Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccccc2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 8, 80 mg, 0.156 mmol), phenylboronic acid (27 mg, 0.22 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.016 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.16 mL, 0.32 mmol). After stirring for 72 h at 75° C., the reaction mixture is filtered, basified with aqueous NH4OH solution and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 59 mg (74% of theory); ESI mass spectrum: [M+H]+=512; Retention time HPLC: 0.98 min (Z003—001).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](B(O)O)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:21]2[CH:26]=[N:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:23][CH:22]=2)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: FC(F)(F)COc1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(B(O)O)c1
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: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-((tert-Butyldimethylsilyloxy)methyl)-2-fluoropyridin-3-ylboronic acid (0.400 g, 1.40 mmol) was placed into a flask with a mixture of DME/H2O (6 mL/2 mL). To the reaction mixture was added 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.358 g, 1.40 mmol), Na2CO3 (1.87 g, 17.6 mmol), and Pd(PPh3)4 (0.081 g, 0.07 mmol) and the reaction was allowed to stir at 80° C. overnight. The reaction was cooled to rt and concentrated. A solution of saturated NaHCO3 (5 mL) was added, and then this mixture was extracted with EtOAc (3×20 mL). The combined organic layer was then washed with saturated NaHCO3 (1×10 mL), brine (1×10 mL), dried (MgSO4), filtered, and concentrated. Purification by column chromatography (9:1 hexane:EtOAc) gave 5-((tert-butyldimethylsilyloxy)methyl)-2-fluoro-3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyridine.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[C:51](=O)[CH3:52])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:51]([C:44]2[CH:45]=[C:46]([O:49][CH3:50])[CH:47]=[CH:48][C:43]=2[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:52]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(C2CCCCC2)c(C(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CCCCC2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 21 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (86 mg, 0.22 mmol) was reacted with Compound 545a (50 mg, 0.22 mmol) in ethanol (3 mL) using 10% w/v KOH in Ethanol (436 μL, 0.66 mmol) to produce the title compound (26 mg, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([C@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[F:30])[CH3:23])=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([NH2:48])=[O:47]>CN(C=O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:23])[C@H:24]5[CH2:29][CH2:28][N:27]([CH2:45][C:46]([NH2:48])=[O:47])[CH2:26][C@H:25]5[F:30])=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:36])([F:37])[F:35])[CH:3]=1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@H]1CCNC[C@H]1F
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@H]1CCN(CC(N)=O)C[C@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{[(3R,4S)-3-fluoropiperidin-4-yl](methyl)amino}-1,3-thiazol-4(5H)-one (previous Example 54) (90 mg, 0.16 mmol) in DMF (2 mL) was added potassium carbonate (45 mg, 0.32 mmol) followed by 2-Bromo-acetamide (27 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (63 mg, 64%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1([NH2:7])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccn2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccccn2)CCC1
Reaction time: 6 h
Yield: 38.5 %

Procedure:
Crude (1-pyridin-2-yl-cyclobutyl)-carbamic acid tert-butyl ester (7.0 g, 5.64 mmol) was dissolved in DCM (20 mL) and TFA (20 mL) was added dropwise. After 6 h, the reaction was concentrated in vacuo and partitioned between DCM (100 mL) and water (20 mL). The aqueous layer was extracted with DCM (2×50 mL). The aqueous layer was then concentrated in vacuo. The brown oil was dissolved in water (3 mL) and purified via Mass-directed reverse phase HPLC purification which yielded 322 mg of 1-pyridin-2-yl-cyclobutylamine as a formic acid salt (yellow solid), m/z=149.5 [M+1]+.
Reaction SMILES: [CH:1](OCC)=[O:2].[NH2:6][CH:7]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:8][N:9]1[CH2:16][CH:15]2[CH2:17][CH:11]([CH2:12][N:13]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:10]1>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:7]([NH:6][CH:1]=[O:2])[CH2:8][N:9]2[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][N:13]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:12]3)[CH2:16]2)=[CH:25][CH:26]=1)#[N:31]
Reactant: CC(C)OC(=O)N1CC2CC(CN(CC(N)c3ccc(C#N)cc3)C2)C1
Reactant: CCOC=O
Product: CC(C)OC(=O)N1CC2CC(CN(CC(NC=O)c3ccc(C#N)cc3)C2)C1
Yield: 40 %

Procedure:
Ethyl formate (0.5 mL) was added to a stirred solution of iso-propyl 7-[2-amino-2-(4-cyanophenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from Example 9(viii) above; 0.71 g; 2.0 mmol), and the reaction mixture was refluxed for 5 h. The solvent was evaporated and the residue partitioned between diethyl ether and NaOH (2 M). The organic layer was separated, washed with water, dried and then concentrated. The resulting residue was then recrystallized from MeOH and di-iso-propyl ether to give the title compound in 40% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.448 mmol; prepared according to the procedure of Example 46, Step B), 4-fluorobenzenamine (0.056 ml, 0.582 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.132 g, 99%) as a pale yellow solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])[CH:5]=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][N:19]([CH2:21]N(C)C)[CH3:20].C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH3:18][N:19]([CH2:21][CH:10]([CH2:11][CH2:12][CH2:13][Cl:14])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:16][CH3:17])=[C:2]([Cl:1])[C:7]=1[Cl:8])=[O:15])[CH3:20]
Reactant: COc1ccc(C(=O)CCCCCl)c(Cl)c1Cl
Reactant: CN(C)CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(=O)C(CCCCl)CN(C)C)c(Cl)c1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2,3-Dichloro-4-(5-chloropentanoyl)anisole (29.5 g, 0.1 mole) and N,N,N',N'-tetramethyldiaminomethane (25.5 g, 0.249 mole) were stirred and heated at 50° C. and then acetic anhydride (36.8 g, 0.36 mole) was added dropwise with stirring at such a rate that the temperature rose to 100° C. After heating at 95° C. for an additional 2 hours, the mixture was kept at ambient temperature for 15 hours, poured into crushed ice (400 g), strongly basified with 10 normal sodium hydroxide and extracted with ether. The ether extract was dried over Na2SO4 and the solvent removed in vacuo to give 2-(dimethylaminomethyl)-5-chloro-1-(2,3-dichloro-4-methoxyphenyl)-1-pentanone as a viscous oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][F:23])=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])[C:3]([O:5]C)=[O:4].O1CCCC1>[OH-].[Na+].O>[NH2:1][C@@H:2]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][F:23])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(OCF)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CCC(Cc1ccc(OCF)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 5.9 %

Procedure:
Dimethyl (2S)-2-amino-5-[4-(fluoromethoxy)benzyl]hexanedioate (37 mg, 113 μmol) was solved in 2 ml of a mixture of tetrahydrofurane and water (2:1), and to the solution, four drops of 1N sodium hydroxide were added. The mixture was stirred at room temperature for 14 h and then concentrated in vacuo. The residue was purified by preparative HPLC and the according fractions were lyophilized to yield 2 mg (4.3%) of the title compound.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([CH3:59])([C:11]([NH:13][C@H:14]([C:18]([N:20]([C@@H:22]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:23]([O:53][CH3:54])[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([O:51][CH3:52])[C@@H:33]([CH3:50])[C:34](=[O:49])[NH:35][C@H:36]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:26])[CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:8][C:9]([CH3:59])([C:11]([NH:13][C@H:14]([C:18]([N:20]([C@@H:22]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:23]([O:53][CH3:54])[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([O:51][CH3:52])[C@@H:33]([CH3:50])[C:34](=[O:49])[NH:35][C@H:36]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:26])[CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Reaction time: 8 h

Procedure:
To a mixture of #87 (58 mg, 0.068 mmol, 1 eq.) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (10 mL), washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo to give #88 (52 mg, quantitative). LC-MS 757.6 [M+H+], retention time=0.69 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.6 Hz) and 8.87 (br d, J=8.6 Hz), total 1H], 7.80-7.85 (m, 1H), [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.1 Hz), total 1H], [7.63 (d, J=3.1 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.20-7.31 (m, 4H), 7.13-7.19 (m, 1H), [5.39 (ddd, J=11, 8.5, 4 Hz) and 5.49-5.56 (m), total 1H], [4.51 (dd, J=9, 8 Hz) and 4.61 (dd, J=9, 8 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.94 and 3.03 (2 br s, total 3H), 2.10 and 2.10 (2 s, total 3H), 1.16 (br s, 3H), 1.04-1.12 (m, 6H), 0.72-0.80 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccnc1Nc1cccc(Cl)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of N2-(3-chlorophenyl)pyridine-2,3-diamine (29 mg, 0.13 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (27 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol), 4-methylmorpholine (32 μL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) in DCM (5 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting {(S)-1-[2-(3-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (44 mg), was dissolved in AcOH (3 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (35 mg, 72% over two steps). LCMS (Method C): RT 3.34 min [M+H]+ 373.2.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:27][CH:26]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 3.21 g of p-chlorophenol to give a gel which crystallized on trituration with 50 ml of petroleum ether (6.45 g). Recrystallization from 50 ml of hexane yielded a 5.8 g of a white solid, mp 79°-82° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:45])[NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:45])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)[C@@H]1C[C@@H](F)CN1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
(2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (18 mg, 0.03 mmol) was dissolved in a solution of CH2Cl2 (1 mL)/TFA (1 mL) at rt. The reaction mixture was stirred overnight and concentrated to dryness under a stream of argon. The resulting residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10%-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (2S,4R)-4-fluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-1-(4-fluorophenyl)-2-phenylethyl)pyrrolidine-2-carboxamide (Example 276) as a white solid (13 mg, 83% yield). 1H NMR (500 MHz, MeOH-d4) δ ppm 7.22-7.13 (m, 7H), 7.07-6.96 (m, 7H), 6.68 (d, J=5 Hz, 2H), 6.40-6.18 (m, 1H, —CF2H), 5.43 (app d, J=50 Hz, 1H, —CFH), 4.55-4.51 (m, 1H), 4.01 (d, J=10 Hz, 1H), 3.92 (d, J=15 Hz, 1H), 3.65-3.49 (m, 2H), 2.72-2.64 (m, 1H), 2.10-1.96 (m, 1H); LC/MS: RT=3.310 min [M+H] 541.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:3]1[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: O=C1CCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCC2)c(Cl)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A suspension of molecular sieves (4 Å) and 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) in THF (50 mL) was cooled to −15° C. 1.3 M isopropyl magnesium chloride lithium chloride complex solution in THF (19.6 mL, 25.4 mmol) was added within 30 min. Stirring was continued for 1 h at −15° C. Cyclobutanone (1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continued for 2 h at −15° C. and for further 2 h at 0° C. Water (2.5 mL) was added, the mixture was concentrated in vacuo, and poured onto sat. aqueous NH4Cl solution. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (3.33 g, 70%) as white solid, MS (ESI): m/e=198.1 [MH+].
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[C:11]=1[Br:1])=[O:6]
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
Bromine (1.69 g, 0.54 ml, 10.54 mmol) was added dropwise to a stirred solution of methyl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49α, 1.85 g, 7.03 mmol) in acetic acid (20 ml) at 10° C. The resulting reaction mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. Acetic acid was removed from the reaction mixture under reduced pressure and residue obtained was dissolved in ethyl acetate (150 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (50 ml) followed by washing with brine (50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to obtain the title compound (2.1 g, 87.5%)