Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>[Pt].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:12](=[O:14])[CH3:13])=[C:6]([OH:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Pt]
Solvent: CO
Product: CC(=O)Nc1ccc(F)cc1O
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (5 g, 31.8 mmol), acetic anhydride (4.86 g, 47.7 mmol) and platinum on carbon (5%, 200 mg) in methanol was hydrogenated at 35 psi for 3 hours. The catalyst was filtered off and the residue was purified by silica gel flash chromatography to give the subtitled compound (4.7 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.OO.C([O-])(O)=[O:32].[Na+]>CO.OS(O)(=O)=O.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:21][CH:22]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: O=C([O-])O
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 61 %

Procedure:
To a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (2.00 g, 5.43 mmol) in MeOH (40 mL) were added an aqueous solution of, 30-40% by weight, H2O2 (5.0 mL) and a few drops (10-12) of conc. H2SO4. The resultant mixture was stirred for 24 h. Reaction mixture was neutralized with saturated aqueous NaHCO3 and then diluted with EtOAc (200 mL). Reaction mixture was washed with water (2×30 mL), brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 4:1) as an eluent to give 1.180 g (61%) of the title compound (233) as a white foam. The 1H NMR and mass spectral data are consistent with the data reported in Example 41 (Step 1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19]N(C)C)[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[NH2:26][C:27]([NH2:29])=[S:28].C[O-].[Na+].O>CO>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:29]=[C:27]([SH:28])[N:26]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2nc(S)ncc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.5 g (4 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide, 1.5 g (20 mmol) of thiourea and 5 ml of a 4M methanol solution of sodium methoxide in 30 ml of methanol was stirred at room temperature for 5 hr. The mixture was poured into water and extracted with ether. The aqueous solution was acidified with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with methylene chloride to give an orange solid. Recrystallization from methylene chloride gave the product as orange crystals, mp 323°-325° C. (dec.).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6].O.Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:1])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methylmagnesium bromide (60 mL of a 3.0 M solution in diethyl ether) at 0° C. was added dropwise a solution of 3-bromoacetophenone (29.8 grams) in 75 mL of diethyl ether. Once the addition was complete, the mixture was stirred for 0.5 hours and poured into water. The aqueous phase was acidified with 1M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate, concentrated to afford 30.4 grams of the title compound. 1H NMR δ7.72 (br s, 1), 7.49 (d, 1, J=7.8), 7.37 (d, 1, J=7.9), 7.25 (dd, 1, J=7.8, 7.9), 4.19 (s, 1), 1.50 (br s, 6).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:18])[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](O)=[O:22].C1CCC(N=C=NC2CCCCC2)CC1.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:19][CH2:20][C:21]([O:18][CH:16]([CH3:17])/[CH:15]=[CH:14]/[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:22]
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(/C=C/c1cccc(Oc2ccccc2)c1)OC(=O)CCl
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
The product from step (b) (12.01 g) and chloroacetic acid (5 g) were taken up in methylene chloride, DCC (15 g) was added, and the mixture stirred for 5 minutes. DMAP (0.5 g) was then added, causing the mixture to boil, and the mixture stirred for 1 hour. Ether (200 ml) was then added, the mixture filtered, and the filtrate washed with satd. aqu. NaHCO3, 2 M aqu. HCl, and satd. aqu. NaCl, dried over MgSO4 and stripped. The residue was taken up in ether/pet.ether (1:1, 100 ml). filtered, and stripped to give the desired product (15.7 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)=[O:14].[ClH:41].CO>>[ClH:41].[ClH:41].[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][NH:18][CH2:17]1)=[O:14]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
tert-Butyl (3S, 5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (51 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and the mixture was stirred at room temperature for 41 hr and concentrated to give the object product (44 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][NH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][N:36]1[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=1
Reactant: CC1CNC(=O)CN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1CNC(=O)CN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 7.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (350 mg, 0.662 mmol, Intermediate B) was combined with 5-methylpiperazin-2-one (79 mg, 0.695 mmol, Anichem, North Brunswick, N.J.), potassium carbonate (275 mg, 1.99 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (4.41 mL) was heated at 120° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give the title compound (28 mg) as a mixture of four diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:29][CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Reactant: NC1CCOCC1
Agent: Cl
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Yield: 63 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxylic acid was reacted with tetrahydro-pyran-4-ylamine hydrochloride similarly to as described in example 2 with non-critical modifications to afford 117 mg (63%) 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (11%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[Na].CCOCC.[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=O)[CH3:19]>C(O)C>[C:21]([C:22]1[O:10][C:9]2[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=2[C:2](=[O:3])[CH:1]=1)([O:20][CH2:18][CH3:19])=[O:27]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2,4-dihydroxyacetophenone (15.2 g) in diethyloxalate (40 ml) is added with stirring to a solution of sodium (9.2 g) in ethanol (200 ml). The mixture is then heated at 100° C. for 3.5 hours, cooled and is added to dry ether (500 ml). The mixture is allowed to sit overnight. The resulting precipitate is filtered off and dissolved in water, and the solution is neutralized with 4N hydrochloric acid and extracted with ether. The ether extracts are combined and are concentrated down in vacuo. The resulting residue is dissolved in ethanol (100 ml) and concentrated hydrochloric acid is then added (2 ml). The solution is heated under reflux for 2 hours and is then concentrated in vacuo. The resulting solid is recrystalized in ethanol to give 2-carboethoxy-7-hydroxy-4-oxo-4H-1-benzopyran which is used directly in the next step.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=CC=1>B(F)(F)F>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: c1ccc2ncccc2c1
Reactant: Cc1ccccc1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 300° C. in the presence of a HF.BF3 catalyst. After the reaction, the catalyst was recovered in a gas state, and a low boiling point component was removed to obtain a pitch. The optically anisotropic phase was 2 volume % as observed under a polarization microscope, the softening point was 176° C., the quinoline-insoluble content was 1.6% by weight, and the toluene-insoluble content was 34% by weight.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[CH3:39][C:35]1([CH3:40])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]2[CH:30]=[C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:38]=[CH:37][C:36]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 106 mg (0.304 mmol) of 4-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]butan-1-ol and 116 mg (0.334 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The crude product is purified by means of RP flash chromatography on C18 silica gel. The product is in the form of the hydrochloride.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[ClH:7].Cl.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:24])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:9].[ClH:7].[CH:1]([NH:4][C:5](=[SH:24][CH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:26][CH:25]=2)[CH2:16][CH2:17]1)[OH:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 56.3 %

Procedure:
The procedure described in Example 2 was followed, using 0.5 g of isopropyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.7 g (28% of theory) of N-isopropyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 247°-250° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](=[O:13])[CH3:12].[CH3:14]COCC>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[CH2:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CCOCC
Reactant: CC(=O)[C@H]1Cc2ccccc2[C@H]1C
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)c2cc(C)ccc2C1
Yield: 84 %

Procedure:
1-(3,5-Dimethyl-inden-2-yl)ethanone is prepared by the same procedure as cis-1-(2,3-dihydro-1-methyl-1H-inden-2-yl)ethanone in Example 4b. A mixture of dry ether and tetrahydrofuran is used as solvent. Yield 84%.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][N:24]1[C:28](=O)[CH2:27][CH2:26][C@@H:25]1[CH2:30][C:31]#[N:32]>C1C=CC=CC=1>[CH3:23][N:24]1[C:28](=[S:10])[CH2:27][CH2:26][C@@H:25]1[CH2:30][C:31]#[N:32]
Reactant: CN1C(=O)CC[C@@H]1CC#N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CN1C(=S)CC[C@@H]1CC#N
Yield: 157.5 %

Procedure:
Lawesson's reagent (Tokyo Kasei Kogyo) (2.26 g, 5.6 mmols) was added to a benzene (40 ml) solution of the 2-((2R)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile (1.48 g, 10.7 mmols), and the mixture was heated for 2 hours under reflux. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 80 g, MeOH—CHCl3 5:95 v/v) to obtain 2-((2R)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (1.36 g, 82.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([C:22]3[O:23][C:24]([CH3:27])=[N:25][N:26]=3)[CH:19]=[CH:18][C:17]=2[CH3:28])=[CH:12][CH:11]=1)=[O:9].I[CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]([CH3:33])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[C:20]([C:22]3[O:23][C:24]([CH3:27])=[N:25][N:26]=3)[CH:19]=[CH:18][C:17]=2[CH3:28])=[CH:14][CH:15]=1)=[O:9]
Reactant: CI
Reactant: COc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1
Product: COc1cccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-(3-Methoxybenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.58-7.45,(5H, m), 7.30,(1H, t), 6.93-6.72,(3H, m), 4.67-4.51,(2H, m), 3.76,(3H, s), 2.92-2.89,(3H, m), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.39 min, MH+ 428.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[CH3:31][O:32][CH2:33]OCOC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([C:18]([O:27][CH2:31][O:32][CH3:33])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reactant: COCOCOC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
2-(5-(Benzyloxy)-6-propylpyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (537 mg, 1.37 mmol) was dissolved in N,N′-dimethylformamide (2.5 mL) and added with sodium hydride (purity 50%) (79 mg, 1.64 mmol) and methoxymethyl ether chloride (113 μL, 1.50 mmol) under ice-cold conditions The resultant mixture was stirred under ice-cold conditions for 1.5 hours and then further stirred at room temperature for 45 minutes. After completion of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 3-(benzyloxy)-6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridine (407 mg, yield 68%) was obtained as a colorless oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[N:33]=[C:34]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5C(OC(C)(C)C)=O)[NH:35][CH:36]=3)[CH:26]=[CH:25]4)[N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[NH:33][C:34]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[NH:38]5)=[N:35][CH:36]=3)[CH:26]=[CH:25]4)[N:19]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(C#Cc2ccc3cc(-c4c[nH]c([C@@H]5C[C@H]6C[C@H]6N5C(=O)OC(C)(C)C)n4)ccc3c2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: C(#Cc1c[nH]c([C@@H]2C[C@H]3C[C@H]3N2)n1)c1ccc2cc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)ccc2c1
Reaction time: 4 h
Yield: 128.3 %

Procedure:
4M HCl (1.546 mL, 6.18 mmol) in dioxane was added to a solution of tert-butyl (1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.309 mmol) in dioxane (3 mL) and the reaction was vigorously stirred for 4 h. The reaction slurry was concentrated to yield an HCl salt of (1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (177 mg) as a yellow solid. LC-MS retention time 3.403 min; m/z 893.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) d ppm 8.42 (s, 1H), 8.16 (s, 2H), 8.05 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.97 (dd, J=8.8, 1.8 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=8.5, 1.5 Hz, 1H), 5.01 (dd, J=10.8, 7.8 Hz, 1H), 4.78 (dd, J=10.8, 8.3 Hz, 1H), 3.57-3.77 (m, 2H), 3.50-3.56 (m, 1H), 2.61-2.92 (m, 4H), 2.13-2.21 (m, 1H), 2.06-2.13 (m, 1H), 1.25 (ddd, J=7.8, 5.0, 2.5 Hz, 1H), 0.99-1.14 (m, 2H).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:31]>CC(O)C>[NH2:31]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1

Procedure:
In 9.5 ml of 2-propanol was dissolved 1.9 g of 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl acetoacetate, and an ammonia gas was blown thereinto with ice-cooling for 30 minutes, after which the resulting mixture was subjected to reaction at room temperature for one day. Subsequently, the solvent was removed by distillation under reduced pressure to obtain oily 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl 3-aminocrotonate. This oily product and 1.15 g of methyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 9.5 ml of 2-propanol, and the resulting solution was subjected to reaction under reflux for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Merck Silica Gel, 70-230 mesh, eluant: n-hexane:acetone (2:1 by volume)] to obtain 2.34 g (yield 79.0%) of yellow and oily 3-[3-[ (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)N3CCCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)N2CCCCC2)c1
Yield: 58.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (68 mg, 0.24 mmol) in methanol (6 mL) and 1N sodium hydroxide aqueous solution (2.5 mL, 2.5 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 55 mg of 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 83.8%. LC-MS(M+1)=393.2.