Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[NH4+]>O>[CH2:15]([N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH2:10]1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C2=CCCN(CCc3ccccc3)C2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2=CCCN(CCc3ccccc3)C2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 6 g of the product of Step A and 12 g of pyridinium hydrochloride was heated at 200° C. with stirring for 21/2 hours and the mixture was cooled and diluted with water. Ammonium hydroxide was added to the mixture which was then extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with an 8-2 chloroform-acetone mixture to obtain 4.9 g of 3-(1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)-phenol melting at 155° C.
Reaction SMILES: COC1C=C(OC2C=CC(O)=CC=2)C2CC(C3C=CC(OC)=CC=3)CCC=2C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:40]([N:43]([CH:74]([CH3:76])[CH3:75])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[C:63]3[CH2:62][CH:61]([C:64]4[CH:69]=[CH:68][C:67]([O:70]C)=[CH:66][CH:65]=4)[CH2:60][CH2:59][C:58]=3[CH:57]=[C:56]([O:72]C)[CH:55]=2)=[CH:49][CH:48]=1)([CH3:42])[CH3:41]>>[CH:74]([N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[C:63]3[CH2:62][CH:61]([C:64]4[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=4)[CH2:60][CH2:59][C:58]=3[CH:57]=[C:56]([OH:72])[CH:55]=2)=[CH:49][CH:48]=1)([CH3:75])[CH3:76]
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCCN(C(C)C)C(C)C)cc4)c3C2)cc1
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(O)cc4)c3C2)cc1
Agent: Cl
Product: CC(C)N(CCOc1ccc(Oc2cc(O)cc3c2CC(c2ccc(O)cc2)CC3)cc1)C(C)C
Yield: 22.3 %

Procedure:
Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen 1-yloxy]phenoxy}ethyl}amine (408 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (86 mg).
Reaction SMILES: [C@:1]12([CH3:30])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>C(O)C>[C@:1]12([CH3:30])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][C@@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:11]
Reactant: COc1cc(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Solvent: CCO
Product: COc1cc([C@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
(R/S)-1-(4-Iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (3.4 g) was dissolved in boiling ethanol (150 ml), the solution was kept in a warm oil bath and slowly cooled to room temperature and stood overnight. Needle crystals were formed gradually and collected by filtration to yield pure single diastereomer (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (870 mg, 51%). The remaining mother liquor was concentrated in vacuo, and the residue was dissolved again in boiling ethanol (150 ml), and the solution was quickly cooled to room temperature and needle crystals were formed within two hours. The crystals were collected by filtration to yield pure single diastereomer (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate. The crystallization process was repeated twice to yield additional pure (S)-diastereomer (total 1.07 g, 63%). 1H NMR (400 MHz, CDCl3) for (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.94 (s, 1H, Ph-H), 6.84 (s, 1H, Ph-CH), 3.93 (s, 3H, OCH3), 2.42 (m, 1H, CH), 2.11 (m, 1H, CH), 1.92 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.11 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.97 (s, 9H, C(CH3)3), 0.86 (s, 3H, CH3). 1H NMR (400 MHz, CDCl3) for (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1 propyl(1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.95 (s, 1H, Ph-H), 6.80 (s, 1H, Ph-CH), 3.96 (s, 3H, OCH3), 2.37 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.14 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.06 (s, 3H, CH3), 0.98 (s, 9H, C(CH3)3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].O>C(OCC)C.O1CCCC1>[CH3:19][O:20][C:21]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:22]=1[CH:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:24]
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(O)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-bromopyridine (1.4 ml) was dissolved in diethylether (40 ml), and the mixture was cooled to −78° C. under argon atmosphere 1.6M n-butyllithium hexane solution (9.1 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 2-methoxy-4-nitrobenzaldehyde (2.4 g) in tetrahydrofuran (600 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, water was added to the mixture, and the mixture was concentrated. The mixture was extracted with ethyl acetate, organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (2-methoxy-4-nitrophenyl)(pyridin-2-yl)methanol (1.9 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:6])=[O:7]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cc(Cl)ccc3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O

Procedure:
5-[(2,5-Dichlorobenzyl)sulfonyl]-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid to give the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:18][CH2:17][C:16]1[CH:20]=[C:21]([CH:22]=[C:14]([C:13]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]2[C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[O:12])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1csc([C@H]2CCCN2)n1
Reactant: COC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(CO)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A solution of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole (511 mg, 3.037 mmol) and 3-(hydroxymethyl)-5-(methoxycarbonyl)benzoic acid (702.5 mg, 3.34 mmol) in DCM (50 mL) were added diisopropylthylamine (3 mL, excess), HOBt (410 mg, 3.34 mmol) and EDCI (754.1 mg, 3.948 mmol). The resulting solution was stirred at room temperature for overnight. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate saturated aqueous solution and separated. The aqueous layer was extracted one more time with chloroform. The combined organic layers were concentrated to give a residue, which was purified with flash chromatography to produce the desired compound (840 mg). 1H NMR (300 MHz, CDCl3), d: 8.011 (m, 1.5H), 7.876 (br, 0.5H), 7.683 (m, 1H), 6.749 (m, 1H), 5.579 (m, 0.7H), 5.061 (br, 0.3H), 4.641 (br, 1.2H), 4.525 (br, 0.8H), 3.875 (m, 3H), 3.692 (m, 1H), 3.457 (m, 1H), 2.345 (m, 5H), 2.034 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]([C:24]1[CH:29]=[CH:28][C:27](/[C:30](/[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:31](\[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH2:32][CH3:33])=[CH:26][CH:25]=1)=O>C1COCC1.[Cl-].[Na+].O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH:22]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:29][CH:28]=2)=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:45][CH:44]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC/C(=C(\c1ccc(F)cc1)c1ccc(C=O)cc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)OC)cc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of trimethyl phosphonoacetate (412 mg, 2.26 mmol) in THF (15 mL) at 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (2.26 mL, 2.26 mmol) dropwise. After stirring 15 min the mixture was cooled to −78° C. and a solution of aldehyde (4) (625 mg, 1.89 mmol) in THF (8 mL) was added dropwise. The solution was allowed to warm to rt. After stirring 4 h, brine was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, and dried (MgSO4). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester (5) as a white solid (658 mg, 90%): 1 H NMR (CDCl3) δ 7.52 (d, J=16.1 Hz, 1 H), 7.15 (m, 11 H), 6.86 (d, J=8.1 Hz, 2 H), 6.28 (d, J=16.1 Hz, 1 H), 3.76 (s, 3 H), 2.47 (q, J=7.7 Hz, 2 H), 0.93 (t, J=7.7 Hz, 3 H); APcI m/z: 428 (M+H+CH3CN+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][NH:17]C(=O)OC(C)(C)C)[CH2:11]3)[CH2:9][N:8]([C:26](=[O:34])[NH:27][C:28]3[S:29][C:30]([Cl:33])=[CH:31][N:32]=3)[C:5]2=[CH:6][CH:7]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[N:8]([C:26]([NH:27][C:28]3[S:29][C:30]([Cl:33])=[CH:31][N:32]=3)=[O:34])[CH2:9]2)[CH2:11]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 7 h

Procedure:
The t-butyl (2-(5-bromo-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoethyl)carbamate (18 mg, 0.032 mmol) obtained in Example 19 was dissolved in ethyl acetate (0.5 mL). Thereafter, a 4 N solution of HCl/ethyl acetate (200 μL, 0.800 mmol) was added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 7 hours. Thereafter, the reaction solution was neutralized, was then filtered, and was then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:ammonia-methanol=10:1) to obtain the captioned compound in the form of a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][CH2:39][OH:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (54 mg) and 3-bromo-1-propanol (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (36 mg, yield 62%).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[N-:14]=[N+:15]=[N-:16].[Na+].C(OCC)C>CN(C1C=CN=CC=1)C.O>[CH2:1]([N:14]=[N+:15]=[N-:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=NCc1ccccc1
Reaction time: 6 h

Procedure:
2.07 ml of benzyl alcohol (20 mmole), 2.99 g of DMAP (1.2 eq) and 1.86 ml of MeSOCl2 (1.2 eq) were sequentially added to 25 ml of DMF. After stirring the mixture for 6 hours, 3.96 g of NaN3 (3 eq) was added thereto, and the mixture was stirred for 12 hours. The reaction mixture was treated with a mixture of diethyl ether and water, the ether extract was dried under MgSO4, ether was removed under a reduced pressure, and the resulting residue was subjected to column chromatography (silica gel 60, 230˜400 meshes, Merck) to obtain the title compound as a pale yellow liquid. The chromatography was conducted using a mixture of hexane and CH2Cl2 as an eluting solution whose mix ratio was gradually varied from 2:1 to 1:1 (v/v).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)-quinoxaline (0.7173 g, 1.786 mmol) in DMF (8.930 mL, 1.786 mmol) was added sodium azide (0.2322 g, 3.572 mmol) at room temperature and the mixture was stirred at room temperature. After 30 min, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give bluish-brown syrup. The bluish-brown syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 2-(azidomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)quinoxaline: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, dd, J=8.6, 1.2 Hz), 8.10-8.14 (1H, m), 7.99 (1H, d, J=7.8 Hz), 7.95 (1H, dd, J=8.4, 7.6 Hz), 7.79-7.91 (3H, m), 4.41-4.67 (2H, m); LC-MS (ESI) major peak of m/z 364.0 [M+H]+. The crude product was carried on crude without purification for the next step. To a solution of 2-(azidomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)-quinoxaline (0.5736 g, 1.58 mmol) in methanol (17.500 mL, 1.58 mmol) was added palladium, 10 wt. % on activated carbon (0.0839 g, 0.0789 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2. After 45 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give blue syrup. The blue syrup was purified by column chromatography on a 80 g of Redi-Sep™ column using 0 to 12% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 3 min, 12% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 for 4 min, 12% to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 22 min as eluent to give (5-chloro-3-(2-(trifluoromethyl)phenyl)quinoxalin-2-yl)methanamine as a blue syrupy solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.15 (1H, dd, J=8.6, 1.2 Hz), 8.04 (1H, dd, J=7.6, 1.2 Hz), 7.97 (1H, d, J=7.6 Hz), 7.74-7.92 (4H, m), 3.62-3.91 (2H, m), 1.98 (2H, br. s.); LC-MS (ESI) m/z 338.0 [M+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:37][S:38]([CH:41]4[CH2:43][CH2:42]4)(=[O:40])=[O:39])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62](O)[C:61]3[C:56](=[CH:57][C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62]([O:15][CH:16]3[CH2:33][CH:32]4[CH:18]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]5[C:29]([C:35]([NH:37][S:38]([CH:41]6[CH2:42][CH2:43]6)(=[O:40])=[O:39])=[O:36])([NH:30][C:31]4=[O:34])[CH2:28]5)[CH2:17]3)[C:61]3[C:56](=[CH:57][C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47]
Reactant: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CC2C1=O
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
DIAD (22 uL, 0.11 mmol) was added to a mixture of the metathesis product 103 (23 mg), 2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxyquinolin-4-ol (24 mg, 0.08 mmol), and PPh3 (30 mg, 0.11 mmol) in 1 mL dry THF, in an ice bath. The mixture was stirred at rt overnight and then evaporated. The residue (1.2 mL of a 1.5-mL MeCN solution) was purified by prep-HPLC (Hypercarb 7 uL 100×21.2 mm, 40% to 99% aqueous MeCN in 10 min) to give 3.18 mg MV062308 as cream solids (13% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](CBr)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[CH2:20]([NH:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1)CCC>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:20][NH:24][CH:25]2[N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:28]=[N:27][N:26]2[CH2:3][CH2:4][CH2:5][CH3:6])[C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: CCCCNc1nnnn1-c1ccccc1
Product: CCCCN1N=NN(c2ccccc2)C1NCc1cccc(C(=O)OC)c1-c1ccccc1C

Procedure:
The desired compound was prepared according to the method of Example 1174B starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D, and the compound from Example 1180A.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH:15]3[CH2:14][N:13]([C:26]4[N:27]=[CH:28][CH:29]=[CH:30][N:31]=4)[CH:10]4[CH2:11][CH2:12][NH:8][CH:9]34)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(C3CN(c4ncccn4)C4CCNC34)c[nH]c2c1
Reaction time: 2.5 h
Yield: 94.7 %

Procedure:
To a solution containing 70 (210 mg, 0.49 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 2.5 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 150 mg (93%) of 71 which was used without further purification. Mass spectrum, m/z [324] (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH:2]=[CH2:3]>CO>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1cccc(C(C)(C)C)c1O
Solvent: CO
Product: CCCc1cccc(C(C)(C)C)c1O
Yield: 97.9 %

Procedure:
A solution of 2-allyl-6-t-butylphenol (1.9 g) (see Example 3) in 100 ml MeOH is hydrogenated in a Parr system for 75 min at 25° C. (50 psi of H2). The mixture is then filtered and concentrated in vacuo to give 2-n-propyl-6-t-butylphenol (1.88 gram; 98% yield), which is used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)cc1
Yield: 96.8 %

Procedure:
4-Chlorobenzaldehyde (144 mg, 1.02 mmol) reacted with phenylboronic acid (185 mg, 1.36 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (178 mg, 3.18 mmol) in THF at 50° C. to give the title compound (180 mg, 96%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.96 (d, 2H, J=8.32 Hz), 7.76 (d, 2H, J=8.22 Hz), 7.65 (d, 2H, J=7.08 Hz), 7.52-7.14 (m, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.88, 147.10, 139.62, 135.11, 130.21, 128.96, 128.42, 127.61, 127.30. GC/MS(EI): m/z 182 (M+), 152. Anal. Calcd for C13H10O: C, 85.69; H. 5.53. Found: C, 85.69; H, 5.77.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Solvent: CCCCO
Product: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide (210 mg, 0.60 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (360 mg, 1.8 mmol) in n-BuOH (3 mL) was stirred at 155° C. in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by reverse phase HPLC to give (R)-tert-butyl 1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 47% yield).