Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:20]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2CCCCN2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCCC3c3ccccc3)cc2)nc1
Reaction time: 21 h
Yield: 2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.152 g, 0.628 mmol), 2-phenyl-piperidine hydrochloride salt (0.122 g, 0.620 mmol), triethylamine (0.178 mL, 1.28 mmol) in methanol (6.0 mL) and stir. After 21 hours, add sodium borohydride (0.108 g, 2.85 mmol). After about 24 hours, concentrate and purify the residue by silica gel chromatography (25:1→4:1 methylene chloride:methanol) then reverse-phase HPLC to provide 0.0047 g (2%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.2 (M+1); 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.3 Hz), 7.52 (d, 2H, J=7.3 Hz), 7.41 (t, 2H, J=7.3 Hz), 7.37-7.28 (m, 3H), 7.11 (d, 2H, J=8.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 3.81 (d, 1H, J=10.7 Hz), 3.39 (s, 2H), 3.20-2.94 (m, 2H), 2.17 (s br, 1H), 1.93-1.61 (m, 4H), 1.59-1.44 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35]([C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:21])([F:22])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1)=[O:36]
Reactant: CON(C)C(=O)c1ccccc1Br
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 mLl (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of 2-Bromo-N-methoxy-N-methyl-benzamide(244 mg, 1.0 mmol) in 1mL of THF. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration of the solvent the residue was purified by flash chromatograph (20% ethyl acetate in hexane) to afford 180 mg of title compound as an off white solid. MS: (M+Na)/z=621.2, (M−32)/z=567.0.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 5.0 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole in 50 ml of methanol is refluxed under nitrogen with 0.25 g of concentrated sulfuric acid for 2 hours. The reaction mixture is cooled and evaporated and partitioned between 50 ml of ether and 50 ml of ice-cold, saturated sodium bicarbonate solution. The organic phase is separated, dried over potassium carbonate and evaporated to yield 3-(4-methoxycarbonylbutyl)-N-(3-pyridyl)indole.
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:16][CH2:15][C:13]4[N:12]=[CH:11][O:10][CH:14]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: NCc1cocn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cocn1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 32% yield: mp 188-191° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.29-7.25 (m, 2H), 7.07-7.01 (m, 2H), 6.21-6.17 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.46 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.42 (m, 2H) 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.4, 160.9, 157.5, 155.3, 152.9, 151.3, 136.8, 135.8, 131.4, 131.3, 130.1, 129.9, 117.5, 115.9, 115.7, 47.3, 41.9, 41.6, 35.6, 17.2; MS (ES+) m/z 416.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[CH3:17][C:18](OC(C)=O)=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:18](=[O:19])[CH3:17])[N:3]=1
Reactant: Cc1n[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
3-Methylindazole (1.00 g, 7.6 mmol) (J. Med. Chem. 2706 (1997)] was dissolved in 10 ml THF and stirred at room temperature under a blanket of argon. Pyridine (0.64 ml, 7.9 mmol) was added, followed by Ac2O (0.79 ml, 8.3 mmol) and catalytic DMAP (90 mg, 0.7 mmol). The reaction proceeded for 2 h and was then partitioned between 1N HCl and dichloromethane. The organic phase was dried over MgSO4 and concentrated under vacuum to a tan solid (1.2 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1[OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethoxy)benzaldehyde (1.0 g, 4.542 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (2.04 g, 9.08 mmol). The resulting clear solution was stirred for 16 hours at room temperature. A white precipitate had formed and this was filtered off. The filtrate was evaporated to a white solid, which was diluted with ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the solvents were evaporated. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL) dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (650 mg, 57%)
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][C:4]=1[CH2:17][CH2:18][CH3:19].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[C:9]([C:8]1[CH:25]=[CH:24][C:23](=[O:26])[N:7]2[C:3]([CH3:2])=[C:4]([CH2:17][CH2:18][CH3:19])[NH:5][C:6]=12)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CC(=O)OC
Reactant: CCCc1nc(CC(=O)c2ccccc2)[nH]c1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCCc1[nH]c2c(C(=O)c3ccccc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.08 mmol) of 2-(5-Methyl-4-propyl-1H-imidazol-2-yl)-1-phenylethanone hydrochloride (example XX), 60 mg (1.11 mmol) of sodium methylate and 90.5 mg (1.08 mmol) methyl propiolate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CCCCCC>[CH3:15][Si:16]([CH3:18])([CH3:17])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 31.8 %

Procedure:
To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.0 mmol) in anhydrous DMF (50 mL), trimethylsilyl chloride (3 mL, 30.1 mmol) and triethylamine (8.3 mL, 60.2 mmol) were added at 80° C. and stirred for 10-12 h. The reaction mixture was cooled to room temperature, diluted with hexane and washed with saturated NaHCO3. Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by flash column chromatography to give tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oil (2.16 g, 32%); MS: 271 (M+).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[O:18][CH3:19])=[CH:15][CH:14]=[CH:13][C:12]=2[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[OH-].[Na+].Cl>CO.O1CCCC1>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:18][CH3:19])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])[N:9]=1)#[N:28]
Reactant: COC(=O)CNC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Yield: 79.5 %

Procedure:
To a mixture of [(1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (21 mg, 0.05 mmol), and methanol/tetrahydrofuran (0.9 mL, 1:3.5) was added 2N sodium hydroxide (29.2 μL, 0.06 mmol) at room temperature. The yellow solution was stirred at that temperature for fifty-five minutes before it was acidified with 1N HCl (69.1 μL) to pH=3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of methanol, dichloromethane and acetic acid (0.1%) to give the title compound as a pale brown solid (15 mg): MS: (+) m/z 378.00 (M+1).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[N:18]1([C:23](=[NH:25])[NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:3]1[NH:25][C:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:24][C:2]=1[CH3:16]
Reactant: COC(=O)c1ccc(C)c(C(=O)C(C)Br)c1
Reactant: N=C(N)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2[nH]c(N3CCCC3)nc2C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromopropanoyl)-4-methylbenzoate (compound 197.2, 500.0 mg, 1.75 mmol) in N,N-dimethylformamide (15 mL). Pyrrolidine-1-carboximidamide hydrochloride (compound 197.1, 260.8 mg, 1.75 mmol) was treated with K2CO3, then added to the reaction. The reaction mixture was stirred for 1 h at 50° C. The reaction mixture was diluted with 30 mL of H2O. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with PE/EtOAc (1:1)˜EtOAc/methanol (15:1) as eluent to furnish 230.0 mg (44%) of the title compound as a dark blue solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[CH:38](OCC)(OCC)OCC>B(F)(F)F.CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:38][O:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:29])([CH3:30])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncon4)cc3Cl)nc2O1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of the product of Step A (61 mg, 0.11 mmol) in 5.0 mL of triethyl orthoformate was added one drop of BF3.Et2O. After stirring at 110° C. for 1 h, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 7:13 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.84 (t, J=11.4, 1H), 2.27 (dd, J=6.2, 13.0, 1H), 5.50 (m, 1H), 5.84 (br. s, 1H), 7.01 (d, J=8.3, 2H), 7.16 (d, J=8.2, 2H), 7.45 (m, 1H), 7.58 (s, 1H), 7.96-8.04 (m, 2H), 8.77 (s, 1H).
Reaction SMILES: C1(S(N=N[C:12]2[CH:13]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:15]=[C:16]([Br:18])[CH:17]=2)(=O)=O)C=CC=CC=1.[K].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].O>CS(C)=O>[Br:18][C:16]1[CH:15]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:13]=[C:12]([S:34][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[CH:17]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(N=NS(=O)(=O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
0.22 g (0.00055 mol) of N-[3-[2-(phenylsulphonyl)-diazenyl]-5-bromophenyl]-N-methylacetamide was dissolved in 15 ml of dimethyl sulphoxide, treated with 0.185 g (0.000825 mol) of 4-nitrothiophenol potassium salt and stirred at 40° C. for 18 hrs. The reaction mixture was poured into 300 ml of water, extracted with diethyl ether, the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered and the filtrate was freed from solvent. The residue was chromatographed on silica gel with 1% MeOH in dichloromethane. There was obtained 0.217 g (100%) of N-[3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-N-methylacetamide as a yellow oil. MS (EI): me/e=382, 380 (C15H13BrN2O3S+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:18]C)(=[O:17])[CH2:11][CH2:12][C:13]([O:15]C)=O.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)C>[OH:15][C:13]1[C:9]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:6])[CH:8]=2)[CH:1]=[C:11]([C:10]([OH:18])=[O:17])[CH:12]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: Cc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cc(C(=O)O)cc(O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-methylbenzaldehyde (0.70 g) and dimethyl succinate (0.95 g) in tetrahydrofuran (15 mL) was added potassium tert-butoxide (0.73 g) at room temperature, and the reaction mixture was stirred overnight. To the reaction mixture were added water and diethyl ether, and the two layers were separated. The aqueous layer was acidified with 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. This organic layer was washed with a saturated sodium carbonate aqueous solution. The aqueous layer was acidified with 1 mol/L hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, and concentrated. To the residue were added acetic acid (5 mL), acetic anhydride (5 mL) and sodium acetate (3.0 g), and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction mixture was poured into water. The resulting mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated sodium hydrogen carbonate aqueous solution, and concentrated. To the obtained residue were added methanol (20 mL) and 1 mol/L sodium hydroxide aqueous solution (20 mL), and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, methanol was removed under reduced pressure. The obtained solution was acidified with 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give the title compound (0.20 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[NH:50][N:49]=[C:48]([NH2:51])[CH:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:40])([CH3:41])[C:37]([NH:51][C:48]5[CH:47]=[C:46]([CH3:45])[NH:50][N:49]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:15][CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4cc(C)[nH]n4)c3)cc12
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 5-methyl-1H-pyrazol-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (6.4 mg, 21%). 1H NMR (500 MHz, DMSO-d6) d ppm 11.90 (1H, br. s.), 9.84 (1H, br. s.), 8.51-8.56 (1H, m), 8.41 (1H, br. s.), 8.23-8.28 (1H, m), 7.98-8.03 (2H, m), 7.86-7.93 (3H, m), 7.76-7.83 (2H, m), 7.59 (1H, t, J=7.63 Hz), 7.37-7.43 (2H, m), 6.28 (1H, br. s.), 2.87 (3H, d, J=4.88 Hz), 2.17 (3H, s), 1.54 (6 H, s). LC-MS retention time: 1.56 min; m/z (MH+): 554. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 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 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=10.47 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=9.58 min, purity=96%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OO)=O)[CH:3]=1.C1C2CC=CCC=2C=CC=1.[C:22]([O:25][CH2:26][CH3:27])(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)C>[O:25]1[CH:26]2[CH:22]1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH2:27]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(C)=O
Agent: C1=CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
Reaction of a 5,8-dihydronaphthalene of formula III or formula IV with m-chloroperbenzoic acid yields a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene having the structure ##STR6## The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene in an organic solvent, e.g., ethyl acetate. The resulting mixture is added to a mixture of ethyl ether and aqueous sodium bicarbonate, and mixed to form a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](Cl)=[O:18])[CH3:15].O>N1C=CC=CC=1>[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](=[O:18])[O:13][C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:12])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=C1NCCc2ccc(O)c(Cl)c21
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)NCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A mixture of 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 5.6 g, 28 mmol), and diethylcarbamic chloride (4.3 g, 31 mmol) in pyridine (100 mL) was stirred at 100° C. for 5 hours. To the reaction mixture was added H2O (300 mL). The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with 1 N HCl (2×300 mL) and brine (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1f, 7.6 g, 90%) as brown oil.