Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CCOc1cc(I)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C#CC(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (566 mg, 1.05 mmol, example 27), copper(I) iodide (9.5 mg, 0.11 mmol), dichlorobis(triphenylphosphine)-palladium(II) (148 mg, 0.211 mmol) and 3,3-dimethyl-1-butyne (0.182 mL, 1.48 mmol) were dissolved under nitrogen in a flame-dried Schlenk tube in a mixture of triethylamine (1.7 mL) and dimethylformamide (1.7 mL). The reaction mixture was warmed in a 50° C. oil bath for 20 h, allowed to cool to room temperature and then partitioned between 2% sodium carbonate solution (70 mL) and diethyl ether (2×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 1% methanol in methylene chloride) to give 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole as an off-white foam (0.432 g, 83%). LC-MS: 491.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(Ph3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([B:16](O)O)[CH:15]=1>C(OCC)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]([B:16]2[O:8][C:5]([CH3:7])([CH3:6])[C:2]([CH3:4])([CH3:3])[O:1]2)[CH:15]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(Cl)ccc2OCc2ccccc2)OC1(C)C
Reaction time: 24 h

Procedure:
Pinacol (3.24 g) was added to a solution of [5-chloro-2-(phenylmethoxy)phenyl]-boronic acid (6 g) in diethyl ether, and stirred for 24 h. 4 A molecular sieves and pinacol (1.5 g) were added, stirred for a further 24 h. The sieves were filtered and the filtrate was washed with water and brine, then dried (MgSO4) and concentrated in vacuo. Yield 6.8 g.
Reaction SMILES: [I-].[CH3:2][S+:3]([CH3:5])[CH3:4].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].OO.C(Cl)(Cl)(Cl)Cl>O.C(O)C>[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:2][S+:3]([CH3:5])[CH3:4]
Reactant: O=S(=O)(O)O
Agent: C[S+](C)C
Agent: OO
Agent: [I-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: O=S(=O)([O-])O
Reaction time: 6 h
Yield: 32 %

Procedure:
Trimethylsulphonium iodide (9.8 g, 0.048 moles) was dissolved in water (50 ml). Sulphuric acid (4.8 g at 98%, 0.048 moles) and hydrogen peroxide (2.72 g at 30%. 0.024 moles) were each diluted to 10 ml with water and added to the stirred trimethylsulphonium iodide solution. Carbon tetrachloride (150 ml) was added to extract the iodine that was produced and the mixture was stirred for 6 hours. The layers were separated. To the aqueous layer was added carbon tetrachloride (150 ml) and this was stirred overnight. The layers were separated and the aqueous layer was extracted with aliquots of carbon tetrachloride (20 ml) until no further pink colouration was visible. Palladium on carbon (3%, 0.25 g) was added to the aqueous solution to destroy any unreacted peroxide. The solution was filtered after 60 minutes, and washed with ether (2×20 ml). The water was removed under reduced pressure to produce an oily residue which was dried under vacuum at 780° C. The oil was dissolved in hot ethanol and cooled in an acetone/solid carbon dioxide bath to produce a white solid. The solid was filtered off, maintaining the temperature below 0° C. and dried under reduced pressure at 78° C. to yield a very deliquescent residue (2.7 g, 32% yield of theory). This material was dissolved in hot ethanol and allowed to cool slowly in an acetone/solid carbon dioxide bath to produce a waxy solid. The solid was filtered off, maintaining the temperature below 0° C. and dried under reduced pressure at 80° C. to yield a very deliquescent residue, melting point 20°-21° C. C3H10S2O4 (174.2): calculated C 20.7, H 5.8, S 36.8; found C 20.7, H 5.9, S 36.6. 1H NMR (DMSO-D6 /TMS): & 2.91(s, 9H, CH3 --S); 7.4-7.6(s, 1H, HSO4). pH=1.8-1.9 (HSO4-).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C@H:12]2[CH2:13][C:14]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:15][C@H:11]2[CH2:10][C:9](=O)[NH:8]1.O.[OH-].[Na+]>O1CCCC1>[O:16]1[CH2:17][CH2:18][O:19][C:14]21[CH2:13][C@@H:12]1[CH2:7][NH:8][CH2:9][CH2:10][C@@H:11]1[CH2:15]2
Reactant: O=C1C[C@@H]2CC3(C[C@@H]2CN1)OCCO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1C[C@@H]2CC3(C[C@@H]2CN1)OCCO3
Reaction time: 1 h
Yield: 136.4 %

Procedure:
In an ice-water bath, lithium aluminium hydride (47 mg, 1.27 mmol) was dissolved in 10 mL of tetrahydrofuran followed by the addition of 10 mL of a solution of (cis)-spiro[1,3-dioxolane-2,6′-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine]-3′-one 14e (120 mg, 0.60 mmol) in tetrahydrofuran. The resulting solution was stirred for 1 hour, added with 1 μL of water, 1 μL of 15% sodium hydroxide solution in batches, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound (cis)-spiro[1,2,3,4,4a,5,7,7a-octahydrocyclopenta[c]pyridine-6,2′-1,3-dioxolane] 14f (150 mg) as a yellow oil liquid, which was used in the next step without further furification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:9].[C:25]1([CH:31]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:1][CH:2]([CH2:3][N:41]1[CH2:42][CH2:43][N:38]([CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40]1)[CH2:4][O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:9]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cn1ccc2c(NC(=O)c3ccccc3OCC3CO3)cccc21
Product: Cn1ccc2c(NC(=O)c3ccccc3OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cccc21

Procedure:
Using the procedure of Example 28, of Step C, 4 g of 2-[(2-oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)benzamide of Example 34 and and 6.3 g of diphenylmethylpiperazine were reacted to obtain 5.95 of 2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1-methyl-1H-indol-4-yl)benzamide and then 4.9 g of its hydrochloride melting at 196° C. after crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(O)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Oc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCCCC4)c3)c2c1
Temperature: 90 °C
Yield: 70.6 %

Procedure:
A solution of Example 180a (80.0 mg, 0.166 mmol) in dioxane (2 mL) was treated with 20% NaOH (0.20 mL). The reaction was heated at 90° C. for 2 hours. The solvent was evaporated. The residue was dissolved in water, neutralized with trifluoroacetic acid, treated with DMSO/MeOH, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (40.2 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, CD3OD) ppm 1.30 (q, J=12.51 Hz, 3H), 1.39-1.56 (m, 2H), 1.69 (m, 1H), 1.75-1.86 (m, 2H), 2.04 (dd, J=12.51, 3.36 Hz, 2H), 3.72 (m, 1H), 6.76 (d, J=1.22 Hz, 1H), 6.90 (d, J=1.22 Hz, 1H), 7.84 (d, J=2.44 Hz, 1H), 7.91 (s, 1H), 7.97 (s, 1H). MS (DCI+) m/z 343.2 (M+H)+.
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])(OC(C)(C)C)=O.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([NH:39][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH2:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@@H](CO)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a mixture of 4.10 g (20 mmol) of N-Boc-L-serine, 2.97 g (22 mmol) of HOBT, 2.42 mL (22 mmol) of NMM, and 2.40 mL (22 mmol) of benzylamine in 50 mL of anhydrous DMF at 0° C. was added 4.21 g of WSC. The mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. This was then taken up in 300 mL of EtOAc and washed with 100 mL of H2O (2×) and brine (1×). The combined organic layers were dried over MgSO4 and concentrated. After drying under vacuum overnight, the residue was dissolved in 20 mL of CH2Cl2 and treated with 20 mL of CF3CO2H at 0-10° C. for ca. 7 h. The solvent and CF3CO2H were removed under vacuum. The trace CF3CO2H was removed azeotropically with CHCl3 at the end. The residue was purified by preparative HPLC, eluting with 8% (10% conc. NH4 0H in MeOH)--CH2Cl2 to afford 3.57 g (92%) of the serinamide: mp 97-98° C.; 1H NMR (CDCl3) δ7.82 (br s, 1H), 7.26 (m, 5H), 4.42 (ddd, J=16.7, 15.0, 6.0 Hz, 2H), 3.85 (dd, J=10.8, 5.2 Hz, 1H), 3.70 (dd, J=10.8, 5.3 Hz, 1H), 3.44 (m, 1H), 2.22 (br s, 3H); FDMS 195 (M+1). Anal. (C10H14N2O2) C, H, N.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[OH-].[K+]>C(O)CCC>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reactant: CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCCCOc1ccc2nc(-c3ccc(CCCCC)cc3)ccc2c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Then, 0.23 g (0.79 mM) of 2-(4-pentylphenyl)-6-hydroxyquinoline, 0.17 ml (0.82 mM) of 1-bromodecane and 2.6 ml (0.02 g of potassium hydroxide per 1 ml of butanol) of a solution of potassium hydroxide in butanol were placed in a 20 ml-round bottomed flask and refluxed for 2 hours and 50 minutes under stirring. After the reaction, the reaction mixture was left standing overnight in a freezer at -20° C. to precipitate a crystal. The crystal was recovered by filtration and successively washed with methanol and water. The resultant crystal was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene and methanol) to obtain 0.23 g of 2-(4-pentylphenyl)-6-decyloxyquinoline (Yield: 67.5%).
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>C1(C)C=CC=CC=1.O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: NCc1cccc(Cl)c1
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]cc(C)c12
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2ncnc(Nc3ccsc3C(=O)NCc3cccc(Cl)c3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Trimethyl aluminum (0.35 mL, 0.69 mmol, 2M in toluene) was added to a solution of 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.17 mmol) and 3-chlorobenzylamine (0.11 mL, 0.87 mmol) in toluene (2 mL), and stirred overnight at 70° C. The reaction mixture was cooled to room temperature, diluted with H2O and EtOAC, and filtered through an Extrelut column. The column was washed with EtOAC and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAC in hexanes to provide the desire product (34 mg, 49% yield) as an off-white solid. LC-MS (M+H=398, obsd.=398).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[N:35]1C=CC=CC=1.O.FC(F)(F)C(=O)OI(C1C=CC=CC=1)OC(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:35])[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])=[CH:33][CH:34]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(N(Cc3ccc(F)cc3)C(=O)C3(C(N)=O)CC3)cc2F)ccn1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1(C(=O)N(Cc2ccc(F)cc2)c2ccc(Oc3ccnc(N)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of N-(4-fluorobenzyl)-N-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.05 mmol) in DMF (1 mL) at room temperature was added pyridine (0.2 mL), water (0.1 mL), and [bis(trifluoroacetoxyl)-iodo]benzene (Aldrich, 34 mg, 0.08 mmol). The reaction mixture was stirred at rt for 2 h, and then quenched by adding 2 mL of methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aq. K2HPO4, concentrated and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in a small amount of CH3CN/H2O and lyophillized to dryness to give the title compound (21 mg, 90%) as a white solid. 1H NMR (DMSO-d6) δ 10.87 (br s, 1H), 8.44 (t, 1H, J=6.0 Hz), 7.91 (d, 1H, J=6.6 Hz), 7.88 (d, 1H, J=13.2 Hz), 7.37-7.29 (m, 6H), 7.13 (t, 2H, J=8.8 Hz), 4.29 (d, 2H, J=6.1 Hz), 1.38 (d, 4H, J=2.2 Hz); MS (ESI+) m/z 439.14 (M+H)+.
Reaction SMILES: [C:1](/[CH:6]=[C:7]1\[CH2:8][CH2:9][CH2:10][C:11]2[C:16]\1=[CH:15][CH:14]=[CH:13][CH:12]=2)([O:3][CH2:4][CH3:5])=[O:2].C(/C=C1/CCCC2C/1=CC=CC=2)(OCC)=O>>[CH:7]1([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)/C=C1\CCCc2ccccc21
Agent: CCOC(=O)/C=C1/CCCc2ccccc21
Product: CCOC(=O)CC1CCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 64 and making non-critical variations but starting with (E)-1-carbethoxymethylene-1,2,3,4-tetrahydronaphthalene (CVII-A, EXAMPLE 63), ethyl 1-(3,4-dihydronaphthyl)acetate (CVII-B, EXAMPLE 63) and (Z)-1-carbethoxymethylene-1,2,3,4-tetrahydronaphthalene (CVII-C, EXAMPLE 63), the title compound is obtained, NMR (CDCl3, TMS) 7.25-7.05, 4.16, 3.38-3.30, 2.83-1.64 and 1.27 δ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:19]Br.O>CN(C)C=O>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:3][C:2]=2[O:1][CH2:19]1
Reactant: BrCBr
Reactant: O=C(CCc1ccc(O)c(O)c1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccc2c(c1)OCO2)N1CCCC1
Reaction time: 4 h

Procedure:
0.92 g of N-[3-(3,4-dihydroxyphenyl)-propionylpyrrolidine was dissolved in 10 ml of N,N-dimethylformamide and then 1.2 g of dibromomethane and 1.2 g of potassium carbonate anhydride and 100 mg of cupric oxide were added to the solution and the resulting solution was stirred at 130°-140° C. for 4 hours. After cooling, the solution was poured over iced water, extracted with ethyl acetate, washed with water and then dried with sodium sulfate anhydride. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on a silica gel column with a mixed solvent (chloroform:methanol=100:l) and thus 0.59 g of oily N-[3-(1.3-benzodioxol-5-yl)propionyl]pyrrolidine was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)ncc2F)CC1

Procedure:
A solution of 2,4-dichloro-5-fluoro-pyrimidine (1.28 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 2.23 g (88%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.38-1.48 (m, 2H), 1.41 (s, 9H), 1.78-1.82 (m, 2H), 2.84 (br s, 2H), 3.93-3.96 (m, 2H), 4.00-4.08 (m, 1H), 8.02 (d, J=6.0 Hz, 1H), 8.09 (d, J=4.0 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 28.06, 30.75, 43.33, 47.34, 78.66, 139.86 (d, J=20.3 Hz), 145.03 (d, J=255.7 Hz), 152.63 (d, J=13.4 Hz), 153.49 (d, J=2.7 Hz), 153.83. MS (ISP): 331.3 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](CS([O-])(=O)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[CH3:17])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=S(=O)([O-])Cc1ccc(-n2cccc2)cc1
Reactant: Cc1ccc(C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(C)c(Nc2ccc(-n3cccc3)cc2)c1
Temperature: 110 °C
Yield: 105.2 %

Procedure:
Following general procedure A, a mixture of 4-(1H-pyrrol-1-yl)phenylmethanesulfonate (119 mg, 0.5 mmol), 2,5-dimethylaniline (75 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (138 mg, 95%), mp 97-98° C. 1H NMR (300 MHz, CDCl3) δ: 7.31 (d, J=9.0 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.04 (m, 5H), 6.82 (d, J=7.5 Hz, 1H), 6.37 (t, J=2.5 Hz, 2H), 5.40 (s, 1H), 2.33 (s, 3H), 2.27 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 142.4, 141.1, 136.9, 134.4, 131.2, 125.6, 123.3, 122.3, 119.9, 119.8, 118.5, 110.0, 21.5, 17.8 ppm. IR (neat, cm−1): 3386, 2920, 1519, 1310, 1072, 829, 726. Anal. Calcd. for C18H18N2: C, 82.41; H, 6.92. Found: C, 82.03; H, 7.03.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.C[O:11][C:12](=[O:25])[CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]I.I[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31].[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO.C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCOC(C)=O.CN(C=O)C>[C:21]([O:20][C:18]([NH:17][CH:13]([CH2:14][CH2:15][C:27]1[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=1)[C:12]([OH:11])=[O:25])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C(CCI)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(I)c1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)NC(CCc1cccc(C#N)c1)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To 0.39 g (6.0 mmol) of Zn powder under Ar2 is added 0.5 mL of DMF and then 26 μL (0.3 mmol) of 1,2-dibromoethane. After stirring at 60° C. for 30 minutes, the mixture is cooled and 7.6 μL (0.06 mmol) of TMSCl is added. After stirring for 30 minutes, 0.34 g (1.0 mmol) of 4-iodo-2-tert-butoxycarbonylamino-butyric acid methyl ester is added and the mixture is stirred at 35° C. for 30 minutes. The mixture is cooled to rt, and 23 mg (0.040 mmol) of Pd(dba)2, 24 mg (0.080 mmol) of (o-tolyl)3P, and then 0.22 mg (0.95 mmol) 3-iodobenzonitrile are added. After stirring at rt for 3 h, EtOAc is added and the mixture is washed with saturated NH4Cl and brine. The extract is concentrated and purified by preparative HPLC to provide 0.14 g (44%) of Boc-(3-cyano)homophenylalanine-OMe. To 0.12 g (0.38 mmol) of this material in 1 mL of 1:1 MeOH/THF is added 0.38 mL (0.75 mmol) of 2 M NaOH. After stirring for 1 h, 1 M NaHSO4 is added, and the mixture is extracted with EtOAc. The extract is washed with brine, dried over Na2SO4, filtered, and concentrated to provide 0.11 g (96%) of 2-[(tert-butoxycarbonyl)amino]-4-(3-cyanophenyl)butanoic acid.