)-3-(pyridin-4-yl)alanine (500 mg, 1.9 mmol) in THF (12 mL) was added N-methylmorpholine (200 μL, 1.9 mmol) and the solution was stirred for 5 min, cooled at −15° C. and treated dropwise with isobutyl chloroformate (249 μL, 1.9 mmol). The mixture was stirred for 10 min and pyrrolidine (1.08 g, 15.2 mmol) was added and allowed to warm to 25° C. with stirring for 3 h. The solvent were removed under reduced pressure and the residue was partitioned between EtOAc and NaH2PO4 pH=7.2. The aqueous layer was discarded and the organic layer was washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered and evaporated. The resulting solid was purified by column chromatography (SiO2) with a gradient of 0% to 10% [v/v] MeOH in EtOAc to give tert-butyl (S)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06190 (167 mg, 28% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
To around bottom flask containing 1-{5-[3-(4-fluorophenyl)(1H-indazol-5-yl)](4H-1,2,4-triazol-3-yl)]-4-methoxybenzene (100 mg, 0.26 mmol) was added anhydrous dichloromethane (2 ml). The flask, under a nitrogen atmosphere, was placed in an ice/salt bath. To the flask was added boron tribromide (1.3 ml, 1.3 mmol). The reaction was allowed to stir at 0° C. for one hour and at room temperature for an additional four hours. The reaction was quenched with water and the solvent was removed. The product was extracted from the reaction mixture with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated. The product was purified by semipreparative HPLC (20–80% acetonitrile over 30 minutes) to yield the title compound (18 mg, 18.7% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.95 (s, 1H), 8.65 (s, 1H), 8.1 (m, 3H), 7.95 (m, 2H), 7.78 (d, 1H), 7.4 (m, 2H), 6.85 (m, 2H), ES-MS m/z 372 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH2:22])=[N:10]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Temperature: 72 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) (380 mg, 0.875 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (95%, 138 μL, 0.877 mmol) were combined in methanol (15 mL) and heated at 72° C. for 18 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (Gradient: 45% to 100% ethyl acetate in heptane), affording the product as a white solid. Yield: 266 mg, 0.805 mmol, 92%. LCMS m/z 331.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.33 (ddd, J=9.6, 8.8, 6.6 Hz, 1H), 6.92-7.00 (m, 2H), 4.42 (ddd, doublet of [half of ABX pattern], J=47.4, 10.0, 3.3 Hz, 1H), 4.38 (ddd, doublet of [half of ABX pattern], J=48.0, 10.0, 5.5 Hz, 1H), 4.13 (dd, J=11.1, 2.2 Hz, 1H), 3.81-3.93 (m, 1H), 3.74 (d, J=11.1 Hz, 1H), 3.06-3.14 (m, 1H), 2.78 (ddd, J=11.9, 4.1, 3.7 Hz, 1H), 1.43-1.61 (m, 2H), 1.17 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[NH3:15]>>[N+:1]([C:4]1[C:5]([C:10]([NH2:15])=[O:11])=[C:6]([C:7]([OH:9])=[O:8])[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: N
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
52.5 g (0.27 mol) of 3-nitrophthalic anhydride were stirred in portions over the course of 30 minutes into 75 ml of concentrated aqueous ammonia at room temperature. The mixture was then cooled to 0° C., after which a precipitate crystallized out and was filtered off with suction. This precipitate was dissolved in 125 ml of water by gently heating, and 25.6 ml of 32% strength hydrochloric acid were rapidly added. The mixture was cooled to 0° C., and the crystals which separated out were filtered off with suction. 45 g of the product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:24](=[O:25])[NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and benzyl isocyanate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:28][OH:29]>C(O)C>[OH:29][NH:28][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)[CH2:24][CH2:23]1)=[NH:26]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=N)NO)CC3)cc2)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarbonitrile (60 mg, 0.16 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol) in ethanol (5 mL) was heated at 80° C. for 2 h, then cooled to ambient temperature overnight. The mixture was concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 60 mg (93%) of N-hydroxy-4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboximidamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (m, 2H), 7.87 (m, 2H), 7.69 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 3.91 (d, 2H, J=6.0 Hz), 3.84-3.74 (m, 2H), 3.22 (s, 3H), 3.02-2.96 (m, 2H), 2.05 (bs, 2H), 1.86-1.76 (m, 2H), 1.36-1.22 (m, 2H); LRMS (ESI), m/z 404 (M+H).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([CH:21]([CH3:23])[CH3:22])=[N:13][CH:12]([NH:24]C(OC(C)(C)C)=O)[C:11]1=[O:32])(=[O:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([CH:21]([CH3:22])[CH3:23])=[N:13][CH:12]([NH2:24])[C:11]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(C(C)C)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1sccc1CN1C(=O)C(N)N=C(C(C)C)c2ccccc21
Yield: 79.7 %

Procedure:
A solution of (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.370 g) in ethyl acetate (50 ml) was treated with gaseous hydrogen chloride at 5˜10° C. in an ice-bath for 30 minutes. The resultant mixture was extracted with 3N aqueous hydrochloric acid (2×10 ml). The aqueous layer was basified with sodium hydrogen carbonate and extracted with ethyl acetate (2×50 ml). The extracts were combined, over sodium sulfate, filtered and concentrated in vacuo to afford (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.230 g), which was used in a following reaction step without further purification.