Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:23][CH3:24])=[N:6][C:7]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:9]=1[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:2]=C.S(=O)(O)[O-:26].[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.CO.O.[Os](=O)(=O)(=O)=O>[Si:12]([O:11][CH2:10][C:9]1[CH:8]=[C:7]([C:19]([F:21])([F:22])[F:20])[N:6]=[C:5]([O:23][CH3:24])[C:4]=1[CH2:1][CH:2]=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=S([O-])O
Reactant: C=CCc1c(CO[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)nc1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of 3-allyl-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.62 g, 7.25 mmol), N-methylmorphine N-oxide (849 mg, 7.25 mmol), osmium tetroxide (4 wt. % in water, 10 mL, 400 mg) in acetone/water (4:1) (100 mL) was stirred at room temperature overnight. The reaction was quenched by sodium bisulfite (3.50 g, 36 mmol). After acetone was evaporated, the mixture was diluted with water, and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was stirred with sodium periodate (1.86 g, 8.7 mmol) in MeOH/water (1:1) (60 mL) for 30 min. The reaction was filtered and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted by ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) to yield [4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]acetaldehyde (1.61 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 9.68 (t, J=1.5 Hz, 1H), 7.46 (s, 1H), 4.67 (s, 2H), 4.01 (s, 3H), 3.76 (d, J=5 Hz, 2H), 0.96 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[N:17]=[C:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])[NH:19][CH:20]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH3:8].[N:16]1[N:17]=[C:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([N:12]2[CH2:13][CH:14]3[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]3[CH2:11]2)=[O:24])[NH:19][CH:20]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Product: N
Temperature: 25 °C
Reaction time: 14 h
Yield: 8 %
Yield: 150 %

Procedure:
To a solution of Intermediate 15 (1.0 g, 4.73 mmol) in DCM (24 mL) was added 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid (895 mg, 4.73 mmol) followed by EDCl (1.36 g, 7.09 mmol), HOBt (959 mg, 7.09 mmol) and TEA (1.97 mL, 14.19 mmol). The mixture was stirred for 14 h at room temperature and then washed 2× with saturated aqueous NH4Cl solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (DCM to 8% 2M NH3 in MeOH/DCM) afforded the desired product as a pale yellow foam (1.36 g, 75%). MS (ESI): mass calculated for C20H25N5O3, 383.45, m/z found 384.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 12.62 (s, 1H), 8.19-8.03 (m, 2H), 7.56-7.44 (m, 2H), 7.39-7.32 (m, 1H), 3.96-2.72 (m, 10H), 1.53-1.35 (m, 9H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:10]([NH:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=2[CH:39]([CH3:41])[CH3:40])=[O:28])[C:9]1=[O:42].[F-].[K+].O>CN(C=O)C>[CH2:7]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:10]([NH:26][C:27]([NH:29][C:30]2[C:31]([CH:39]([CH3:40])[CH3:41])=[CH:32][CH:33]=[CH:34][C:35]=2[CH:36]([CH3:38])[CH3:37])=[O:28])[C:9]1=[O:42])[CH2:6][CH2:5][C:4]#[CH:3]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC#C[Si](C)(C)C)c3ncccc23)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 105.3 %

Procedure:
To a solution of N-[1-(5-trimethylsilyl-4-pentynyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (81 mg, 0.133 mmol) in DMF (4 ml) was added potassium fluoride (138 mg, 2.38 mmol), and the mixture was stirred at room temperature for 7 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (58 mg, 0.14 mmol).
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C(OCC)(=O)C.[Zn]>[OH:20][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CBr
Reactant: CCCCCCCC=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCCCCCCC(O)CC(=O)OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 7.1 g of zinc powder (108 mmol) in 42 ml of ethyl acetate. After 1.7 ml of trimethylchlorosilane (13.4 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 15.3 g of undiluted methyl bromoacetate (100 mmol) were subsequently added dropwise within 7 min, and the temperature was maintained at 65° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 0° C., 10.7 g of undiluted octanal (83 mmol) were added, and the temperature was maintained at 5° C. by external cooling. After stirring had been continued at 50C for 30 min, 25° C. for 2 h and 40° C. for 20 min, the mixture was cooled to 0° C., acidified with 30 ml of 10% hydrochloric acid to a pH of 1 and the mixture was stirred for 10 min. Excess zinc was then filtered off and the organic phase removed. The organic phase was then stirred with 10 ml of concentrated ammonia solution at 0° C. for 10 min. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure. Methyl 3-hydroxydecanoate was obtained in a yield of 14.2 g (84% of theory) and had a boiling point of 59° C. (0.04 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9]2)=[C:4]([O:17]C)[CH:3]=1.B(Br)(Br)Br.CO.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9]2)=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Cl)ccc1B1OCc2ccccc21
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)ccc1B1OCc2ccccc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 1,3-dihydro-1-(4-chloro-2-methoxyphenyl)-2,1-benzoxaborole as a white solid (AN-2551, 0.5 g, 1.93 mmol) in anhydrous methylene chloride (25 mL) at −78° C. Was added dropwise a solution of boron tribromide in methylene chloride (1.0 M, 1.93 mL, 1.93 mmol) under nitrogen. The mixture was stirred at −78° C. for 1 h and at room temperature for 4 h. Then the reaction flask was re-cooled to −78° C. and methanol (10 mL) was added. The reaction mixture was warmed to room temperature and 6N HCl (2 mL) was added. The mixture was evaporated to give a residue that was mixed with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue was purified by flash column chromatography eluted with a mixed solvent of hexanes and ethyl acetate (4:1, v/v) to provide the desired compound 1,3-dihydro-1-(4-chloro-2-hydroxyphenyl)-2,1-benzoxaborole as a white solid (0.32 g, 1.31 mmol) in 67.8% yield. M.p. 96-98° C.; 1H NMR (MeOH-d4, 300 MHz): δ 8.19 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.52-7.51 (m, 2H), 7.43-7.38 (m, 1H), 6.96-6.91 (m, 1H), 6.89-6.88 (m, 1H) and 5.41 (s, 2H) ppm.
Reaction SMILES: [I-].C[N+]1C=C[N:5]([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)[CH:4]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:36](CNC)[CH:37]=1.[CH3:48]CN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[F:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:36]([CH:37]=1)[CH2:4][N:5]([CH3:48])[C:8](/[N:9]=[C:10]1\[S:11][C:12]([CH3:29])=[CH:13][N:14]\1[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=2[CH:16]=1)=[O:30]
Reactant: CNCc1cc(F)ccc1Oc1ccccc1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N(C)Cc2cc(F)ccc2Oc2ccccc2)s1
Temperature: 60 °C

Procedure:
To a solution of Example 81A (0.1 g, 0.18 mmol) and 1-(5-fluoro-2-phenoxyphenyl)-N-methylmethanamine (0.20 mmol) in anhydrous acetonitrile (3 mL) was added Hunig's base (0.025 g), and the solution was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with 50 mL of CH2Cl2 and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was choromatographed over silica using CH2Cl2 to give the titled compound. 1H NMR (CD3OD) δ ppm 2.25 (3H), 2.90 (3H), 4.60 (2H), 6.90-7.60 (12H); MS (ESI) 578 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[Li:9]CCCC>C1(C)C=CC=CC=1>[CH:1]([C:4]1[N-:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[Li+:9]
Reactant: [Li]CCCC
Reactant: CC(C)c1ncc[nH]1
Solvent: Cc1ccccc1
Product: CC(C)c1ncc[n-]1
Product: [Li+]

Procedure:
A slurry of 2-isopropylimidazole (4.00 g, 36.3 mmol) in toluene (40 mL) at −78° C. was treated with 17.4 mL of a 2.8 M n-BuLi (48.7 mmol) solution in hexanes. This solution mixture was then refluxed for one day during which time the slurry became orange. The slurry was then filtered over a medium glass frit and dried to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1csc(C)n1
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1csc(C)n1
Yield: 89.2 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline (150 mg, 0.46 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (78 mg, 0.56 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml) and a 5M solution of hydrogen chloride in isopropanol (105 μl) was heated at reflux for 90 minutes. The solid obtained was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline hydrochloride as a pale yellow solid (190 mg, 82%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCNC4)c23)cc1
Reactant: N#CCCCBr
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCN(CCCC#N)C4)c23)cc1
Temperature: 25 °C

Procedure:
Add 147.5 mg (0.996 mmol) of 4-bromobutyronitrile at RT to a mixture of 200 mg (0.498 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo[2,3-d]pyrimidine, 0.25 ml (1.5 mmol) of diisopropylethylamine and 8.3 mg of potassium iodide in 2 ml of THF. The mixture is stirred under reflux for 10 h. After adding a further 0.25 ml (1.5 mmol) of diisopropylethylamine and 147.5 mg (0.996 mmol) of 4-bromobutyronitrile, continue to stir under reflux overnight. After cooling to RT, dilute with dichloromethane, wash with satd. sodium hydrogencarbonate solution, remove the organic phase, dry over sodium sulphate and concentrate under reduced pressure. After purifying the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient) 189 mg of the target product are obtained (81.1% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH2:25]([C:27]1[CH:35]=[CH:34][C:33](OC)=[CH:32][C:28]=1[C:29](Cl)=[O:30])[CH3:26].[O:38]=[C:39]1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH2:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30])[CH3:26]
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: CCc1ccc(OC)cc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: CCc1cccc(OC)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 90 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.16 mmol) obtained in Example 1, (3), and 2-ethyl-5-methoxybenzoyl chloride (0.24 mmol), the title compound (69 mg, yield 90%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].O=S(Cl)[Cl:10].[CH3:12]O>>[ClH:10].[NH2:4][CH2:3][CH:2]([CH3:1])[C:5]([O:7][CH3:12])=[O:6]
Reactant: CC(CN)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C(C)CN
Product: Cl

Procedure:
To the solution of DL-3-aminoisobutyric acid (CAS number: 144-90-1, Aldrich) (2.7 g, 26.4 mmol) in MeOH (50 mL) was added SOCl2 (6.17 g, 52.8 mmol) dropwise at 0° C. under N2 atmosphere. The reaction was refluxed for 18 hours. The solvent was removed in vacuo to give crude Compound W which was used directly in the next step.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:16](\[CH2:22][CH2:23][OH:24])/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[OH-].[Na+]>C(O)C.O>[NH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12](/[C:15](=[C:16]2/[C:17](=[O:19])[O:24][CH2:23][CH2:22]/2)/[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
Ethyl (E)-3-(4-t-butylaminosulphonylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)-2-propenoate (10 g), prepared in Example 59, is dissolved in 20 ml of ethanol, and a solution of 2 g of sodium hydroxide in 10 ml of water is added. The mixture is refluxed for 2 h. After evaporation to dryness, the residue is taken up with water, acidified with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated under vacuum. The residue is added in portions to 500 ml of concentrated sulphuric acid. The mixture is stirred for 15 minutes at room temperature and then poured into iced water and the crystals formed are filtered off, washed with diethyl ether and then taken up with 100 ml of warm acetone. 50 ml of diethyl ether are added to the solution obtained and the crystals formed are filtered off and dried to give 6 g of (E)-3-[1-(4-aminosulphonylphenyl)-1-(4-fluorophenyl)methylidene]dihydrofuran-2-one in the form of crystals melting at 202° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([O:13]C)=[O:12])[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)c1cncc(-n2cnnn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(-n2cnnn2)c1
Reaction time: 1 h

Procedure:
The methyl 5-(1H-tetrazol-1-yl)nicotinate obtained in step A was dissolved in THF (50 mL) and treated with 1N lithium hydroxide (50 mL) and stirred for 1 hour. The mixture was diluted with water and the resulting solid isolated by filtration and drying under high vacuum to provide 5-(1H-tetrazol-1-yl)nicotinic acid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([N:11]=[C:12]=[O:13])=[CH:3][C:2]=1[C:14]([F:17])([F:16])[F:15].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1.Cl>O1CCCC1.C(N(CC)CC)C>[F:17][C:14]([F:15])([F:16])[C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:23]2[C:22]3[C:26](=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=3)[NH:25][C:24]=2[OH:28])=[O:13])[CH:5]=[C:6]([C:7]([F:10])([F:8])[F:9])[CH:1]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Under argon atmosphere, 3,5-bis(trifluoromethyl)isocyanate (255 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of 6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (172.2 mg, 40.7%) as a pink solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]O)[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C.CS([Cl:43])(=O)=O.O>C(Cl)Cl>[Cl:43][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:20]=[CH:19][N:18]=1
Reactant: COCc1cc(-c2nc(-c3ccnc(CO)c3)no2)ccc1-c1ccccc1C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccnc(CCl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanol (0.282 g; 0.73 mmol) and DIEA (0.25 mL; 1.46 mmol) in DCM (6 mL) was added methanesulfonyl chloride (0.062 mL; 0.80 mmol). The mixture was stirred at ambient temperature for 1 hour and water added. The mixture was passed through a hydrophobic frit and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.78 (1 H, d, J=5.1 Hz), 8.44 (1 H, d, J=1.8 Hz), 8.26 (1 H, s), 8.18 (1 H, dd, J=7.9, 1.9 Hz), 8.02 (1 H, dd, J=5.1, 1.5 Hz), 7.37-7.22 (4 H, m), 7.13 (1 H, d, J=7.5 Hz), 4.79 (2 H, s), 4.28-4.18 (2 H, m), 3.34 (3 H, s), 2.08 (3 H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][N+:3]=1[O-:13].CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CC(O)(C)C>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][N+:3]=1[O-:13])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(NCCNC(=O)OC(C)(C)C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32.2 %

Procedure:
To 2-chloro-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide (2.5 g) in t-BuOH (50 mL) was added DIEA (3.4 mL) and tert-butyl 2-aminoethylcarbamate (3.0 g). The resulting reaction mixture was stirred at 80° C. for 2 days. The solvent was then removed and the residue purified by reverse phase chromatography to afford the desired product (1.3 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]4[O:20][CH2:19][O:18][C:13]=4[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.[Cl:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1>>[ClH:22].[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]4[O:20][CH2:19][O:18][C:13]=4[CH:14]=3)[C:9]2=[O:21])[CH2:2]1
Reactant: COc1cccc(OCCCCl)c1
Reactant: O=C1c2cc3c(cc2CCN1CC1CCCNC1)OCO3
Product: COc1cccc(OCCCN2CCCC(CN3CCc4cc5c(cc4C3=O)OCO5)C2)c1
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3-methoxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl.O>[C:28]([O:12][C:7]1[C:6]([O:13][CH3:14])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[O:10][CH3:11])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(C)=O)cc(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
3.0 g (15.3 mmol) of 3,5-dimethoxy-4-hydroxyacetophenone is dissolved in dichloromethane (30 ml) and 2.53 g (18.3 mmol) of K2CO3 is added. Triethylamine (2.6 ml) is then added dropwise. The reaction medium is cooled down to 0° C. and acetyl chloride (1.31 ml; 18.3 mmol) is added. The mixture is stirred for 24 hours at ambient temperature then poured into ice-cooled water. After extraction with dichloromethane, the organic phase is washed with sodium chloride in a saturated aqueous solution before being dried over magnesium sulphate, filtered and concentrated under vacuum. The product obtained is purified by crystallization from ether in order to produce a white solid with a yield of 99%. Melting point: 145° C.