Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:23][C:21](=[CH2:22])[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1)=[O:24]
Reactant: C=C(C)C(=O)Cl
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc2ccc(=O)oc2c1
Temperature: 15 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
40 g (247 mmol) of 7-hydroxy-coumarin (umbelliferone) were suspended in 700 ml of tetrahydrofuran and treated in succession with 38 ml (271 mmol) of triethylamine and 0.603 g (5 mmol) of 4-dimethylaminopyridine (DMAP). 28.4 g (271 mmol) of methacryloyl chloride were added dropwise to the suspension, cooled to about 15° C., in the course of 30 minutes. The reaction batch was stirred at room temperature for 4 hours and subsequently filtered over a thin silica gel layer. The silica gel layer was rinsed thoroughly with THF. After evaporation of the solvent the crude product was dissolved in about 300 ml of dichloromethane and treated with 1.5 l of ethanol. The dichloromethane was again removed on a rotary evaporator. The product crystallized from the remaining ethanolic solution overnight in a refrigerator. It was filtered off, dried and recrystallized once again from 1.1 l of ethanol according to the described procedure. Filtration and drying at 40° C. in a water-jet vacuum gave 42.9 g of 2-oxo-2H-1-benzopyran-7-yl 2-methyl-acrylate as white crystals. λmax. (in CH2Cl2)=312.6 nm (ε=9610 l/mol cm) and 282.3 nm (ε=11450 l/mol cm).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[CH:9]=[O:10].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:5]2[CH:6]=[CH:7][C:2]([I:1])=[C:3]([CH:9]=[O:10])[C:4]2=[O:8])=[CH:14][CH:13]=1
Reactant: O=Cc1c(I)cc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Reaction time: 24 h
Yield: 48.3 %

Procedure:
4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (12.0 g, 48.3 mmol), 4-fluorophenylboronic acid (20.1 g, 144.7 mmol), copper(II) acetate (17.55 g, 96.75 mmol), and myristic acid (44 g, 193 mmol) were combined in toluene (700 mL), treated 2,6-lutidine (45 mL, 385 mmol), and stirred vigorously for 1 day. Additional 4-fluorophenylboronic acid (5 g) was added and the reaction was stirred vigorously for an additional 3 days. The reaction mixture was concentrated and then suspended in 10% methanol/EtOAc. Diatomaceous earth was added and the mixture was stirred for 5 minutes. The mixture was filtered through a plug of diatomaceous earth. The filtrate was concentrated, and suspended in EtOAc and water. The mixture was again filtered through diatomaceous earth, rinsing forward with EtOAc. The filtrate was washed with 1N HCl, dried over Na2SO4, and concentrated under vacuum. The resulting solid was triturated with EtOAc to yield 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (8.0 g, 42% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH-].[Na+].Cl>CO>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)O
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution containing 5.7 (0.017 mole) of the title compound of Example 1, 35 ml of 1N aqueous sodium hydroxide solution (0.035 mole) and 3 ml methanol was refluxed overnight. The resulting solution was cooled to room temperature, acidified to pH 1.5 with 2N aqueous hydrochloric acid and extracted with 3×50 ml ethyl acetate. The combined ethyl acetate extracts were washed with 50 ml water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound as an oil (5.0 g, 96% yield) which was used in the subsequent reaction without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH3:13][C:14]([CH3:34])([CH3:33])[C@@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[NH2:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:16][C@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[C:14]([CH3:34])([CH3:33])[CH3:13])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](N)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid (14.6 g, 91 mmol) in CH2Cl2 (300 mL) was added 1,1-dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (28.1 g, 91 mmol), EDC (20.9 g, 109 mmol), HOBt (2.45 g, 18 mmol), and NMM (25.2 g, 249 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with sat. NaHCO3 (150 mL), 1N HCl (150 mL), sat. NaHCO3 (150 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by column chromatography (petroleum ether/ethyl acetate, 2:1). Concentration of the desired fractions afforded the title compound (40.5 g) as a yellow solid. LCMS (m/z): 455.3 (M+H).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[C:5]1([C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])[OH:6].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:6][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8]
Reactant: FC(F)Cl
Reactant: Oc1ccccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccccc1OC(F)F

Procedure:
275 g of chlorodifluoromethane are passed into a solution of 100 g of pyrocatechol, 220 g of sodium hydroxide and 60 g of sodium dithionite in 500 ml of water and 400 ml of dioxane at 50°-55° C. analogously to L. N. Sedova et al., Zh. Org. Khim. 6, 568 (1970). After distillation at 61°-62° C./1.0-1.1 kPa, a mixture of 1,2-bis(difluoromethoxy)benzene and 2-difluoromethoxyphenol is obtained, the products being separated by chromatography on silica gel by means of cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[Cl:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](=O)C)=[CH:21][CH:20]=1.[Na].[CH3:31]O>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:23]=[C:24]([CH3:25])[CH2:31][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:7])=[O:6])=[CH:28][CH:29]=1
Reactant: CO
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: [Na]
Product: CC(=Cc1ccc(Cl)cc1)CNCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
7.30 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in 150 ml of methanol, to the solution was added 6.30 g of p-chlorobenzalacetone, and the mixture was stirred at a room temperature for 36 hours. After addition of 1.32 g of sodium tetrahydrideborate with ice-water cooling, the mixture was stirred for 30 minutes. The reaction mixture was concentrated to half of original volume under a reduced pressure, and after adding 300 ml of ethyl acetate, washed three times with water. The aqueous layer was extracted with 100 ml of ethyl acetate, and the extract was washed with water as described above. The ethyl acetate layers were combined, washed twice with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure to remove the solvent. The resulting residue was purified using a silica gel column (silica gel: 200 g; eluant: 5% methanol in chloroform), to obtain 6.78 g of the title compound in a colorless amorphous form, while recovering the residual starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](O)(=O)C1C=CC=CC=1>>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH:9]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1
Product: c1ccc2[nH]cnc2c1

Procedure:
A known method consists in condensing 1,2-diaminobenzene with benzoic acid in the presence of polyphosphoric acid to give benzimidazole, and sulphonating this with, for example, chlorosulphonic acid (Am. Chem. Soc. 79, 427 (1957)).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CCOCC>[OH2:22].[ClH:39].[ClH:39].[NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(NC2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: Cl
Product: O=C1OCC(CCN2CCC(Nc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 9.2 %

Procedure:
A mixture of 0.3 g of 4-anilinopiperidine, 0. 8 g of the compound obtained in step C of EXAMPLE 4 and 0.69 g of potassium carbonate in 5 ml of acetonitrile is heated at 50-60° C. for 5 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed twice with water and with saturated NaCl solution and dried over Mgso4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HC1 in ether and the precipitate formed is wrung to give 0.12 g of the expected product. M.p.=158° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=O)(C)(C)C.CC([OH:24])C.[OH-:25].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[C:11]([OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Reactant: [OH-]
Reactant: CC(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O
Temperature: 4 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (4.91 g, (2S,3S):(2R,3S)=99.2:0.8) obtained in the same manner as in Reference Example 1 were added 2-propanol (24.6 ml) and water (2.0 ml). 4N Aqueous sodium hydroxide solution (6.1 ml) was then added, and the mixture was stirred at 4° C. for 3 hr. After the completion of the reaction, citric acid (0.525 g) dissolved in water (28.7 ml) was added. The reaction mixture was once heated to 27° C. and cooled to −10° C. over 5 hr. The mixture was stirred at −10° C. for 10 hr, and crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration. The wet crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=100:0. To the obtained wet crystals was added acetonitrile (3.0 ml) and then a solution of citric acid (3.15 g) in water (2.5 ml) was added. The mixture was stirred at 70° C. for 2 hr. The mixture was cooled to room temperature and adjusted to pH=7.0 with 8N potassium hydroxide solution. To this solution were added sodium hydrogencarbonate (3.44 g), TEMPO (0.0246 g) and potassium bromide (4.88 g) and 12% aqueous sodium hypochlorite solution (25.4 g) was added dropwise at room temperature over 1 hr. After the completion of the dropwise addition, the mixture was stirred for 3 hr and sodium hydrogensulfite (0.853 g) was added to the reaction mixture. To this solution was added 8N aqueous potassium hydroxide solution (8.2 ml) and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was cooled to room temperature and analyzed by HPLC, and as a result, it was confirmed that (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid (3.02 g, yield 94%) was obtained. The reaction mixture was then cooled to 0° C. and adjusted to pH=5.5 with 6N aqueous hydrochloric acid solution. The mixture was stirred at 0° C. for 1 hr and the resulting crystals were collected by filtration. The crystals were dried under reduced pressure to give (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid as crystals (2.41 g, yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:30][CH3:31])[CH2:9][C@@H:10]([C:26]([O:28][CH3:29])=[O:27])[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:30][CH3:31])[CH2:9][C@H:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@H](OC)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](CCN1CCNCC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-((3S,5R)-5-(4-fluorophenyl)-5-methoxy-3-(methoxycarbonyl)pentyl)piperazine-1-carboxylate in 200 μL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+](C1C=C(S(O[CH2:26][C@:27]2([CH3:30])[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C>ClCCl>[CH3:26][C@@:27]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][O:28]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(CON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of N-hydroxypthalimide (5.3 g, 32.5 mmol), [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (5.9 g, 21.6 mmol) and triethylamine (10.6 ml) in dichloromethane (15 ml) was stirred under nitrogen at ambient temperature for 24 h. The reaction mixture was poured onto a silica column and eluted with dichloromethane to give the sub-title compound as a colourless solid (3.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-])=O.[BH4-].[K+].[H][H]>CO.Cl[Cu]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1
Reactant: [H][H]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C

Procedure:
To a suspension of 6-nitro-2H-1,4-benzoxazin-3(4H)-one 1 (0.5 g, 0.0026 mol) and CuCl (0.77 g, 0.0078 mol) in anhydrous methanol (25 mL), stirred at 25° C. was added potassium borohydride (0.98 g, 0.018 mol) in portions (exothermic with evolution of hydrogen gas). The reaction mixture was stirred at 25° C. for 30 min. The black precipitate formed was filtered and washed with methanol. The combined filtrate and washings was evaporated to give 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one which was purified by silica gel column chromatography using ethyl acetate. Brown solid (0.29 g, 67%). 1H NMR (400 MHz, CDCl3): δ 4.34 (s, 2H); 4.81 (s, 2H); 6.09 (dd, J=2.8, 8.4 Hz, 1H); 6.14 (d, J=2.8 Hz, 1H); 6.59 (d, J=8.4 Hz, 1H); 10.44 (s, 1H).
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)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH:26][CH2:1][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)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: NCCc1ccccc1F
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2ccccc2F)ccc1Oc1ccc(C(N)=O)cn1
Yield: 84.5 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-fluorophenethylamine (0.0256 g, 0.184 mmol) gives the title compound (0.0615 g, 84.7%): TOF MS ES− 396.2 (M+H)+, HRMS calcd for C22H23N3O3F 396.1723 (M+H)+, found 396.1722, min 0.39; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.8 min, 98.9% purity.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]3[C:22]=2[O:21][C:20](=[O:23])[CH:19]=[C:18]3[NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=2[Cl:32])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1cncn1

Procedure:
The title compound was prepared from 1,2,4-triazole and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 98. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 8.50 (s, 1H), 7.94 (d, 1H), 7.93 (s, 1H), 7.19 (d, 1H), 4.64 (s, 1H), 4.19 (t, 2H), 3.96 (t, 2H), 3.90 (s, 3H), 1.84 (m, 2H), 1.69 (m, 2H), 1.43 (m, 2H); MS (ESI): 489.9.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:19]1([C:18]2[O:25][C:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][CH:10]=3)=[N:14][N:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4ccccc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 3.17 g of benzoyl chloride was added. Temperature was elevated to 100° C., and stirring was conducted for 2 hours under flux. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 6.11 g (yield 91%) of PhpyOXDPh. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.23-8.26 ppm (3H), 8.14-8.17 ppm (2H), 7.90-7.99 ppm (2H), 7.48-7.58 ppm (6H).
Reaction SMILES: Cl.[CH:2]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:3]2[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:2]2[C:11]([OH:13])=[O:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1NCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
1,3-Dihydro-2H-isoindole-1-carboxylic acid, hydrochloride (0.31 g, 1.9 mmol), p-toluenesulfonyl chloride (0.4 g, 2.09 mmol), and Na2CO3 (0.403 g, 3,8 mmol) were dissolved in water (4 mL). The reaction mixture was stirred at rt for 20 hr. The residue was dissolved in water and washed with EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with CH2Cl2 (2X). The organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by HPLC to give N-[4-methylbenzenesulfonyl]-1,3-dihydro-2H-isoindole-1-carboxylic acid (0.047 g). MS m/e 318.1 (M+)
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:14]2[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[C:8](=O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN.[OH-].[K+]>C(O)COCCO.O>[C:1]([C:5]1[CH:16]=[CH:15][C:14]2[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(s1)C(=O)c1cc(C(C)(C)C)ccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc2c(s1)Cc1cc(C(C)(C)C)ccc1-2
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2.40 g (0.0095 mol) of 6-(tert-butyl)-2-methyl-8H-indeno[2,1-b]thiophen-8-one and 2.6 mL (0.05 mol) of hydrazine monohydrate in 25 mL of diethylene glycol was stirred at 80° C. in 40 min and then refluxed for 1 h. The resulting mixture was cooled to r.t., treated with a solution of 2.68 g (0.035 mol) of KOH in 9.4 mL of water and subsequently refluxed for 2 h. The resulting mixture was poured in 150 mL of water, the precipitate was filtered, washed 5 times with 100 mL of water and dried. Yield 1.25 g (54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[N:17](S(C)(=O)=O)[C:16]([C:29]1([CH3:32])[CH2:31][O:30]1)=[CH:15]2>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[C:21]([F:22])([F:24])[F:23])[NH:17][C:16]([C:29]([OH:30])([CH3:31])[CH2:32][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15]2
Reactant: CC1(c2cc3cc(Cl)c(C(F)(F)F)cc3n2S(C)(=O)=O)CO1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(CSc1ccc(F)cc1)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluoro-phenyl thiol (55 mg, 0.425 mmoL) was treated with NaH (60%, 17 mg, 0.425 mmoL) in THF (2 mL) at 0° C. After 10 min., 5-chloro-1-methanesulfonyl-2-(2-methyl-oxiranyl)-6-trifluoromethyl-1H-indole, the epoxide derivative compound prepared as in Example 72 (100 mg, 0.425 mmoL) in THF (1 mL) was added into the reaction via syringe. The reaction was slowly warmed to room temperature. THF was removed and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, then concentrated to yield a crude white solid. The crude material was purified using column chromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield the title compound as a white solid.