Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=2)=[O:9])=[CH:6][N:5]=1>CO.O>[Br:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Reaction time: 4 h
Yield: 37.8 %

Procedure:
KOH pellets (5 g) were added to a suspension of methyl 6-(6-bromonicotinamido) nicotinate 3 (5 g, 14.8 mmol) in methanol and water (150/50 ml). The reaction mixture was stirred for 4 hours. Then the solvent was evaporated and the pH was adjusted to below 2. The white solid was filtered off and washed with cold water and dried under vacuum to give 6-(6-bromonicotinamido)nicotinic acid 4 (1.8 g, 37%). Mp. 270-272° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]5[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=5[Cl:32])=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc(Cl)cc3Cl)cc2)C1
Temperature: 110 °C
Yield: 22.2 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (2,4-dichlorophenyl)boronic acid (98 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was heated in an aluminum block at 110° C. for 2 h. The cooled reaction was diluted with ethanol then evaporated under reduced pressure to a yellow residue. The residue was triturated from methanol and the filtered methanol layer was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-70% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired product fractions were combined and evaporated in vacuo to a residue that was recrystallized from hexanes/ethyl acetate to afford the title compound as a white solid (26 mg, 21.8%). MS(ES)+ m/e 457.0, 459.2 [M+H]+, chlorine pattern.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[CH:26][C:27](O)=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[CH:26]/[C:27]3[NH:1][C:2]4[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=4[N:8]=3)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCCO2
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCCO4)nc2n(CC)c1=O
Yield: 50.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.85 g (14.4 mmol) of 5,6-diamino-1,3diethyluracil and 2.70 g (13.1 mmol) of 3-(1,4-benzodioxan-6-yl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.45 g (yield 51%) of Compound 80 as a pale yellow powder.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Cu][C:35]#[N:36]>CN1C(=O)CCC1>[C:35]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8])#[N:36]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide Example 1 (d), 120 mg, 0.20 mmol) and copper (I) cyanide (66.7 mg, 0.74 mmol) in NMP (2.5 ml) was stirred overnight at 140° C. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was first purified by preparative HPLC and then by flash chromatography eluting with dichloromethane/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>CN(C)C=O>[O:1]([CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCOc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCOc1ccccc1

Procedure:
252.3 g (1.40 mole) of 4-phenoxybutyric acid, 154 ml (2.1 mole) of thionyl chloride and a few drops of dimethylformamide are heated under reflux with exclusion of moisture. After evolution of gas has ceased (about 2 hours), the mixture is fractionated under water pump vacuum. The acid chloride distils at 149°-151° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.Cl.[CH3:14][O:15][NH2:16]>C(O)C>[CH3:14][O:15][N:16]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[CH2:2][Br:1]
Reactant: CON
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CON=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To 4.00 g of 2-bromo-1-(2,4-dichlorophenyl)ethanone in 20 ml of ethanol, 1.25 g of methoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with 20 ml of water and extracted with ethyl acetate (20 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and then dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.85 g of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:14]([OH:16])=[O:15].[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)(Cl)Cl>[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:21]1[CH:22]=[CH:23][C:18]([C:13]([CH3:17])([CH3:12])[C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: NC(=O)N1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
Add AlCl3 (8.31 g, 62.3 mmol) to carbon tetrachloride (65 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (03.5 mL, 31.2 mmol), stir for 15 minutes and add, by dropwise addition over 15 minutes, a solution of 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (5.64 g, -26.0 mmol) in carbon tetrachloride (60 mL). Stir at room temperature for 17 hours, pour into ice water (100 mL) and separate the layers. Wash the aqueous layer with methylene chloride (2×70 mL), 5% aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (6.55 g, 78%) as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The 4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (6.81 g, 14.2 mmol) in methylene chloride (DCM) (60 ml) was cooled to 0° C. and was treated with Hunig's base (9.9 ml, 56.8 mmol). The mixture was kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (3.3 g, 15.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 ml) and was washed water (100 ml) and a saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the title compound as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.42 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m, 2H), 7.43-7.39 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H), 7.05-6.98 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s, 3H), 3.74 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m, 1H). LCMS: 581 [M+H].
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([O-:21])[CH:11]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].F[C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33]>>[F:30][C:29]1[C:24]([O:21][C:10]2[CH:9]=[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)=[C:25]([N+:32]([O-:34])=[O:33])[CH:26]=[CH:27][C:28]=1[F:31]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(C)(C)NC(=O)c1cc([O-])cc(C(=O)NC(C)(C)C)c1
Agent: [Na+]
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene 111 (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Temperature: 95 °C
Yield: 53.2 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.20 g, 0.53 mmol), phenylacetylene (0.06 mL, 0.55 mmol), bis(triphenylphosphine)palladium(II) chloride (25 mg, 0.04 mmol), and triethylamine (0.16 mL, 1.14 mmol) in 3 mL of N,N-dimethylformamide was heated at 95° C. under argon for 19 hours. Workup as described in Example 1h and purification by flash chromatography, eluting with ethyl acetate/dichloromethane, afforded 0.1 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]=O)=[CH:21][CH:20]=1.[C:29]([CH2:31]P(=O)(OCC)OCC)#[N:30]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]=[CH:31]/[C:29]#[N:30])=[CH:21][CH:20]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/C=C/C#N)cc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2,4-pentadienenitrile. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.159°-160° C.
Reaction SMILES: [C:1]1([N:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]3=[CH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:17][C:9]1[C:8](=[O:16])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc2n(n1-c1ccccc1)CCCC2
Agent: [Al]
Solvent: ClCCl
Product: O=c1c(Br)c2n(n1-c1ccccc1)CCCC2
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of 1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one (0.21 g) in methylene chloride (4 mL) was added N-bromosuccinimide (0.18 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 3-bromo-1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one (0.15 g) as a light brown solid. MS (ESI+): 295.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][C:36]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:35]=[CH:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCCc1oc(-n2cnc(-c3ccccc3)c2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 4,5-diphenylimidazole (270 mg), anhydrous potassium carbonate (220 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 12 hours. The reaction mixture was poured into water, the resulting solid precipitate was filtered and air-dried. Recrystallization of this solid from acetone-isopropyl ether gave 4-(4-chlorophenyl)-2-(4,5-diphenyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (220 mg, 46%). Melting point 118-119° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:11][N:10]([CH3:31])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[C:12]1[C:4]2[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=3)[CH:3]=2)[N:10]([CH3:31])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 73.8 %

Procedure:
A mixture of Example 182B (238 mg, 0.485 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.485 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (31.4 mg, 0.048 mmol) and potassium phosphate (309 mg, 1.454 mmol) in 9 mL tetrahydrofuran and 3 mL water was heated at 60° C. for 3 hours. Water was added, extracted with ethyl acetate (3×), washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-50% ethyl acetate in heptanes to give the title compound (212 mg, 0.358 mmol, 73.8% yield) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:40]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:40])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 88.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.18 g, 90.0%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[C:3]=1[F:14].[O:15]=[C:16]1[O:20][CH:19]([O:21][CH2:22][CH2:23][C:24]2C=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41]C(=O)C2C=CC(N)=C(Cl)C=2)[CH3:40])=[O:32])[CH2:17]1>>[CH2:22]([O:21][CH:19]1[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41][C:6](=[O:8])[C:5]2[C:4]([F:13])=[C:3]([F:14])[C:2]([NH2:1])=[C:10]([F:11])[C:9]=2[F:12])[CH3:40])=[O:32])[CH2:17][C:16](=[O:15])[O:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1c(F)c(F)c(N)c(F)c1F)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 73 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbmoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-2,3,5,6-tetrafluoro-benzoic acid according to the procedure used to prepare 98a to afford 58 mg of title compound (73% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.30-1.50 (m, 3H), 1.62-2.35 (m, 4H), 2.45-3.12 (m, 2H), 3.50-3.90 (m, 2H), 4.20-4.95 (m, 5H), 5.42 (s, 0.4H), 5.52 (s, 0.1H), 5.64 (d, 0.4H), 5.82 (d, 0.1H), 7.25-7.65 (m, 5H). Analytical HPLC: 16.56, 16.90 min. LC-MS (ES+): m/e=567.2 (M+H+).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide (10.0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.4 g of (4R-cis)-6-(2-aminoethyl)-2,2 -dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide as an oil;