Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(OCC)(=O)C>[C:11]([NH:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NNc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: CC(=O)NNc1ccc(Cl)cc1Cl

Procedure:
Generally in a process of condensing a hydrazonoyl derivative of formula (A) to form a compound of formula (1), the free hydrazine (1) as described above, for example, 2,4-dichlorophenylhydrazine (1) is reacted with acetic anhydride at a temperature of about 10° C. in an appropriate solvent such as ethyl acetate, yielding the corresponding 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2). The hydrazine (2) is then chlorinated with phosphorous oxychloride at a temperature of about 110° C. in an appropriate solvent such as toluene, yielding the hydrazonoyl derivative of formula (A), N-(2,4-dichlorophenyl)ethanehydrozonoyl chloride. The hydrozonoyl chloride (A) is condensed with a ring forming agent, for example, potassium cyanate at a temperature of about 40° C. to about 65° C. in an appropriate solvent such as DMAC, yielding the corresponding compound of formula (1), 45-dihydro-1-(2,4-dichlorophenyl)-3-methyl-1,2,4-triazol-5(1H)-one. The condensing of hydrozonoyl chloride (A) to the compound of formula (1) in solvents such as DMAC is routinely aided by the presence of a catalyst, such as potassium fluoride. A detailed procedure for the preparation, and the potassium fluoride-catalized condensing of the hydrozonoyl chloride (A) with the ring forming agent potassium cyanate in DMAC to yield a compound of formula (1) is set forth in Example 1 hereinbelow.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:2]1(/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Ic1ccccc1
Product: C(=C/c1ccccc1)\c1ccccc1

Procedure:
Iodobenzene (32 μL, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above to give 81% conversion to (E)-stilbene by GC analysis.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH2:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH:19][S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)(=[O:39])=[O:38])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)quinolin-8-amine (0.10 g, 0.347 mmol) in CH2Cl2 (10 mL) was added DIPEA (0.120 mL, 0.695 mmol) followed by pyridine-2-sulfonyl chloride (0.065 g, 0.366 mmol). The mixture was stirred at room temperature for 18 hours. An aqueous solution of saturated NaHCO3 was added (30 mL), the resulting precipitate was collected by filtration and washed with methanol to obtain N-(2-(3-(trifluoromethyl)phenyl)quinolin-8-yl)pyridine-2-sulfonamide (0.025 g, 17% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)cc1
Temperature: 95 °C
Yield: 60 %

Procedure:
A mixture of compound 3 (4.01 g, 10.1 mmol), 1-bromo-4-iodobenzene (5.73 g, 20.2 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and potassium carbonate (4.2 g, 30 mmol) in dioxane/water (60 ml/10 ml) was degassed and heated at 95° C. overnight. After being cooled to RT, the mixture was filtered to collect the precipitate, which was redissolved in hot dichloromethane. The dichloromethane solution was filtered and concentrated with presence of methanol until a large amount of white precipitate forms. Filtration and drying in air gave a white solid (2.58 g, in 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]3=[O:7])=[N:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nc3)CC2)c(C)c1
Yield: 44.9 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (176 mg) was obtained.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O>C(#N)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Potassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5° C. A solution of 2-amino-5-methylthiophene-3-carbonitrile (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45° C. to obtain the title compound (140 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[NH3:13].O>O1CCCC1>[NH2:13][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(N)c(Cl)nc1C#N
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 6.1 g (0.050 mol) of 28% aqueous ammonia was dropwise added at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from a solvent mixture of toluene and ethyl acetate to obtain 4.2 g of slightly yellow crystals (yield: 93.6%, melting point: 205-208° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH:15][C:16]([O:18]C)=O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]3[C:8]=2[C:12](=[O:13])[NH:14][NH:15][C:16]3=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)NNC(=O)c1[nH]ccc1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)n2ccc(-c3ccccc3)c12
Temperature: 85 °C
Yield: 88 %

Procedure:
To a solution of methyl 2-(3-phenyl-1H-pyrrole-2-carbonyl)hydrazinecarboxylate (4.00 g, 15.0 mmol) in ethanol (60 mL) was added potassium hydroxide (4.33 g, 770 mmol) at room temperature and heated to 85° C. for 30 min. The reaction mixture was evaporated under reduced pressure to give a brown solid, which was redissolved in water (100 mL) and acidified with saturated citric acid solution to pH 7. The solid obtained was filtered through the Buchner funnel and further it was triturated with hexane to yield 8-phenyl-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (3.00 g, 86.0%) as a white solid. LCMS method B-3: retention time 1.59 min, [M+1]=228.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.88 (d, J=2.8 Hz, 1H), 7.29-7.39 (m, 3H), 7.64-7.66 (m, 2H), 7.76 (d, J=2.8 Hz, 1H), 11.43 (br s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)#[N:2].[OH-:45].[Na+].OO.Cl>CS(C)=O.C(O)C>[CH3:32][O:31][C:9]1[C:8]2[C:3]([C:1]([NH2:2])=[O:45])=[N:4][C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[O:35])=[CH:6][C:7]=2[N:11]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C#N)c12
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(N)=O)c12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(4-cyano-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (70 mg, 0.121 mmol, synthesized from Intermediate 42B following Scheme 3-Step 2/Method A) was taken up in DMSO (605 μl) and Ethanol (605 μl). NaOH (1.8 ml, 1.815 mmol) was added followed by dropwise addition of hydrogen peroxide (180 μl, 2.056 mmol). The reaction was heated to 60° C. and was allowed to stir for 30 minutes. Room temperature was attained and 1N HCl was added and the products were extracted into EtOAc (3×). The organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give (R)-3-methoxy-6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxamide. The products were carried forward without purification. MS: [M+H]+ m/z 597.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[C:7][CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:17]([N:24]=[N+:25]=[N-:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:7]([CH3:8])=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1C
Temperature: 150 °C

Procedure:
Tributyl(1-propynyl)tin (3.87 g, 11.8 mmol) and benzyl azide (2.2 mL, 17.6 mmol) were combined and heated to 150° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 464.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].Cl[C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:35](=[O:36])[O:37][CH3:38])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.030 g (0.0607 mmol) of the product from Example 26 in CH2Cl2 (0.6 mL) at 0° C. was treated with methyl chloroformate (5 μL; 0.0607 mmol) followed by diisopropylethylamine (10 μL; 0.0607 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 551.9 (M+1), 553.9 (M+3); Rt=4.24 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4](Cl)[N:3]=1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:17]2[CH2:18][CH2:19][CH2:16][CH2:15]2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of ethyl 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (3.00 g, 12.6 mmol: J. Med. Chem., 1986;29:2363) and triethylamine (2.63 mL, 18.90 mmol) in acetonitrile (15 mL) was added pyrrolidine (1.05 mL, 12.6 mmol) dropwise. After being stirred at 60° C. for 1 hour, the reaction mixture was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue was purified on a silica gel column using hexane/dichloromethane (7:3) as eluent giving 2.5 g of the title compound as a solid, mp 95° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[C:19](OCC)(=O)C.O>CO.S(=O)(=O)(O)O>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Commercially available 4-bromo-3-nitro-benzoic acid (1.17 g, 4.76 mmol) was dissolved in methanol (5 mL) containing five drops of concentrated sulfuric acid. The mixture was heated in air at 90° C. for six hours and more MeOH (7 mL) followed by concentrated sulfuric acid (0.6 mL) was added. Heating was continued another 24 hours. Extractive work up (ethyl acetate-water) followed by drying over MgSO4, filtered and concentrated under vacuum giving the title compound in quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2]
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)ccc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (38 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 214. MS m/z 411.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.23 (dd, 1H), 9.13 (d, 1H), 8.56 (dd, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.86-7.78 (m, 2H), 7.74 (d, 1H), 7.63 (dt, 1H), 7.50 (s, 1H), 3.97 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]2[C:29](=[O:30])[CH2:28][NH:27][C:26]2=[O:31])=[O:23])[C:11](=[O:20])[NH:12][O:13]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]2[C:29](=[O:30])[CH2:28][NH:27][C:26]2=[O:31])=[O:23])[C:11](=[O:20])[NH:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
A solution of 0.280 g of 2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in 10 ml of methanol was treated with 0.028 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.069 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[NH:27][CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4.C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(C)=O)CC3
Temperature: 60 °C
Yield: 81.9 %

Procedure:
Acetic anhydride (3.14 g, 30.76 mmol) was added to a solution of (+)-3-methoxy-morphinan hydrochloride (1.5 g, 5.1 mmol) in THF (30 ml) and triethylamine (8.7 g, 85.98 mmol) in the presence of nitrogen. The resulting solution was heated at 60° C. for 15 hr. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was dissolved in methylene chloride (50 ml), washed with water (40 ml×2) and dried (MgSO4). Evaporation of the dried solution gave a tan viscous oil (1.25 g, 81% yield); ms (ESI+): m/z 300 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH3:53])[CH3:51])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Reactant: CN(C)CCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. N,N-Di-methyl-3-amino-propyl-amine (12 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by flash column chromatography (Merck silica gel 60, 40-63 μm; 0.5% ammonium hydroxide/methanol) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamide (3 mg, 6.5%) as a clear oil: ESI-LRMS m/e calcd for C31H40ClN5O4S [M+] 613.25, found 614.21 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.44-1.94 (m, 8H, 4×CH2), 2.10-2.32 (m, 3H, CH), 2.78 (s, 6H, 2×NCH3), 3.06 (t, J=6.4 Hz, 2H, NCH2), 3.25 (s, 3H, SO2CH3), 3.56-3.66 (m, 2H, CH2), 3.69 (t, J=7.6 Hz, 1H, CH), 5.15 (s, 2H, NCH2), 6.72 (d, J=2.3 Hz, 1H, Ar), 7.13 (d, Jo=8.1 Hz, 2H, Ar), 7.33 (d, J=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.91 (d, Jo=8.1 Hz, 2H, Ar), 8.05 (d, Jo=8.1 Hz, 1H, Ar), 8.37 (brm, 1H, NH), 8.59 (s, 1H, NH).