Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].[I-].[K+].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1>N1C=CC=CC=1>[F:19][C:9]1[CH:8]=[C:7]([C:2]#[N:3])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#C[Cu]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 151 °C
Reaction time: 24 h

Procedure:
Copper (I) cyanide (10.69 g, 0.12 mol) and potassium iodide (6.21 g, 0.037 mol) are added to a stirred pyridine solution (10 mL) of 4-bromo-2-fluorobiphenyl (10 g, 0.040 mol). The reaction mixture is heated at 150-152° C., 5 mL pyridine is distilled out and heating is continued at 150-152° C. for 24 hrs. The reaction mixture is cooled to 95-1000, toluene (100 mL) is added to it. It is cooled to 35-40° C. and an aqueous ammonia solution (25%, 100 mL) is added. After stirring for half an hour, toluene layer is separated and washed with aqueous ammonia solution (2×50 mL), then demineralized water (3×100 mL). The toluene layer is charcoalized and concentrated to give 2-fluorobiphenyl-4-carbonitrile.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)c1ccccc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccccc1
Reaction time: 8 h
Yield: 217.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.50 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, overnight. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was combined with 5.0 g of crude, previously prepared material and purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 6.3 g (58%) of product, mp 196°-198° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][C:52]=1[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[C:52]([CH3:63])[CH:53]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1Cl
Yield: 40.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (7 mg). MS (ESI, pos. ion) m/z: calcd for C22H20ClFN2O4: 430.1096, found 430.1094.
Reaction SMILES: C(O)(=O)C.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)=[O:8].[N+:28]([O-])([OH:30])=[O:29]>O>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([N+:28]([O-:30])=[O:29])=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)ccc1Oc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Temperature: 90 °C
Yield: 59 %

Procedure:
To 71 ml of an acetic acid solution containing 14.0 g of N-(5-chloroacetylamino-2-phenoxyphenyl)methanesulfonamide was added 4.4 g of 60% nitric acid with heating at 90° C. with stirring, followed by stirring for 20 minutes. Water was added to the reaction solution of which temperature was allowed to return to room temperature. The precipitate was collected by filtration and recrystallized from ethanol-n-hexane to give 9.3 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide as yellow needles.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:29][C:30]([Cl:34])([Cl:33])[CH2:31]O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:9]([O:11][CH2:31][C:30]([Cl:34])([Cl:33])[Cl:29])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
Fmoc-Ser(tBu)-OH (1 g, 2.6 mmol) was dissolved in CH2Cl2 (7 mL). DMAP (0.15 g, 1.3 mmol, 0.5 equiv) and 2,2,2-trichloroethanol (Tce) (0.3 mL, 3.1 mmol, 1.2 equiv) were first added, and then DCC (0.63 g, 3.1 mmol, 1.2 equiv) in CH2Cl2 (2.5 mL) was added under N2 atmosphere at 0° C. The reaction mixture was allowed to stir for 18 h at room temperature. The organic reaction was cooled to 0° C., filtered and the filtrate was concentrate in vacuo. The resulting crude was dissolved in EtOAc (7 mL) and washed with 10% aqueous citric acid (2×10 mL), saturated aqueous NaHCO3 (2×10 mL) and brine (2×10 mL), dried (MgSO4), and concentrated in vacuo to give Fmoc-Ser(OtBu)-OTce (1.34 g), which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-]>C1(C)C=CC=CC=1.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>[F:10][C:5]1[CH:4]=[C:3]([O:11][CH3:12])[C:2]([CH2:15][CH:14]=[CH2:13])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COc1cc(F)c(C#N)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(C#N)c(F)cc1OC

Procedure:
A mixture of compound 5-bromo-2-fluoro-4-methoxybenzonitrile (10.0 mmol), allyl-tributyl-stannane (12.0 mmol), LiCl (20.0 mmol) and Pd(PPh3)4 (0.2 g) in anhydrous toluene was refluxed under N2 overnight. Distilled off the solvent under reduce pressure, the residue was purified with silica gel cloumn chromatography to give the product 2-fluoro-4-methoxy-5-(prop-2-en-1-yl)benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 4-Fluoro-3-nitro aniline (0.5 g, 3.2 mmol), 4-bromobenzoyl chloride (0.702 g, 3.2 mmol), diisopropylethylamine (0.56 ml, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hr. The mixture was diluted with dichloromethane (50 mL) and washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound as a yellow solid (0.89 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:34]1)=[O:24]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3cc(OC)c(OC)cc13)C2
Yield: 19.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 111 (19.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.81 and 3.05 (2t, 2H), 3.48-4.06 (m, 11H), 4.41 and 4.93 (2s, 2H), 6.66-6.92 (m, 3H), 7.14-7.27 (m, 1H), 7.37-7.41 (m, 1H), 7.51 and 7.54 (2s, 1H), 7.59-7.63 (m, 1H), 8.15-8.20 (m, 1H), 8.31-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) δ −113.0; MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=12.N1C2=C(OC3C=CC(N)=CC=3[F:39])N=CC=C2C=C1>>[F:39][C:16]1[CH:15]=[C:3]([O:4][C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=23)[CH:2]=[CH:18][C:17]=1[NH2:19]
Reactant: Cn1ccc2ccnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Reactant: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Yield: 89 %

Procedure:
Starting from the compound 264 and following the procedure described above for the synthesis of amine 261 (scheme 59, step 3, example 218), title compound 265 was obtained in 89% yield as an off-white solid. MS (m/z): 258.1 (M+H) (found).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:30][C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1
Reactant: COc1ccc(-c2c(C)nn3c(O)cc(C)nc23)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(C)nn3c(Cl)cc(C)nc23)c(OC)c1
Reaction time: 2 h

Procedure:
Slurry 7-hydroxy-2,5-dimethyl-3-(2,4-dimethoxyphenyl)-pyrazolo[1,5-a] pyrimidine in 10 mL POCl3 and reflux at 130° C. under N2. After 2 h, monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent), quench the reaction carefully at ambient temperature by diluting with 50 mL CH2Cl2 and pouring slowly into non-stirring saturated NaHCO3. Adjust stirring speed to control rate of quenching of residual POCl3 and stir until gas evolution ceases. Separate the layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil, which is used directly without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH:15]C(=O)OC(C)(C)C)=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>>[N:1]1([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: Cl
Product: Nc1ccc2nc(N3CCOCC3)nn2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (363 mg, 1.14 mmol) and hydrochloric acid (5M in diethyl ether, 24.0 g, 20 ml, 100 mmol) was stirred for 5 hours at 25° C. and then the solvent was evaporated under reduced pressure. The light yellow residue was made alkaline using sodium hydroxide solution (2 M in water). The mixture was extracted 2 times with ethyl acetate, the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtrated and evaporated to dryness, affording 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (227 mg, 91%) as grey solid. Mp.: 165° C. MS: m/z=220.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][CH2:15]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][CH2:15][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(C#CCBr)cc(C(F)(F)F)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(C#CCN2CCCCC2)cc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
A mixture of 1-(3,5-bistrifluoromethylphenyl)-3-bromoprop-1-yne (2.53 g), piperidine (5 ml) and anhydrous potassium carbonate (5 g) in dry acetone (50 ml) was heated at reflux with stirring for 18 h. Removal of the solvent under reduced pressure and distillation of the residue under reduced pressure gave 2.26 g of an oil of boiling point 95° C./0.025 mm Hg.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:10]N1C(=O)CCC1=O>C(#N)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:1]#[N:9])[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccccc1N
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N
Temperature: 50 °C
Yield: 46.3 %

Procedure:
A 2 L round bottom flask was charged with 138 g (1.168 mol) of anthranilonitrile (Aldrich) and 1.05 L of acetonitrile. The flask was heated to 50° C. and 172.5 g (1.29 mol) of N-chlorosuccinimide (Aldrich) was added in one portion. The reaction was heated at reflux for 2.0 h (HPLC monitoring), cooled to approx. 35° C., and the solvent is removed by rotovap at reduced pressure. The residue was partitioned between 1.5 L ethyl acetate and 1 L cold water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with 3 portions of cold water, brine, dried over MgSO4 and treated with activated carbon. The solvent was removed by rotovap at reduced pressure to give a pale orange solid which was crystallized from 430 mL of hot 1-chlorobutane and allowed to cool to room temp. overnight. After filtration, the resulting crystals were washed with cold butylchloride and air dried to give 82.5 g of off-white crystals (94% pure by HPLC). This material was recrystallized from 140 mL of s chlorobutane and 125 mL hexane to give 73 g (41%) of the title compound as a colorless solid. An additional 18.8 g (10.5%) was obtained from two recrystallizations of material from the mother liquors.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)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: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After cooling to room temperature water was added to the mixture and then product was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([Cl:9])[CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CO>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:1]
Reactant: ClCc1cccnc1
Reactant: Nc1ccc(S)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2cccnc2)c(Cl)c1
Yield: 44 %

Procedure:
4-amino-2-chlorobenzenethiol (1.2 g) was dissolved in methanol (24 ml), and to this solution was added 3N aqueous solution of sodium hydroxide (7.5 ml) and then, 3-(chloromethyl)pyridine hydrochloride (1.48 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 3-chloro-4-[(3-pyridinylmethyl)sulfanyl]aniline (0.83 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:22]>>[CH3:20][CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propan-2-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propan-2-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOCC>[OH:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[CH3:1]
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(O)cc(C)c1O

Procedure:
A solution of 2,6-dimethyl-1,4-benzoquinone (Xa) (5.66 g, 42 mmol, Aldrich) in Et2O (200 mL) was shaken vigorously in a separatory funnel with two 200 mL portions of aqueous sodium hydrosulfite solution (sodium dithionite, Na2S2O4, 14.5 g, 83.3 mmol) until the Et2O layer turned bright yellow. The ether layer was washed with brine (200 mL×2), dried (MgSO4) and concentrated in vacuo to obtain 4.865 g (35.3 mmol, Y: 83.9%) of the title compound as a white solid; mp, 148-150° C. (acetone-hexane) [mp reported by L. A. Carpino, S. A. Triolo, and R. A. Berglund in J. Org. Chem., 54, p. 3303 (1989): 145-148° C.]; Rf: 0.47 (10% EtOAc in CH2Cl2); IR(KBr) 3312 cm-1 (OH); 1H-NMR (300 MHz, acetone-d6) δ ppm: 2.15 (6H, s, Me), 6.45 (2H, s, Ar-H), 6.58 (1H, s, OH), 7.47 (1H, s, OH); 13C-NMR (75 MHz, acetone-d6) δ ppm: 16.84, 116.00, 126.45, 147.46, 151.54; MS (isobutane-DCI) m/e: 139 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]=[C:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccccc2C=C2CCNC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccccc2CC2CCNC2=O)CC1
Temperature: 50 °C
Yield: 99 %

Procedure:
A mixture of 3-[2-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzylidene]-pyrrolidin-2-one (Example 78), 308 mg, 1.15 mmol) and 10% palladium on carbon (300 mg) in methanol (20 mL) was placed under 50 psi hydrogen and was heated at 50° C. for 8 hours. The mixture was cooled to room temperature, was filtered through Celite™, and the solvent was removed in vacuo to afford 310 mg (99% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 180.1, 144.5, 136.8, 129.9, 127.1, 126.6, 126.2, 56.7, 46.7, 42.7, 40.6, 37.2, 33.9, 33.6, 33.5, 27.7; MS (AP/Cl) 273.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:36][N:35]=NN=3)[CH:14]=2)=[CH:4][N:3]=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[O:40][C:39]([CH2:38][Cl:37])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 105 °C
Yield: 23.5 %

Procedure:
N-{2-Chloro-5-[1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (1.3 g, 2.385 mmol) and chloro acetylchloride (0.285 ml, 3.58 mmol) were placed in toluene (35 ml) and the mixture heated at 105° C. for 30 mins. The temperature was increased to 115° C. and the mixture heated for 1 h. The mixture was cooled to room temperature and the solvent removed in vacuo. This was purified by chromatography on a silica (100 g) cartridge eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol in dichloromethane, to give the title compound as a yellow solid (0.332 g).