Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cccc(O)c1
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 34.96 g (0.231 mol) of N-ethyl-3-hydroxybenzylamine in 200 ml of dimethylsulfoxide were added 25.64 g (0.231 mol) of 1,3-dichloropropene (E/Z=2/1) and 16.7 g (0.121 mol) of ground potassium carbonate under ice cooling. The mixture was stirred for 4 hours at 50° C., poured into 250 ml of ethyl acetate, washed with 200 ml×2 of water and 200 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 26.2 g (yield: 50%) of the above identified compound as an oil.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O.N>CCO.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 95 °C

Procedure:
Iron powder (2.51 g, 45 mmol), water (0.97 ml) and HCl (37%, 0.74 ml), were added to a stirred suspension of the 5-nitroisoindolin-1-one (800 mg, 4.5 mmol) from step 2 of this example in EtOH (11.2 ml). The mixture was heated at 95° C. for 2 h. Ammonia (7N in MeOH) was added (1 mL) to make the pH of the mixture alkaline. The mixture was filtered to removed undissolved solids and the filter cake washed with EtOH (2×40 ml). The filtrate and organic washes were combined and concentrated in vacuum to give the titled compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[N:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:24]2[CH:23]=[C:22]([C:21]3[CH2:20][C:19](=[O:35])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:27]=[CH:26][CH:25]=2)[N:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridazin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M185) (245 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (144 mg, 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of 6-indole carboxylic acid (0.91 g, 5.67 mmol) in 33 mL of 2:1 THF/MeOH is added (trimethylsilyl)diazomethane (5.0 mL of a 2.0M solution in hexanes, 10.0 mmol). The mixture is stirred for 3 h and concentrated in vacuo to give the title compound (0.87 g, 4.97 mmol). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.70 (bs, 1H), 8.20 (s, 1H), 7.82 (dd, 1H), 7.67 (d, 1H), 7.45 (m, 1H), 6.60 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH3:48])[CH2:45][CH2:46][CH3:47])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH3:48])[CH2:45][CH2:46][CH3:47])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CCCN(C)C(=O)CCl
Product: CCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 49.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-methyl-N-propylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](OS(OCC)(=O)=O)[CH3:15].C(N(CC)CC)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CCOS(=O)(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(N)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-amino-6-nitrobenzoic acid (29.2 g, 0.16 mol), diethylsulfate (24.7 g, 0.160 mol) and triethylamine (16.2 g, 0.160 mol) in N-dimethylformamide (250 ml) was stirred at 20°-25° for 20 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was flash chromotographed over silica gel and the ethyl ester (10.8 g) eluted first with toluene then with 50% toluene -50% chloroform.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.Cl[CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12]>CO>[CH3:15][C:14](=[O:16])[CH:10]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Sc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C(Sc1nc[nH]n1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium hydroxide (13 g) in methanol (200 ml), with cooling it on ice, was added 3-mercapto-1H-1,2,4-triazole (20 g), followed by 3-chloro-2,4-pentanedione (24 ml). Then, mixture was stirred at room temperature overnight. Insoluble materials in the reaction solution were filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered through a small amount of silica gel, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was recrystallized in ethyl acetate-hexane to yield the title compound (33.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[I:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:14])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cccn2cc(C3CC3)nc12
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccn2c(I)c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
[step 2] 8-Chloro-2-cyclopropylimidazo[1,2-a]pyridine (2.23 g, 11.6 mmol) obtained in step 1 was dissolved in DMF (23 mL), N-iodosuccinimide (2.36 g, 12.7 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To the mixture was added water (100 mL), and the precipitated crystals were collected by suction filtration to give 8-chloro-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (3.46 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1)(=O)=O>CN(C=O)C>[N:39]1[CH:40]=[CH:41][N:42]=[CH:43][C:38]=1[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)OCc1ccc(-c2cnccn2)cc1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4cnccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (20 mg, 0.077 mmol) and cesium carbonate (38 mg, 0.12 mmol) in DMF (1 mL) was added 4-(pyrazin-2-yl)benzyl methanesulfonate (41 mg, 0.15 mmol). The reaction mixture was stirred at room temperature overnight. The solid was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound (15 mg). LCMS m/z=428.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 2.07-2.14 (m, 1H), 2.50 (dd, J=16.7 and 11.2 Hz, 1H), 2.70-2.87 (m, 4H), 3.50-3.57 (m, 1H), 4.18-4.24 (m, 2H), 5.18 (s, 2H), 6.87 (dd, J=8.8 and 2.4 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.64 (dd, J=2.3 and 1.6 Hz, 1H), 9.04 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH3:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:15][C:7]1[N:8]([CH3:14])[C:9](=[O:13])[C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(=O)n(C)c(C)c(-c3ccccc3)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1

Procedure:
To a solution of 12 (3.08 g, 11.0 mmol) in carbon tetrachloride under Argon was added N-bromosuccinimide (1.96 g, 11.0 mmol). The contents of the reaction flask were heated to reflux. After 3 h an additional portion of N-bromosuccinimide (0.50 g, 2.81 mmol) was added to the reaction flask. After 7 h the solvent was removed in vacuo and sat. sodium bicarbonate was added. Extracted with methylene chloride (4×) and dried the combined organic portions with magnesium sulfate (anh.). Removal of the solvent in vacuo followed by trituration with ether gave 13 as a light solid (3.47 g, 9.70 mmol, 88.2%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH2:15]O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][I:41])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: II
Reactant: OCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cnc(C2(CI)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
500 mg of [1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropyl]methanol (step 2) was dissolved in 20 ml dichloromethane and the solution was cooled in an ice bath. Then 560 mg triphenylphosphine and 150 mg imidazole were added. When a clear solution had formed, 550 mg iodine was added in portions. The reaction was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane, washed with a saturated solution of sodium thiosulfate and the organic phase was concentrated. The residue was triturated with 30 ml of hexane. The solid was removed by filtration and the filtrate was concentrated. The residue was purified on 20 g of silica gel, eluent hexane/ethyl acetate (20:1). Thus, 610 mg of 3-chloro-2-[1-(iodomethyl)cyclopropyl]-5-(trifluoromethyl)pyridine was obtained as a pale yellow oil. 1H-NMR (CDCl3): 8.76 ppm (s, 1H), 7.93 ppm (s, 1H), 3.61 ppm (s, 2H), 1.49 ppm (m, 2H), 1.17 ppm (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CCOC(C)=O>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ncccc1N
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of ethyl N-(3-nitropyridin-2-yl)glycinate (26 g) and 10% palladium on carbon (50% wet, 7.3 g) in AcOEt (250 mL) was hydrogenated under balloon pressure at room temperature for 8 h. The catalyst was removed by filtration. To the filtrate were added triethylamine (5.0 mL) and 10% palladium on carbon (50% wet, 7.3 g). The mixture was hydrogenated under balloon pressure at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-50% AcOEt in hexane) to give the title compound (18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:16]1([CH2:22][C:23](=[NH:26])[NH:24]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:16]1([CH2:22][C:23]2[N:26]=[C:13]([CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:15][N:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N=C(CC1CCCCC1)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(CC3CCCCC3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 0.39 g (1.88 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.333 g (2.00 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of 2-cyclohexyl-N-hydroxyacetimidamide (compound of Example 44; 0.6 g, 3.8 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mass was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Benzyl isocyanate (0.02 g, 0.15 mmol) was added to a solution of 3-phenyl-3-neopentyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.043 g, 0.15 mmol prepared in a manner analogous to compound 2) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.041 g, 63%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.87 (s, 9H), 1.88 (d, J=14.88 Hz, 1H), 2.28-2.43 (m, 2H), 2.38 (d, J=14.88 Hz, 1H), 3.16-3.28 (m, 1H), 3.53 (s, 1H), 3.96 (dt, J=19.03, 2.50 Hz, 1H), 4.42 (d, J=5.65 Hz, 2H), 4.59 (s, 1H), 4.88-4.99 (m, 1H), 7.20-7.41 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]([NH:18]C(=O)OC(C)(C)C)[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([C@@H:14]([NH2:18])[CH:15]([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 92 %

Procedure:
The product from Example 7, Step (a) (1.57 g) was dissolved in dichloromethane (14 ml) and trifluoroacetic acid (4 ml) was added. After 2 hours at room temperature the solution was evaporated and aqueous NaOH (2M) was added. The product was extracted with ethyl acetate, the combined organic extracts dried, filtered and concentrated to give the sub-title product as an oil (1.12 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.C([O-])(=[O:17])C.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[O:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:17])[NH:3][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc(Oc2ccccc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(Oc2ccccc2)n[nH]1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
A mixture of 3-chloro-6-phenoxy-pyridazine (1.01 g, 4.89 mmol) and sodium acetate (1.40 g, 17.06 mmol) in glacial acetic acid (50 mL, 0.1M) was heated to 110° C. overnight. After this time the reaction was cooled to 25° C. and was diluted with water (450 mL). The reaction was brought to pH=5-6 by the addition of a 5N aqueous sodium hydroxide solution. The resulting solution was extracted with ethyl acetate (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The resulting oil was azeotroped with methanol four times and dried in vacuo to afford 6-phenoxy-2H-pyridazin-3-one (0.78 g, 86%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 7.00 (d, J=10.0 Hz, 1H), 7.13-7.27 (m, 3H), 7.34-7.46 (m, 3H), 12.29 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[OH:9])=[CH:11]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2ccoc2)c1O
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
2-Bromo-6-methylphenol (800 mg, 4.28 mmol), 3-furan boronic acid (574 mg, 5.13 mmol), sodium carbonate (1400 mg, 12.8 mmol) and Pd2(dppf)2Cl2 (699 mg, 0.82 mmol) were dissolved in dimethoxyethane/water 10 mL/10 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-3-yl)-6-methylphenol (273 mg, 26%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1([SH:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:21][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Sc1cccc2ccccc12
Product: O=C(O)c1ccccc1Sc1cccc2ccccc12

Procedure:
According to the same process, starting from 2-iodobenzoic acid and 1-naphthalenethiol, also 2-(naphthalene-1-ylsulfanyl)-benzoic acid (Table 2; compound 4) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].CCOCC>C(#N)C>[Br:1][C:17]1[CH:16]=[CH:15][C:14]([OH:19])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:18]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)ccc1O
Reaction time: 4 h
Yield: 100 %

Procedure:
N-bromosuccinimide (580 g) was gradually added to a solution of 2-(tert-butyl)phenol (489 g) in acetonitrile (4000 ml) while cooling on ice. After stirring for 4 hours at below 20° C., ether (3000 ml) was added and the reaction mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (746 g) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH2:21][C:22]2[O:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[O:15])=[CH:4][CH:3]=1.[Br:33]N1C(=O)CCC1=O>>[Br:33][C:24]1[O:23][C:22]([CH2:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:15])=[N:26][C:25]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H]2Cc2nc(-c3ccccc3)co2)c(-c2ccc(F)cc2)s1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(C(=O)N2CCC[C@H]2Cc2nc(-c3ccccc3)c(Br)o2)c(-c2ccc(F)cc2)s1
Yield: 74.8 %

Procedure:
The title compound (0.066 g) was prepared by treating the compound of example 172 (0.075 g) with N-bromosuccinimide (0.030 g) according to the method of example 164.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]([C:23]([O:22][CH2:20][CH3:21])=[O:28])=[C:5]([CH3:4])[NH:27][C:25]=1[NH2:26])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 62 %

Procedure:
Boiling a solution of 13.4 g of (1-naphthylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 174°C (ethanol).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:17])C.O[Li].O>CCO.O>[F:17][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:15]([Cl:16])[C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1c(Cl)cc2ccccc2c1F
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 1.43 g (5.34 mmol) of N-(1-fluoro-3-chloro-2-naphthyl)carbamic acid ethyl ester, and 4.48 g (106.8 mmol) LiOH.H2O in 30 mL of EtOH and 70 mL of H2O is heated to reflux for 16 hours under an atmosphere of nitrogen. After cooling to room temperature, the mixture is concentrated in vacuo to give a residue that is extracted 3 times with 30 mL CH2Cl2. The combined organic layers are washed with 30 mL of saturated aqueous NaHCO3, 30 mL of saturated brine, dried over MgSO4 and the solvents evaporated to give 1-fluoro-3-chloro-2-aminonaphthalene as a brown solid.