Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[S:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33]C)=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:16]1[CH2:17][CH2:18][S:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCSCC3)c[nH]c12
Temperature: 25 °C
Yield: 76.1 %

Procedure:
TMSOTf (2.1 mL, 11.8 mmol) was added dropwise over 2.25 min to a solution of tetrahydro-4H-thiopyran-4-one (0.686 g, 5.9 mmol) in DCM (75 mL) at 0° C. (bath temp). A solution of ethyl 5-bromo-1H-indole-7-carboxylate (1.5 g, 5.9 mmol) in DCM (25 mL) was added dropwise via addition funnel over 20 min. Triethylsilane (3.76 mL, 23.6 mmol) was added in one portion and the reaction was allowed to warm to room temperature over 15 h. Saturated aqueous Na2CO3 (35 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (1×75 mL). The combined organic layers were concentrated under reduced pressure, the crude product was washed with MeOH (2×8 mL) and dried under high vacuum, giving 1.59 g (76%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C(=O)([O-])O.[Na+].[ClH:40]>CS(C)=O.C(O)C.N1C=CC=CC=1>[ClH:1].[ClH:40].[CH3:28][O:27][C:23]1[CH:22]=[C:21]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]4)=[CH:8][CH:7]=3)[CH2:31][CH2:30]2)[CH:20]=[C:19]([O:18][CH3:17])[C:24]=1[O:25][CH3:26]
Reactant: O=C1CCc2ccc(OCCCCl)cc2N1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Solvent: CS(C)=O
Product: COc1cc(N2CCN(CCCOc3ccc4c(c3)NC(=O)CC4)CC2)cc(OC)c1OC
Reaction time: 5 h
Yield: 61 %

Procedure:
12.4 Grams of 7-(3-chloropropoxy)-3,4-dihydrocarbostyril, 1 g of pyridine and 2.6 g of 4-(3,4,5-trimethoxyphenyl)piperazine are mixed in 20 ml of dimethylsulfoxide, then stirred at 80°-90° C. for 5 hours. The reaction mixture is poured into 80 ml of 2% aqueous solution of sodium hydrogencarbonate and the organic layer is extracted with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue thus obtained is dissolved in 30 ml of ethanol and dried hydrogen chloride gas is blown into the ethanol solution. The crystals thus precipitated are collected by filtration and recrystallized from methanol-ethanol to obtain 3.2 g (yield: 61%) of 7-{3-[4-(3,4,5-trimethoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril dihydrochloride in the form of colorless needle-like crystals with a melting point of 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]=[C:5]([C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37]>CC(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]1[C:35]([C:34]([O:33][CH3:32])=[O:39])=[C:36]([CH3:37])[NH:38][C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
350 g of crude ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy) acetoacetate from Example 1 was dissolved in 540 ml of 2-propanol at 80° C. 50 g of methyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 540 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The formed solid was filtered off and washed with 280 ml of glacial acetic acid. The solid was suspended in 225 ml of methanol and agitated for 30 minutes. The solid was filtered off, washed with 75 ml of methanol and dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]1=[O:16].[F:20]C(F)(F)C1C=CC(=O)NC=1.C(=O)([O-])[O-].[Na+].[Na+].BrCC1C=CC=CC=1F.N>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]1=[O:16]
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: O=c1ccc(C(F)(F)F)cn1Cc1cccc(Cl)c1
Agent: Fc1ccccc1CBr
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1ccc(C(F)(F)F)cn1Cc1ccccc1F

Procedure:
The preparation of 1-(3-chlorobenzyl)-5-(trifluoromethyl)pyridin-2(1H)-one includes steps of: dissolving 0.49 g (3.0 mmol) of 5-(trifluoromethyl)pyridin-2(1H)-one in 20 ml of DMF; adding 0.66 g (4.8 mmol) of sodium carbonate and 0.85 g (4.5 mmol) 1-(bromomethyl)-2-fluorobenzene; carrying out refluxing reaction for 3 hours; adding 40 ml of 15% ammonia solution; extracting by ethyl acetate (30+20+20 mL); drying by anhydrous sodium sulfate; filtering; evaporating filtrate; and separating residue by column chromatography with eluent of petroleum ether and ethyl acetate with proportion of 6:1 to obtain 0.65 of the product 1-(2-fluorobenzyl)-5-(trifluoromethyl)pyridin-2(1H)-one as a colorless oil. EI-MS (m/z): 271[M]+. 1H-NMR (CDCl3, 300 MHz): δ ppm: 5.176 (s, 2H, —CH2—), 6.623˜6.655 (d, 1H, J=9, 6 Hz, Ar—H), 7.074˜7.178 (m, 2H, Ar—H), 7.301˜7.377 (m, 1H, Ar—H), 7.410˜7.505 (m, 2H, Ar—H), 7.795 (s, 1H, Ar—H).
Reaction SMILES: C(N(CC)[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1C=C[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])C.C(/S(N)(=O)=O)=C\C1C=CC=CC=1.[F:40][C:41]1[CH:50]=[CH:49][C:44]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:50]=[CH:49][C:44]([N:45]([CH:46]([CH3:48])[CH3:47])[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[O:7])=[CH:43][CH:42]=1
Reactant: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)CC
Reactant: CC(C)Nc1ccc(F)cc1
Agent: NS(=O)(=O)/C=C/c1ccccc1
Product: C#CCC(C(=O)NS(=O)(=O)/C=C/c1ccccc1)C(=O)N(c1ccc(F)cc1)C(C)C
Yield: 36.4 %

Procedure:
In the same manner as in Example 152 (3), the object compound was obtained using the compound (3.00 g) obtained in Example 152 (2) and trans-β-styrenesulfonamide (3.23 g). This was subjected to hydrolysis in the same manner as in Example 1 (3), and condensed with 4-fluoro-N-isopropylaniline (1.29 g) in the same manner as in Example 1 (4) to give a crude product. This was purified by silica gel column chromatography to give the title compound (1.25 g) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:24]3[C:23]4[C:27](=[CH:28][CH:29]=[CH:30][C:22]=4[CH3:21])[NH:26][C:25]3=[O:31])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: Cc1cccc2c1CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 52.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indole-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 52.5%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[NH:31][C:30](=[O:32])[O:29][N:28]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[NH:31][C:30](=[O:32])[O:29][N:28]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1noc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1noc(=O)[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoate (25 mg, 0.055 mmol) in MeOH (2 mL) is added aqueous 1 N NaOH (4 mL). After stirring at room temperature for 2 hours, the crude is quenched with 1N HCl and concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoic acid (22 mg). HPLC retention time=1.64 minutes (condition B); MS (m+1)=430.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=7.1 Hz, 3 H) 1.68 (ddd, J=14.3, 10.5, 4.0 Hz, 1 H) 1.99-2.05 (m, 1 H) 2.55 (ddd, J=10.2, 6.8, 3.9 Hz, 1 H) 2.80-2.97 (m, 2 H) 4.27-4.44 (m, 1 H) 7.28-7.35 (m, 3 H) 7.39 (t, J=7.8 Hz, 1 H) 7.49-7.55 (m, 3 H) 7.58 (t, J=1.9 Hz, 1 H)
Reaction SMILES: [OH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[NH:8][CH:7]=[C:6]([CH:15]=O)[C:5]=3[C:4]=2[CH2:3]1.C([O-])(=O)C.[NH4+].[N+:22]([CH2:25][CH3:26])([O-:24])=[O:23]>>[N+:22]([C:25]([CH3:26])=[CH:15][C:6]1[C:5]2[C:4]3[CH2:3][CH:2]([OH:1])[CH2:14][O:13][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: O=Cc1c[nH]c2ccc3c(c12)CC(O)CO3
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c[nH]c2ccc3c(c12)CC(O)CO3)[N+](=O)[O-]
Temperature: 115 °C

Procedure:
A mixture of the product from Step D (0.64 g, 2.95 mmol) and ammonium acetate (0.23 g, 2.98 mmol) in nitroethane (3 ml) was heated at 115° C. for 2.5 h. The mixture was cooled and the orange solid that formed was collected by filtration, washed with EtOAc and water and dried under vacuum (0.54 g, 67%): mp 240-242° C.
Reaction SMILES: Br[CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][CH2:4][C:3]1=O.BrC1COC(C)CC1=O.Cl.[C:20]([C:23]1[C:24]([CH3:34])=[CH:25][C:26]([CH3:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29])(=[NH:22])[NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:33][C:26]1[CH:25]=[C:24]([CH3:34])[C:23]([C:20]2[NH:21][C:3]3[CH2:4][O:5][CH:6]([CH3:8])[CH2:7][C:2]=3[N:22]=2)=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC1CC(Br)C(=O)CO1
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: CC1CC(=O)C(Br)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(-c2nc3c([nH]2)COC(C)C3)c(C)cc1C
Temperature: 75 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
Into around-bottom flask, was placed a mixture of 4-bromo-6-methyldihydro-2H-pyran-3(4H)-one (compound 464.5) and 5-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 464.6) (700 mg, 3.63 mmol) as a solution in acetonitrile (20 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 750 mg) and potassium carbonate (1.00 g, 7.25 mmol) were added and the mixture was stirred overnight at 75° C. under nitrogen. The mixture was cooled and the solids were removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as the eluent to obtain the title compound as a yellow solid (100 mg, 9%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[C:19]([CH2:20][O:21][CH3:22])=[CH:18][N:17]=[CH:16]1)=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[C:19]([CH2:20][O:21][CH3:22])=[CH:18][N:17]=[CH:16]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1cncc1COC
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1COC

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-{2-(5-methoxymethylimidazol-1-yl)ethyl}pyrrolidine (3.63 g) in ethyl acetate (40 ml) were added successively triethylamine (2.29 ml) and methanesulfonyl chloride (1.09 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water (20 ml). The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2(5-methoxymethylimidazol-1-yl)ethyl}pyrrolidine (3.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].Br[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][N:23]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH3:17][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][N:23]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24]3)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1ncc(N)cc1C(=O)Nc1ccccc1
Reactant: CS(=O)(=O)N1CCc2c(Br)cccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ncc(Nc2cccc3c2CCN(S(C)(=O)=O)C3)cc1C(=O)Nc1ccccc1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
A mixture containing 5-amino-2-methyl-N-phenylnicotinamide (46 mg, 0.2 mmol), 5-bromo-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (58 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (25 mg, 0.04 mmol), K3PO4 (169 mg, 0.8 mmol) in dioxane (1 mL) is stirred at 110° C. for 15 hours. The reaction mixture is filtered through a celite pad to remove any solids. The filtrate is evaporated and the crude product is purified by HPLC to give 2-methyl-5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-ylamino)-N-phenylnicotinamide as a white solid. MS m/z 437.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.58 (s, 1H), 8.20 (m, 2H), 7.71 (d, 2H, J=7.6 Hz), 7.63 (d, 1H), J=2.4 Hz), 7.38 (t, 2H, J=8.4 Hz), 7.23 (m, 2H), 7.15 (t, 1H, J=7.6 Hz), 7.00 (m, 1H), 4.39 (s, 2H), 3.47 (t, 2H, J=6.4 Hz), 2.97 (s, 3H), 2.82 (t, 2H, J=6.4 Hz), 2.54 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.[Cl-].[NH4+]>C1COCC1.O>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)=[N:11][O:12][C:13]=2/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:27][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)nc1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a suspension of sodium hydride (813 mg, 18.6 mmol) in 28 mL THF was added a solution of [3-(4-fluoro-phenyl)-5((E)-styryl)-isoxazol-4-yl]-methanol (5.00 g, 16.9 mmol) in THF (52 mL) and stirring was continued for 1 h at room temperature. A solution of methyl 6-chloronicotinate (3.26 g, 18.6 mmol) in THF (52 mL) was added. The mixture was stirred at room temperature for 3 h. Then water (50 mL) was added cautiously and then saturated ammonium chloride solution (150 mL) and water (100 mL). Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (3.88 g, 94%) as a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH3:13])[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][C:2](=[O:1])[CH3:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: COc1cc(CC(C)O)ccc1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(CC(C)=O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(2-hydroxypropyl)-2-methoxybenzonitrile (1.5 g, 7.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (4.2 g, 9.9 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxopropyl)benzonitrile. The crude residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, 1H, J=1.6 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.83 (s, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 2.25 (s, 3H); LCMS: [(M+1)]+=190.32; tR=2.31 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][C:14]=1[C:15](O)=O>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[N:9]=[C:15]([C:14]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:13]=3[O:12][CH3:11])[NH:10][C:4]=2[CH:3]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(N)c(N)cc1C
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cc(C)c(C)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4,5-dimethyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylaminobenzoic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(C)(C)C)cc4)cc3=O)cn12
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in DMF (3 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (178 mg) and potassium carbonate (197 mg) at room temperature, and the mixture was stirred for 17 h. The mixture was poured into water, and the resultant solid was collected by filtration. The solid was recrystallized from acetone to give the title compound (143 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C3C=CC=CC=3)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc2c1Oc1ccccc1N2

Procedure:
4-methyl-N-(α-phenylethyl)phenoxazine in 30 ml of ethyl acetate and 130 ml of ethanol was hydrogenated at atmospheric pressure (585 mm Hg) in the presence of 1.5 g of 10% palladium-charcoal as catalyst, until the calculated amount of hydrogen was consumed (16 hours). The catalyst was then separated by filtration through celite and the solvent removed under reduced pressure. Chromatography of the solid residue (1 g) on 100 g of silica gel in a column, using hexane-ethyl acetate (80:20) as the eluting solvent produced 4-methylphenoxazine, a white solid, which was recrystallized from pentane, mp: 91° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][S:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[S:37][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CSC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)C(CSC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Using General Procedure G: To a solution of COMPOUND 249 (0.1233 g, 0.40 mmol) in DMF (5 mL) were added 2-tert-butoxycarbonylamino-3-tert-butoxycarbonylsulfanyl-propionic acid (0.1414 g, 0.44 mmol), DIPEA (0.14 mL, 0.80 mmol), EDCI (0.0920 g, 0.48 mmol), and HOBT (0.0649 g, 0.48 mmol), and stirred at room temperature for 16 hours. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1652 g (67%) of thiocarbonic acid S-(3-{4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-2-tert-butoxycarbonylamino-3-oxo-propyl) ester O-tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.47 (s, 9H), 1.67 (s, 5H), 2.08 (d, 6H, J=6.0 Hz), 2.39-2.43 (m, 1H), 2.75-3.14 (m, 3H), 3.80-3.83 (m, 4H), 4.13 (d, 1H, J=15.0 Hz), 4.65 (d, 1H, J=15.0 Hz), 4.88-4.89 (m, 1H), 5.52-5.55 (m, 1H), 7.07-7.11 (m, 2H), 7.37 (d, 2H, J=6.0 Hz), 8.34 (d, 2H, J=3.0 Hz).