Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=[O:4])=[O:3]>ClCCl.CO.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][C:10]([F:11])=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:6]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(F)c(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 3-aminosulfonyl-4-fluoronitrobenzene (360 mg, 1.62 mmol) in dichloromethane (6 mL) and methanol (3 mL) was added 10% Pd/C (36 mg) and shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through Celite and the cake was washed with methanol (5 mL). The combined organic solvent was concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 240 mg of 5-amino-2-fluorobenzensulfonamide as a light yellow solid. 1H NMR (DMSO-d6): δ 7.38 (s, 2H), 7.03-6.94 (m, 2H), 6.70-6.66 (m, 1H), 5.33 (s, 1H).
Reaction SMILES: [OH-].[Na+].[NH:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]1[NH2:12].[C:13](OC)(=O)[CH2:14][OH:15]>C(O)C>[CH3:11][C:6]1[N:5]2[N:12]=[C:13]([CH2:14][OH:15])[N:3]=[C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: COC(=O)CO
Reactant: Cc1cc(C)n(N)c(=N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)n2nc(CO)nc2c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
To a solution of 0.79 g of sodium hydroxide in ethanol (20 mL) was added 2-imino-4,6-dimethyl-2H-pyridin-1-ylamine (1.7 g, 0.012 mol; obtained by HPLC purification of intermediate 10). After being stirred at 50-60° C. for 1 hour, methyl glycolate (1.4 g, 0.016 mol) was added, and the resulting mixture was stirred at reflux for 6 hours. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) to afford (5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-methanol (0.2 g, 10%); 1H NMR (300 MHz, DMSO-d6): δ7.39 (s, 1H), 6.87 (s, 1H), 5.38 (t, J=6.3 Hz, 1H), 4.59 (d, J=6.3 Hz, 2H), 2.64 (s, 3H), 2.38 (s, 3H). A mixture of this compound (31 mg, 0.175 mmol) and SOCl2 (10 mL) in dry CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. The solvent and excess SOCl2 was evaporated under vacuum to yield the title compound as a crude product, which was used for the preparation of final compounds without purification or characterization.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1O)([CH3:15])([CH3:14])[CH3:13].[CH2:23]1[O:26][CH:24]1[CH3:25]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:11][CH2:8][C:24]([CH3:23])([OH:26])[CH3:25])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C1CCCCC1O
Reactant: CC1CO1
Agent: CC(C)(C)C1CCC(O)CC1
Product: CC(C)(O)COC1CCC(C(C)(C)C)CC1

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 20.0 g (0.128 mol) of 4-tert-butylcyclohexanol (cis:trans=4:6) and 8.8 g (0.128 mol) of 2-methylpropionoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 6.2 g of 4-tert-butylcyclohexanol and 14.6 g of 1-(4-tert-butylcyclohexyloxy)-2-methyl-2-propanol (cis:trans=4:6) were obtained in a 50% yield.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])(=[O:5])[CH3:4].I[CH2:21][CH3:22].O>CN(C)C=O>[C:3]([N:6]([C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])[CH2:21][CH3:22])(=[O:5])[CH3:4]
Reactant: CCI
Reactant: CC(=O)Nc1c(C)oc2c([N+](=O)[O-])cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Sodium hydride (60%, 54 mg) was added to a solution of 3-acetylamino-2-methyl-7-nitrobenzo[b]furan (280 mg) in N,N-dimethylformamide (3 ml) at 4° C. The mixture was stirred for 30 minutes and to the mixture was added iodoethane (240 mg). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 3-(N-acetyl-N-ethylamino)-2-methyl-7-nitrobenzo[b]furan as a crystalline solid (310 mg).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.N1C=CC=CC=1.[C:47]([OH:50])(=[O:49])[CH3:48]>>[C:47]([O:50][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2)(=[O:49])[CH3:48]
Reactant: CC(=O)O
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.0 g), pyridine (4 ml) and anhydrous acetic acid (4 ml) was stirred at room temperature for 14 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The solution was dried and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the titled compound (0.6 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]([C:25]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=1)=[O:27]
Reactant: O=Cc1ccncc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnccc2C=O)ccc1C#N
Temperature: 100 °C
Yield: 78.4 %

Procedure:
A mixture of 1a (430 mg, 1.769 mmol), 3-bromo-4-pyridinecarboxaldehyde (299 mg, 1.608 mmol), sodium carbonate (2N in water, 1.608 mL, 3.22 mmol), bis(triphenylphosphine)palladium(II) chloride (28.2 mg, 0.040 mmol) in DMF (6.432 mL) was heated to 100° C. for 2 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage (0-50% EtOAc/heptane; 25M column) giving compound 1b as white solid (280 mg, 78%). LC-MS (M+1) 223.1, t=1.28 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[OH:39]>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)cc2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=502.
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]1([OH:17])[C:5]1[CH:18]=[CH:19][C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:4]=1[O:3]2.[C:25]([OH:28])(=O)[CH3:26].N1C=CC=CC=1.C1C[O:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C>[C:37]([O:17][C:6]1([C:5]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:4]=2[O:3][C:25](=[O:28])[CH3:26])[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:2]1=[O:1])(=[O:38])[CH3:36]
Reactant: COc1ccc2c(c1)C(=O)C1(O)c3ccc(C(C)C)cc3OC21O
Reactant: C1CCOC1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(=O)C(OC(C)=O)(c1ccc(C(C)C)cc1OC(C)=O)C2=O
Temperature: 25 °C
Yield: 51 %

Procedure:
4b, 9b-dihydroxy-7-isopropyl-2-methoxy-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.30 g, 0.91 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.18 g, 1.82 mmol), pyridine (0.07 g, 0.91 mmol) and DMAP (0.03 g), and stirred at room temperature. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.19 g, 51%).
Reaction SMILES: N[CH2:2][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:15])[CH2:2][C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)C(O)(CN)CCC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)CCC2
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 1-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (27.50 g) in 10% aqueous acetic acid solution (250 ml) was added dropwise a solution of sodium nitrite (10.07 g) in water (61 ml) at 8° C.~9° C. The reaction mixture was stirred for 2 hours at the same temperature. The resulting precipitates were collected by filtration. The precipitates were dissolved in ethyl acetate. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate:chloroform=5:1:3) to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (19.39 g) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: NC(N)=S
Reactant: CCc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: CCc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 87.5 %

Procedure:
A mixture of 2-bromo-1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (7.70 g, 22.2 mmol) and thiourea (1.69 g, 22.2 mmol) in 95% EtOH (31.7 mL) was heated at reflux for 180 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (6.30 g) as yellow solids in 88% yield: 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=7.5 Hz, 2 H), 6.95 (d, J=8.5, 2 H), 6.71 (s, 2 H), 6.29 (s, 1 H), 5.45 (bs, 2 H), 2.64 (q, J=7.5 Hz, 2 H), 2.14 (s, 6 H), 1.25 (t, J=8.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].C(OC)(OC)OC.[CH:22](O)([OH:24])[CH3:23]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:22]1[O:24][C:5]2([CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[O:14][CH2:23]1
Reactant: CC(O)O
Reactant: C=CCC1Cc2ccccc2CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Solvent: ClCCl
Product: C=CCC1Cc2ccccc2CC12OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
A mixture of 3-(2-propenyl)-2-tetralone (25.9 g, 139 mmol), trimethyl orthoformate (61.3 ml, 554 mmol), ethanediol (57.5 ml, 1.03 mol), p-toluenesulfonic acid monohydrate (0.27 mg, 1.4 mmol) in dichloromethane (650 ml) was stirred at room temperature, under argon for 2 h. Resulting mixture was partitioned between saturated aqueous sodium bicarbonate (1000 ml) and dichloromethane (3×500 ml). The combined organic extracts were washed with brine (500 ml), dried (Na2SO4) and evaporated in vacuo to give a brown oil (34.9 g). Chromatography on silica using 0-10% ether-hexane gradient elution gave the title compound as a yellow oil (20.1 g, 63%).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[Cl:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1O.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:33][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32][CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]5[Cl:34])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: OC1CCCCC1Cl
Reactant: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCCCC1Cl)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reaction time: 8 h

Procedure:
To a solution of 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (E, 160 mg) in dichloromethane (5 ml) are added, at room temperature, 2-chlorocyclohexanol (57 mg), 4-dimethylaminopyridine (4 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (94 mg). The mixture is stirred overnight, and water is then added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solids are filtered off and the solvent is distilled off. The residue is purified by chromatography. This gives 2-chlorocyclohexyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (100 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[C:7]([CH:19]=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-bromopyridine (5.13 g, 3.2 mmol) in THF (90 ml) at −78° C. was slowly added lithium diisopropylamide (LDA) (2 M in THF, 17.9 ml, 3.6 mmol) and the resulting reaction mixture allowed to stir for three hours. To the reaction mixture was then slowly added DMF (9.49 g, 130 mmol) in THF (10 ml). The reaction mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature. Water (100 mol) was added and then the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4. The solvent was removed and the resulting residue purified over silica gel chromatography eluted with hexane, to yield 2-bromo-pyridine-3-carbaldehyde as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:5][CH:4]=1.Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=4)[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Reactant: Cc1ccc(CCl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cccc(OC(F)(F)F)c4)n3Cc3ccc(C)cn3)n(C)c2=O)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)— dione (110 mg, 0.238 mmol, intermediate 48) in DMF (4 mL) was added 2-(chloromethyl)-5-methylpyridine (33.8 mg, 0.238 mmol, intermediate 50), followed by potassium carbonate (49.5 mg, 0.358 mmol). The reaction was stirred at 55° C. for 2 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a white solid product (120 mg, 88.8% yield) which was used without purification. LCMS MH+ 566.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:18](=[O:29])[N:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)[C:16]2=[O:41])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:26]1[CH2:27][CH2:28][CH:23]([N:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)=[CH:22][CH:21]=3)[C:16](=[O:41])[N:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:18]2=[O:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
0.14 g of acetyl chloride is added to a mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained according to stage 1.6 and 0.24 g of NEt3 in 10 ml of DCM cooled to 0° C. The mixture is stirred at AT overnight. It is washed twice with a saturated NH4Cl solution and filtered, and then the filtrate is evaporated under reduced pressure to give 0.64 g of the expected product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]=2[C:13]([O:32][CH3:33])=[CH:12][C:11]=1[CH2:34]OS(C)(=O)=O>CN(C=O)C>[Br:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]=2[C:13]([O:32][CH3:33])=[CH:12][C:11]=1[CH2:34][N:6]1[CH:5]=[C:4]([CH3:3])[CH:8]=[N:7]1
Reactant: Cc1cn[nH]c1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cn3cc(C)cn3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
NaH (7 mg, 0.3 mmol) is added to a solution of 23 μl (0.30 mmol) 4-methylpyrazole in 2 ml DMF. The resulting mixture is stirred at room temperature for 1 h, then 119 mg (0.23 mmol) methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester is added. Stirring is continued for 20 h. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (dichloromethane:isopropanol=95:5) to afford 80 mg of the title compound as a white foam.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:13]1[C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1CN(c2ncccc2C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 23.5 %

Procedure:
A suspension of azetidin-3-ol hydrochloride (500 mg), 2-chloro-3-(trifluoromethyl)pyridine (425 mg) and cesium carbonate (1.14 g) in DMF (5 ml) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CO>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccccc3)ccc2CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2ccc(-c3ccccc3)cc2c1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
In methanol (35 ml) was dissolved 7-phenyl-3,4dihydro-naphthalene-2-carboxylic acid (1.50 g), and to the mixture was added concentrated sulfuric acid (0.1 ml), and then the mixture was refluxed for 9 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), and to the mixture was added activated manganese dioxide (9 g). The mixture was refluxed for 48 hours and then cooled to room temperature. The manganese dioxide was filtered off, and the filtrate was concentrated. The residue was dissolved in methanol (15 ml), and to the mixture was added 1N sodium hydroxide (10 ml). The mixture was refluxed for 4 hours and then cooled to room temperature. The mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-phenylnaphthalene-2carboxylic acid (783 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 70 mL of a chloroform solution containing 9.53 g of tert-butyl (1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure, the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=50:1] to obtain 5.97 g of a brown oily substance, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one.