Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[N:18]1(C(OC(C)(C)C)=O)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+].[ClH:37]>O.O1CCOCC1.COC(C)(C)C.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O.C1(C)C=CC=CC=1>[ClH:37].[ClH:37].[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3][CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 65 °C

Procedure:
A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (70.8 g, 219 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl piperazine-1-carboxylate (40.0 g, 215 mmol, Sigma-Aldrich, St. Louis, Mo.), 200 mL of toluene, and sodium tert-butoxide (43.3 g, 451 mmol). Nitrogen gas was bubbled through the solution for 5 min then chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (1.57 g, 2.15 mmol, Strem Chemicals Inc, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (2.00 g, 4.30 mmol, Strem Chemicals Inc, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 2 h. The mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give an oil. To this material was added 200 mL of EtOAc and 200 mL of 4N HCl in dioxane. The solution was heated at 80° C. for 12 h and the resulting suspension was then allowed to cool to room temperature. The solid precipitate was collected by filtration to give 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (76.2 g) as a white solid.
Reaction SMILES: C(NC1SC=C(C(=NOCC#C)C(O)=O)N=1)=O.P(Cl)(Cl)(Cl)=O.[ClH:23].N[CH:25]1[C:35](=[O:36])[N:27]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[Cl:23][C:29]1[CH2:30][S:31][C@@H:26]2[CH2:25][C:35](=[O:36])[N:27]2[C:28]=1[C:32]([OH:34])=[O:33]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: Cl
Agent: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1=C(Cl)CS[C@@H]2CC(=O)N12
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.27 g.), N,N-dimethylformamide (400 mg.), phosphoryl chloride (850 mg.) and ethyl acetate (11.2 ml.) were treated in a conventional manner to give the activated acid solution. The activated acid solution was added to a solution of 7-amino-3-cephem-4-carboxylic acid hydrochloride (2 g.), trimethylsilylacetamide (6 g.) and bis(trimethylsilyl)acetamide (3 ml.) in ethyl acetate (40 ml.) at -15° C. all at once, and stirred at -5° to -10° C. for 1.5 hours. After adding water (30 ml.) to the resultant solution, the ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate was added to the aqueous extract, adjusted to pH 2.0 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized with a mixture of ethyl acetate and diisopropyl ether. The precipitates were collected by filtration and dried to give 7-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:54])[C:48]1[CH2:49][NH:50][CH2:51][CH2:52][N:53]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:50]3[CH2:51][CH2:52][N:53]=[C:48]([N:47]([CH3:54])[CH3:46])[CH2:49]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C1=NCCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN=C(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 101.8 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 446 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 178 mg of N,N'-carbonyldiimidazole, 289 mg of 3-dimethylamino-1,2,5,6-tetrahydropyrazine bis(trifluoroacetate) and 289 μl of diisopropylethylamine, 460 mg of the title compound were obtained, as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH:14][C:15]([NH:17][CH3:18])=[S:16])=O.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[N:17]([CH3:18])[C:15]([SH:16])=[N:14][N:13]=1
Reactant: CNC(=S)NNC(=O)CNc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1NCc1nnc(S)n1C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred hot solution of 52.8 g (0.198 mol) 1-[alpha-(2,6-dimethylphenylamino)acetyl]-4-methylthiosemicarbazide in 560 ml ethanol was added quickly 8 g (0.198 mol) sodium hydroxide. The reaction mixture was heated under reflux for 2 hours and allowed to stand overnight. The ethanol was then evaporated under reduced pressure to give a solid residue. Water (500 ml) was added to the solid residue and the resulting aqueous mixture was filtered to remove a small amount of a solid. The filtrate was neutralized with concentrated hydrochloric acid, the colorless solid was filtered, washed with water and partially dried in vacuuo over potassium hydroxide pellets at 50° C. The nearly dried product was dissolved in dichloromethane and the aqueous layer separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 43.5 g of the product as a colorless solid, m.p. 172°-173° C. The product is tabulated in Table I as Compound No. 3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1

Procedure:
In analogy to example 5.4, 5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol and methanesulfonyl chloride were converted to yield Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as light yellow viscous oil, MS: 431 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[NH:15][CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1.[CH:34](O)=O>C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[N:15]([CH3:34])[CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1
Reactant: O=CO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc5cc(Cl)ccc5o4)C3)cc21
Agent: C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cc5cc(Cl)ccc5o4)C3)cc21

Procedure:
A 150 mg portion of 7-[3-(5-chloro-2-benzofuranyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid was added. The mixture was heated on a steam bath for 2 hours, then evaporated to dryness. A 5 ml portion of water was added, the pH adjusted to 7.0 with 1N sodium hydroxide and the solid collected, washed with water and dried, giving 113 mg of the desired product, mp 248°-249° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][C:10]([C:20](=[O:28])[NH:21][CH2:22][C:23]2([CH2:26][OH:27])[CH2:25][CH2:24]2)=[CH:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1.C1OCCOCCOCCOCCOC1.[C:51]1([CH2:57][CH2:58][CH2:59][CH2:60]Br)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:9][C:10]([C:20](=[O:28])[NH:21][CH2:22][C:23]2([CH2:26][O:27][CH2:60][CH2:59][CH2:58][CH2:57][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:24][CH2:25]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: BrCCCCc1ccccc1
Reactant: COCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCC2(CO)CC2)cc1-c1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Product: COCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCC2(COCCCCc3ccccc3)CC2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To a round bottom flask with NaH (0.201 g, 5.03 mmol) and THF (50 mL) cooled to 0° C. was added (3,3″-dichloro-5′-{[1-(hydroxymethyl)-cyclopropylmethyl]-carbamoyl}-[1,1′;3′1″]terphenyl-2′-yloxy)methyl methyl ether (1.88 g, 3.87 mmol). The resulting solution was heated to reflux for 10 min. and then cooled back to room temperature. To this solution was added 15-crown-5 (0.308 mL, 1.55 mmol), tetrabutylammonium iodide (0.573 g, 1.55 mmol), and finally 4-phenyl-butylbromide (3.30 g, 15.5 mmol) in THF (10 mL). The final mixture was heated to reflux for 18 h. At this point, the reaction mixture was quenched with MeOH (10 mL) and then diluted with EtOAc (400 mL). The organic layer was washed with 1 N HCl (40 mL), sat. aq. NaHCO3 (40 mL), and brine (40 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc/petroleum ether gradient) to afford the product (0.777 g, 33%) as a solid; 1H NMR (CDCl3) δ 0.48-0.58 (m, 2H), 0.58-0.67 (m, 2H), 1.47-1.56 (m, 4H), 2.40 (t, J=7.5 Hz, 2H), 2.73 (s, 3H), 3.38 (s, 2H), 3.38-3.48 (m, 4H), 4.40 (s, 2H), 7.07 (d, J=7.5 Hz, 2H), 7.12-7.26 (m, 3H), 7.31-7.42 (m, 4H), 7.42-7.53 (m, 3H), 7.62 (s, 2H), 7.7 (s, 2H); mass spectrum [(+) ESI], m/z 618 (M)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:28][C:4]1[C:3]([CH2:1][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: CN1CCNCC1
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CN2CCN(C)CC2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A mixture of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (27 mg, 0.073 mmol) and 1-methyl-piperazine (8.1 μl, 0.073 mmol) in CH2Cl2 (2.5 ml) was stirred for 48 h, then treated with NaBH(OAc)3 (46.4 mg, 0.2 mmol) and stirred for 24 h. The mixture was diluted with CHCl3, washed with saturated NaHCO3 and H2O, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (22 mg, 66%) (20% MeOH—CHCl3). It has a retention time of 4.90 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=453.1
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:16][CH:15]=1)#[N:14]
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and benzoic acid 5-bromomethyl-2-fluoro-phenyl ester (CAB02146, 1.55 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.32) to give a white solid. Yield: 1.16 g (56%). 1H-NMR (400 MHz, CDCl3) δ=4.91 (s, 2H), 6.67 (d, J=9.0 Hz, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 7.18 (dd, J=9.4, 8.6 Hz, 1H), 7.24 (dd, J=7.0, 2.3 Hz, 1H), 7.49-7.56 (m, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H). LRMS (FAB+): 414.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=O)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH3:17][O:16][C:8]1[C:9]2[O:10][C:11](/[CH:14]=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:12][C:13]=2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(OC)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-methoxybenzo[b]furan-4-carboxylate (from step 7) (2.0 g, 8.53 mmol) in toluene (50.0 mL) was added malonic acid (1.33 g, 12.80 mmol) and Piperidine (0.5 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (1.8 g) as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1CCNC(=O)CC1N
Product: CC1CCNC(=O)CC1NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-4-methyl-ε-caprolactam (General Procedure—C), the title compound was prepare as a mixture of diasteromers. The reaction was monitored by tlc on silica gel (Rf=0.18 in 5% MeOH/dichloromethan).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][C:36]#[N:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:35][C:36]#[N:37])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 92.2 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, bromoacetonitrile (0.081 g, 0.68 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloride in hexane as the eluent gave [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetonitrile as a white solid (0.251 g, 92%), mp 154–155° C. Elemental Analysis for C30H21F3N2O.0.10 CH2Cl2 Calc'd: C, 73.65; H, 4.35; N, 5.71. Found: C, 73.58; H, 4.46; N, 5.64.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](I)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[SH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([NH:17][CH3:18])=[O:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Ic1ccc2c(I)n[nH]c2c1
Reactant: CNC(=O)c1ccccc1S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Sc1ccc2c(I)n[nH]c2c1
Temperature: 70 °C
Yield: 78.1 %

Procedure:
3,6-diiodoindazole (250.00 g), 2-mercapto-N-methylbenzamide (118.48 g), Pd2(dba)3 (9.28 g), Xantphos (11.73 g), DMF (2.5 L, 10 mL/g), followed by CsOH were added sequentially to a 5 L four-neck flask equipped with a mechanical stirrer and a temperature probe. The reaction mixture was then stirred. The dark mixture was degassed three times by alternately connecting to house vacuum and then nitrogen. The mixture was heated to 70° C. over a period of 30 minutes and maintained at the same temperature for fours, at which time HPLC of the aliquot indicated that the 3,6-diiodoindazole was less than 3%. After cooling, the mixture was poured into a mixture of 7.5 L of water, 1.25 L of toluene and 1.25 L of CH2Cl2 in a 22 L extractor. The mixture was allowed to stir at ambient temperature overnight. A thick precipitate formed overnight. The mixture was filtered and the cake was sucked dry. The cake was further dried at 35° C. under house vacuum for six hours to afford 216 g of the final product. The mother liquor was then extracted with 1.5 L of EtOAc. After partitioning, the aqueous layer was discarded. The organic layer was washed twice each with 2 L of water and concentrated. The residue was treated with 250 mL of CH2Cl2 and stored overnight. A thick precipitate formed overnight. The mixture was filtered and the cake was sucked dry. The cake was dried at 35° C. under house vacuum overnight to afford 24.71 g of the final product. The combined yield was 241 g of the final product. The material showed satisfactory purity and was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN1CCCC1=O.O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)nccc12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of 1-chloro-5-nitroisoquinoline (1.0 g, 4.8 mmol) in N-methylpyrrolidinone (2 mL) was added 3-(trifluoromethyl)aniline (917 mg, 5.7 mmol). The reaction mass was heated at 110° C. for 2 h. The reaction mass was diluted with water and was extracted with chloroform. The organic layer was dried, filtered, concentrated and purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=7.8 Hz, 1H), 8.33-8.29 (m, 2H), 7.96-7.89 (m, 3H), 7.68 (t, J=8.1 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.26 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Cl:30])[CH:29]=1)[NH:26][N:25]=[CH:24]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([Cl:30])[CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Reactant: Nc1cc(Cl)c2[nH]ncc2c1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc(Cl)c3[nH]ncc3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
The product of Example 3 Step 2 (250 mg, 0.881 mmol, 1.00 equiv), 5-amino-7-chloroindazole (148 mg, 0.881 mmol, 1.0 equiv), and EDC (203 mg, 1.06 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.148 mL, 1.06 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 38 mg (10%) of the title compound as an off white solid. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[CH2:23]([O:22][C:20](=[O:21])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=1)[CH3:24]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-ethoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.55 g, 31.64 mmol) was added a solution of 4M HCl in dioxane (79 mL, 316.41 mmol)) at RT. After stirring overnight at RT, the solvent was evaporated under reduce pressure. The resulting yellowish viscous oil was triturated with diethylether, and filtered to give 3-piperidin-4-yl-benzoic acid ethyl ester hydrochloride salt (8.53 g, quant.). 1H-NMR (400 MHz, d6-DMSO): δ=1.81-1.86 (t, 3H), 1.91-1.98 (m, 3H), 2.50-2.52 (m, 1H (overlap with DMSO), 2.95-3.05 (m, 2H), 3.32-3.39 (m, 2H), 4.31-4.39 (q, 2H), 7.49-7.52 (m, 2H), 7.81-7.83 (m, 2H), 9.5 (br, 2H). MS: m/z=234 ((M-HCl)+1).