Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]=[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.[OH-].[K+].CO.Cl>O>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:6]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=2)=[CH:5][C:4]([OH:27])=[O:3])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCOC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(C(=CC(=O)O)c2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester (0.76 g, 2.05 mmol), potassium hydroxide (5 N, 8.10 ml, 20.52 mmol), methanol (6 ml), and H2O (1.5 ml) were mixed and stirred at rt for a couple of hours. The methanol was evaporated in vacuo leaving a clear solution, which was extracted with ether (2×60 ml) to get rid of the impurities. The aqueous phase was acidified with conc. HCl to pH around 23 to form a white precipitation, which was extracted with CH2Cl2 (2×100 ml), dried over MgSO4, filtered and concentrated to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid as a foamy solid (0.69 g, 98%); mp, 90-920C: 1HNMR (CDCl3) δ 6.90-6.75 (m, 4H, double bond protons and 2COOH), 6.50-6.24 (m, 12H, Ar), 3.92-3.75 (multiple singlets, 24H, 8OCH3), isomer ratio based on 1HNMR close to 43%:57%; Anal. Calcd. For C19H20O6: C, 66.27; H, 5.85. Found: C, 66.02; H, 5.81.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C@@H:9]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:3]1.[ClH:33]>O.O1CCOCC1>[ClH:33].[ClH:33].[Cl:33][C:31]1[CH:32]=[C:27]([C:4]2[CH:5]=[C:6]([NH:7][C:8](=[O:26])[C@@H:9]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:2]([CH3:1])[N:3]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 ml vial was added 800 mg of 17.8.B, 15 ml of dioxane, 10 drops of water and 4.5 ml of hydrogen chloride (2.0 M solution in diethyl ether). After 16 hours 10 ml of concentrated HCl were added and stirred at room temperature for 16 hours. The solvent was removed with a stream of nitrogen (dried with MeOH) to give 740 mg of 2-((S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetic acid diHCl salt as a light yellow solid (Note: trace methyl ester was observed in final product).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O>>[Cl:12][C:11]1[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (100.0 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at 60° C. for 3 days. the solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[N:36]1.O>C1COCC1.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>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:39]4[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccn(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 53, 100 mg, 0.185 mmol), 1-methyl-3-(tributylstannyl)-1H-pyrazole (62.4 mg, 0.168 mmol, prepared according to Heterocycles, 1997, 45, 1463), and PdCl2(PPh3)2 (11.8 mg, 0.0168 mmol) in THF (1.0 mL) was refluxed overnight. After cooling to room temperature, water was added, the reaction mixture was extracted with EtOAc, and the organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 542.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.66 (1H, d), 7.59 (1H, s), 7.50 (1H, s), 7.38 (111, d), 7.18 (2H, d), 7.08-7.13 (2H, m), 6.97 (2H, d), 6.40 (1H, s), 4.60-5.00 (2H, br s), 3.97 (3H, s), 1.26 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[CH2:6][CH2:5]2
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2cc(Cl)c(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)c(Cl)cc2CCN1c1cnccc1C(F)(F)F
Yield: 8.4 %

Procedure:
Using an analogous procedure and workup as described for the preparation of Example 1A above, 6,7-dichloro-3,4-dihydroisoquinolin-1(2H)-one (I-55d: 100 mg, 0.463 mmol) was reacted with 3-bromo-4-(trifluoromethyl)pyridine (115 mg, 0.509 mmol), 1,4-dioxane (3 mL), copper iodide (7 mg, 0.046 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (20 mg, 0.1388 mmol) and potassium phosphate (245 mg, 1.157 mmol) in a sealed tube at 120° C. for 16 hours to afford the crude product. Purification by column chromatography on silica gel (20% ethylacetate in hexane) afforded 14 mg of the product (8.3% yield).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:12]1[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: C=Cc1cc2c(cc1C)C(=O)OC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc2c(cc1C1CO1)COC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-ethenyl-6-methyl-2-benzofuran-1(3H)-one (1.00 g, 5.75 mmol) in 50 mL of DCM was slowly added m-CPBA (3.50 g, 17.4 mmol) in 50 mL of DCM at 0° C. The mixture was warmed to room temperature, and stirred for 2 days. The mixture was washed with aqueous Na2SO3 until KI indicator paper didn't change color. The organic layer was washed with brine and then concentrated. The residue was purified via silica column to give product 6-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. LC/MS (IE, m/z): [M+1]+=191.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C1COCC1>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was added KMnO4 (163 g, 1.03 mol) in portions and refiuxed for 12 h. The reaction mixture was filtered through celite and acidified with cone. HCl. The product was washed with water and dried to give 4-(3pyridyl)benzoic acid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g 0.44 mol, 50%) was added and stirred at RT for 12 h. The solid was filtered, and washed with TBF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])=[O:25]
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Sc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[4-(1-methylpropylthio)phenoxy]ethanol (4.26 g, 20.0 mmol) and triethylamine (4.2 ml, 30.0 mmol) in 100 ml methylene chloride at 0° is added dropwise methanesulfonyl chloride (1.7 ml, 22.0 mmol). The mixture is stirred at 0° for 20 min, after which it is poured into ice water. The methylene chloride layer is washed with ice water, with cold 10% sulfuric acid, with cold 5% sodium bicarbonate and with cold brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Br)cc2C#N)CC1

Procedure:
5-Bromo-2-fluorobenzonitrile (2.0 g, 10 mmol), Cesium carbonate (6.58 g, 20 mmol) and 1-methylpiperazine (1.35 ml, 12 mmol) in 100 ml DMSO are stirred at 120 C for 1 hour. The reaction is quenched by the addition of water and extracted with ethyl acetate. The organic phases are dried and the solvent evaporated. The product obtained is considered pure enough for the next synthesis steps. LC-MS (m/z, ES+): 280 (MH+), Retention time: 1.03 mins (LC-MS method 8)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]#[N:22])[NH2:17]>CN1C(=O)CCC1>[C:21]([C:20]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:22]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)cc1OCCCN1CCOCC1
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
Sodium hydride (2.0 g of an 85% dispersion in mineral oil, 60 mmol) was added to 4-(3-hydroxypropyl)morpholine (4.8 g, 30 mmol), (Tet. Lett. 1994, 35, 1715), in NMP (50 ml) and the mixture was stirred for 15 minutes. 3-Chloro-4-cyanoaniline (4.8 g, 30 mmol) was added and the mixture was heated at 145° C. for 6 hours. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate and then methylene chloride/methanol (9/1) to give 4-cyano-3-(3-morpholinopropoxy)aniline (2.0 g, 26%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Ca+2].[OH-].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl>O1CCOCC1>[CH2:22]([O:21][C:19]([C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]n(-c2ccc(F)cc2)c(=O)c1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
2-(4-Fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (20.3 g, 0.105 mol) and calcium hydroxide (17.2 g, 0.232 mol) were suspended in anhydrous 1,4-dioxane (200 mL). The resulting suspension was heated at 50° C. for 20 minutes. The heated suspension was cooled to 10° C. and a solution of benzyl chloroformate (14.9 mL, 0.105 mol) in dioxane (10 mL) was added. The resulting reaction mixture was heated at 90° C. for 3 hours. Upon completion of the reaction, the reaction mixture was slowly cooled to 0° C. After adding 1 M hydrochloric acid, the mixture was stirred at room temperature overnight. Then, the produced solid was collected by filtration, washed with cold ethanol and ether, and dried in vacuum to give the target compound (22.88 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([C:23]1[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=1)=[O:22])[NH2:20].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([C:23]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=3)=[O:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)s1
Yield: 96 %

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (200 mg, 0.70 mmol) synthesized in Synthetic Example 1, methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (0.70 mmol, 140.4 mg) of Reference Synthetic Example 39 and tosylic acid monohydrate (36.2 mg, 0.21 mmol), 314.1 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 96%).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCc3ccccc3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(Cc3ccccc3)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (68.5 mg, 0.098 mmol) in CH2Cl2 is treated with i-Pr2NEt (40.2 μL, 0.235 mmol) and pivaloylchloride (23.9 μL, 0.196 mmol). The solution is stirred at room temperature for 18 h. Additional i-Pr2NEt (20 μL, 0.12 mmol) and pivaloylchloride (12 μL, 0.095 mmol) are added and stirring is continued for 9 h. The reaction mixture is partitioned between EtOAc and 1 M NaHCO3, the organic layer is washed with 1 M NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in THF/piperidine (5:1) (6 mL), the solution is stirred at room temperature for 2.5 h and then concentrated in vacuo. The crude product is purified by RP-HPLC to afford the title compound. MS: 559 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.40 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39](I)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[C:39]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(I)cc1F)C(=O)OC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of 0.44 g (2.56 mmol) of palladium chloride and 1.34 g (5.12 mmol) of triphenylphosphine in 200 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 150 mL of acetonitrile, 22.09 g (52.2 mmol) of dimethyl N-(2-fluoro-4-iodobenzoyl)-L-glutamate, 13.830 g (51.2 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0244 g (1.28 mmol) of copper iodide, and 15 mL (107.5 mmol) of triethylamine. The reaction mixture is then heated at reflux for 3 hours and then cooled to room temperature, the solvent is then removed in vacuo and the crude solid chromatographed on silica gel with 1:19 methanol:methylene chloride to give 18.1 g (62.5%) of dimethyl N-(2-fluoro-4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-benzoyl)-L-glutamate as a white solid m.p. 204°-207° C. (dec); Rf =0.60 (1:19 methanol: chloroform), Mass (FD)=565; IR (KBr, cm-1)=813, 1151, 1201, 1270, 1375, 1444, 1481, 1490, 1527, 1548, 1598, 1623, 1649, 1670, 1741, 1753; UV (EtOH) λmax =325 (epsilon=41100), 266 (epsilon=14600), 210 (epsilon=35700).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:28])[CH3:27]>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:27])[CH2:14][CH2:13]1
Reactant: CC(C)Br
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-bromopropane (0.008 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 305 (M+, 5), 290 (79), 191 (30), 163 (18), 56 (bp).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1.[Na].C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1.O>[CH:26]([C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3ccc(Br)s3)[nH]c2cc1Cl
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To a solution of 2-(2-bromothiophen-5-yl)-5,6-dichlorobenzimidazole (100 mg, 0.287 mmol) in tetrahydrofuran (6 mL) was added sodium hydryde (60% oil dispersion; 14 mg, 0.35 mmol) at 0° C. under nitrogen atmosphere. After cooling to −78° C., n-butyllithium (1.6 mol/L in hexane; 0.36 mL, 0.57 mmol), dimethylformamide (0.085 mL, 1.1 mmol) were added, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (19:1 to 9:1 chloroform/acetonitrle) to afford 2-(2-formylthiophen-5-yl)-5,6-dichlorobenzimidazole (36 mg, 42%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.Cl.[CH:25]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:30][NH:31][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCC3CCCC3)(CC1)CC2
Yield: 22.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (70.0 mg) and cyclopentylmethylamine hydrochloride (72.2 mg) were used to obtain (2S,4S)-1-[[N-[4-(N-cyclopentylmethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (19.4 mg).
Reaction SMILES: C(Cl)(=O)C.[CH:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:12][C@@:13]([NH:26][NH2:27])([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:22])=[C:19]([OH:21])[CH:20]=1>C(OCC)(=O)C>[OH:21][C:19]1[CH:20]=[C:15]([CH2:14][C@@:13]([NH:26][NH2:27])([CH3:12])[C:23]([O:25][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:24])[CH:16]=[CH:17][C:18]=1[OH:22]
Reactant: OC1CCCCC1
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (1 mL) was slowly added to cyclohexanol (5 mL) at 0° C. After stirring at 0° C. for 10 min, carbidopa (294 mg, 1.5 mmol) was added slowly as solid. The resulting mixture was warmed to 50° C. for 16 h. After cooling to room temperature, ethyl acetate (40 mL) was added and product was extracted with water (4×5 mL), then the aqueous phase was lyophilized to give the crude product. HPLC of the crude product afforded 50 mg of the title compound as an oil. 1H NMR (CD3OD): δ 1.46 (s, 3H), 1.52–1.80 (m, 10H), 2.92 (dd, J=13.6 Hz, 2H,), 4.85 (m, 1H), 6.49 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 6.68 (d, J=7.6 Hz, 1H). MS (ESI) m/z 309.3 (M+H+).