Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13](=[O:24])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25]([Mg]Br)#[C:26][CH3:27]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13](=[O:24])[C:25]#[C:26][CH3:27])[CH2:16][CH2:15][NH:14][C:17](=[O:18])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1=O
Solvent: C1CCOC1
Product: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a slurry of tert-butyl 4-((6-chloro-3-pyridinyl)sulfonyl)-2-oxo-1-piperazinecarboxylate (1.16 g, 3.09 mmol) in THF (5.0 mL) at 0° C. was added a solution of prop-1-yn-1-ylmagnesium bromide (0.5 M in THF, 13 mL, 6.50 mmol, Sigma-Aldrich, St. Louis, Mo.). After 1.5 h at 0° C., additional prop-1-yn-1-ylmagnesium bromide (4 mL, 2.0 mmol) was added. After an additional 2.5 h at 0° C., the mixture was quenched with saturated aqueous NH4Cl (25 mL). EtOAc (40 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel using (30 to 90% EtOAc in hexanes) to give tert-butyl (2-(((6-chloro-3-pyridinyl)sulfonyl)(2-oxo-3-pentyn-1-yl)amino)ethyl)carbamate as a yellow powder (1.05 g)
Reaction SMILES: [C:1]([C:5]1[N:9]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)(OC)=[O:2].C[O-].[Na+].CO.Cl>C(#N)C>[NH:14]1[C:10]2[N:9]3[C:8](=[N:7][CH:6]=[C:5]3[C:1]1=[O:2])[CH:13]=[CH:12][CH:11]=2
Reactant: COC(=O)c1cnc2cccc(N)n12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=c1[nH]c2cccc3ncc1n32
Yield: 167.7 %

Procedure:
To a solution prepared by dissolving 1.44 g (7.0 mM) of 3-carbomethoxy-5-aminoimidazo[1,2-a]pyridine in 10 ml of acetonitrile followed by addition of 3.2 ml (14.0 mM) of 25% sodium methoxide-methanol and the mixture was refluxed for 1 hour. After completion of the reaction, 1.15 ml (14.0 mM) of 12N-hydrochloric acid was added to the reaction mixture under ice-cooling and the solvent was thoroughly distilled off under reduced pressure to provide 2.01 g (yield 100%) of a crude product as tan-colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:28]([C:10]1[C:11](=[O:27])[N:12]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)NCc3ccccc3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and benzylamine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: [C:1](=[O:64])([O:51][CH:52]1[CH2:57][O:56]C(C2C=CC=CC=2)[O:54][CH2:53]1)[O:2][C@H:3]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=1)[C@@H:4]([N:6]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([F:27])=[CH:20][C:19]=1[O:28][CH3:29])[CH3:5]>[Pd].CCOC(C)=O>[C:1](=[O:64])([O:51][CH:52]([CH2:57][OH:56])[CH2:53][OH:54])[O:2][C@H:3]([C:37]1[CH:38]=[C:39]([C:47]([F:49])([F:48])[F:50])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[C@@H:4]([N:6]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[C:21]([F:27])=[CH:20][C:19]=1[O:28][CH3:29])[CH3:5]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](OC(=O)OC1COC(c2ccccc2)OC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](OC(=O)OC(CO)CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 10% palladium on carbon (9.13 mg, 8.57 μmol) in a solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2-phenyl-1,3-dioxan-5-yl carbonate (78.7 mg, 0.086 mmol) in EtOAc (6.60 mL) was stirred under H2 (double balloon pressure) at 25° C. for 15 h. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2-hydroxy-1-(hydroxymethyl)ethyl carbonate. LCMS calc.=852.26; found=852.10 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[N:15]([CH3:32])[C:14]=1[C:33]([O:35]C)=[O:34].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[N:15]([CH3:32])[C:14]=1[C:33]([OH:35])=[O:34]
Reactant: COC(=O)c1c(-c2cc(N3CCCC3)ccc2F)c2c(NS(=O)(=O)c3ccccc3)ccnc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)c(-c2cc(N3CCCC3)ccc2F)c2c(NS(=O)(=O)c3ccccc3)ccnc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a suspension of methyl 3-(2-fluoro-5-(pyrrolidin-1-yl)phenyl)-1-methyl-4-(phenylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (47 mg, 0.092 mmol) in MeOH (1 mL) stirred under nitrogen at RT was added a aqueous solution of 6M sodium hydroxide (0.077 mL, 0.462 mmol) in one charge. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to RT and concentrated. The crude was purified on normal phase silica eluting with 2M ammonia in MeOH and DCM (0-50%) to give the title compound (35 mg). LCMS (A): m/z (M+H)+ 495, C25H23FN4O4S requires 494 (basic).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].CCO[C:15](OCC)(OCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[C:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: Cc1cc(=O)n(N)c(NN)n1
Solvent: CCCCO
Product: Cc1cc(=O)n2nc(-c3ccccc3)n(N)c2n1

Procedure:
A mixture of 2.0 g of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone, 10 ml of triethyl orthobenzoate and 20 ml of n-butanol was reacted as described in Example 1, giving 1.27 g of the desired intermediate, mp 195° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][C:4]=1[CH3:11])(=[O:10])[CH3:9]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(=O)c1ccc(O)cc1C
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1C

Procedure:
The title product was prepared from 4′-hydroxy-2′-methylacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (76%, white crystals). HPLC-MS: m/z=284.2 (M+1); Rt: 3.95 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH:11]([N:14]1C(=O)O[C:17](=[O:18])[C:16]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]12)([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:18])([CH3:13])[CH3:12]
Reactant: Oc1n[nH]c2ccccc12
Reactant: CC(C)n1c(=O)oc(=O)c2ccccc21
Product: CC(C)Nc1ccccc1C(=O)n1nc(O)c2ccccc21
Yield: 71.3 %

Procedure:
1H-Indazol-3-ol was reacted with N-isopropylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 71.3% yield; m.p. 190°-192° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[S:18]([O:10][CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[OH:11])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc([C@H](O)CO)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(C)c2)cc1
Reaction time: 17 h
Yield: 84.2 %

Procedure:
To a stirred solution of (S)-1-(3-methylphenyl)-1,2-ethanediol (1.78 g, 11.7 mmol) in pyridine (35 ml) was added p-toluenesulfonyl chloride (2.46 g, 12.9 mmol), and 4-dimethylaminopyridine (1.58 g, 12.9 mmol) at 0° C. and the reaction mixture was stirred at 0° C. to rt for 17 h. The reaction mixture was acidified with 6N HCl aqueous solution and extracted with CH2Cl2. The extract was washed with water and brine, dried (Na2SO4), and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography (silica gel: 100 g, ethyl acetate/hexane: 1/9 to 1/3) to afford 2.63 g (73%) of desired product as light yellow oil. Its optical purity was 97% ee by HPLC employing a chiral stationary phase (chiral pak AS, Daicel Chemical Industries, eluted with n-hexane/EtOH: 98/2; detection time: 55 min for (R)-isomer 59 min for (S)-isomer).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:46])[CH:8]=1)[CH3:2].SCC(O)=O.O.[OH-].[Li+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:46])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC)cc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 67 h
Yield: 82 %

Procedure:
To a solution of the residue obtained in Example 34 and mercaptoacetic acid (0.278 mL, 4.00 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (0.336 g, 8.00 mmol), and the mixture was stirred at room temperature for 67 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-40% ethyl acetate/hexane) to give the title compound (0.760 g, yield 82%, 2 steps) as a yellow oil.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([NH:26][C:27](=[O:55])[C@H:28]([CH2:51][CH:52]=[CH:53][CH3:54])[CH2:29][C@@H:30]1[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:31]1[CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH2:47][OH:48])[CH2:23][CH2:24][CH3:25].[OH2:56]>CN(C)C=O>[CH2:22]([NH:26][C:27](=[O:55])[C@H:28]([CH2:51][CH:52]=[CH:53][CH3:54])[CH2:29][C@@H:30]1[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C@H:31]1[CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][C:47]([OH:56])=[O:48])[CH2:23][CH2:24][CH3:25]
Reactant: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO)C(=O)NCCCC
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O)C(=O)NCCCC
Reaction time: 23 h

Procedure:
A solution of 809 mg of pyridinium dichromate in 2 ml of N,N-dimethylformamide is added dropwise via a cannula to a solution of 290 mg of 3-[N-tert-butoxycarbonyl-4(S)-(4-hydroxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-but-2-enyl-propionic acid (N-butyl)amide in 2 ml of N,N-dimethylformamide at room temperature under argon. After 23 h, a further 238 mg of pyridinium dichromate are added. After a total of 29 h, the reaction mixture is poured into water, extracted with diethyl ether (3 times), dried (Na2SO4) and concentrated. Purification over silica gel (mobile phase P) gives the title compound: Rf (P)=0.48; FAB-MS: (M+H)+ =497.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17]4[NH:21][C:20]([C@@H:22]5[CH2:26][CH2:25][CH2:24][N:23]5[C:27]([O:29]C(C)(C)C)=O)=[N:19][CH:18]=4)=[CH:10][C:11]=3[C:12]2([F:16])[F:15])=[CH:4][CH:3]=1.Cl.O1CCOCC1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])C(O)=O)=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17]4[NH:21][C:20]([C@@H:22]5[CH2:26][CH2:25][CH2:24][N:23]5[C:27](=[O:29])[C@@H:46]([NH:45][C:43](=[O:44])[O:42][CH3:41])[CH:50]([CH3:52])[CH3:51])=[N:19][CH:18]=4)=[CH:10][C:11]=3[C:12]2([F:15])[F:16])=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1)C(C)C
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of (S)-tert-butyl 2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.09 g, 2.1 mmol), methanol (10 mL), and 4M HCl in dioxane (10 mL, 40 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after one hour. The resulting residue was dissolved in dimethylformamide (10.6 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (390 mg, 2.2 mmol) and HATU (847 mg, 2.2 mmol). Diisopropylethylamine (1.3 mL, 7.5 mmol) was added and the reaction was stirred at room temperature. After thirty minutes, the reaction was diluted with ethyl acetate. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-1-((S)-2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (712 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C(O)c1ccc(CCCN2CCCC2)cc1
Agent: Cl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(CCCN3CCCC3)cc2)cc1
Yield: 33 %

Procedure:
By essentially following the procedure outlined in Example 2, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[3-(1-pyrrolidinyl)propyl]benzoic acid hydrochloride in 33% yield as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
A solution of crude 24 (50 mmol) in dichloromethane (200 mL) and a solution of potassium bromide (0.7 g) in water (10 mL) were mixed together and stirred in an ice bath. TEMPO (120 mg) was added and a solution of 37% aqueous sodium hypochlorite (48 mL), sodium bicarbonate (5 g) and water (to 100 mL) was added in portions at such a rate that the temperature did not exceed 5° C. Stirring was continued on the ice bath for 20 min. The reaction mixture was diluted with dichloromethane (200 mL) and washed with water (300 mL), 1N hydrochloric acid (300 mL), water (300 mL) and brine (300 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product (19 g) was purified by chromatography on silica (350 g) with 2% ethyl acetate in heptane (7 L). Pure 25 (16.1 g, 88%) was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:12]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-fluoro-1-nitrobenzene (27 μL, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry DMF and heated at 120° C. for 4 h. The mixture was diluted with water and filtered to give a yellow solid which was chromatographed over silica gel (40% EtOAc in hexane) to afford a yellow solid (72 mg, 73%): 1H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m, 5H), 2.45 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.C([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2]([CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[N:14]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: O=Cc1cc(Cl)ccc1Br
Product: COC(=O)c1cc2ccc(Cl)cc2cn1
Yield: 25 %

Procedure:
methyl 7-chloro-isoquinoline-3-carboxylate was prepared using the procedure described in example 12A: 2-bromo-5-chlorobenzaldehyde was reacted with methyl 2-acetamidoacrylate at 110° C. for 24 hours to yield methyl 7-chloro-isoquinoline-3-carboxylate (25%) as brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:19][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:20])=[C:2]([N:24]3[C:25]4[C:26](=[N:27][CH:28]=[C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:30]=4)[C:22]([CH3:37])([CH3:21])[CH2:23]3)[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine (40 mg, 0.138 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (32.1 mg, 0.138 mmol), sodium tert-butoxide (26.4 mg, 0.275 mmol) and XPhos precatalyst (10.4 mg, 0.014 mmol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 2-(3,5-difluorophenyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-1,7-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.59 (1H, d, J=1.0 Hz), 8.57 (1H, d, J=5.9 Hz), 7.69 (1H, d, J=2.3 Hz), 7.51 (1H, dd, J=5.9, 1.0 Hz), 7.15-7.22 (2H, m), 6.94-7.01 (1H, m), 5.82 (1H, d, J=2.3 Hz), 4.13-4.23 (2H, m), 3.71-3.81 (4H, m), 3.59 (2H, tt, J=11.4, 2.8 Hz), 2.95-3.07 (4H, m), 2.29-2.45 (5H, m), 1.71-1.92 (2H, m). Mass Spectrum (ESI) m/e=488.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:33])[CH:9]([NH:25]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:25][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])=[CH:13][CH:12]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of tert-butyl (1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate (2.00 g, 4.05 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was recrystallized from (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (1.08 g, 68%) as colorless crystals.