Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[C:11](Cl)(=O)[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:11]([CH3:12])[NH:7][CH2:6][CH2:5]2
Reactant: NCCc1cccc(F)c1
Reactant: CC(=O)Cl
Product: CC1NCCc2cc(F)ccc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 3-fluorophenethylamine and acetyl chloride, 6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 55%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][C:2]([S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([Cl:16])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Sc1ccncc1)C(=O)O
Product: CC(C)(Sc1ccncc1)C(=O)Cl

Procedure:
9.7 g of the product from step (b) was refluxed for 2 1/2 hours in 225 ml thionyl chloride. The mixture was concentrated in vacuo. The residue was triturated and concentrated in vacuo two times with toluene to yield a white solid which showed the expected carbonyl shift in the IR, indicative of an acid chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>>[O:10]=[C:9]1[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:11])[N:1]1[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)CN1C(=O)c2ccccc2C1=O

Procedure:
(G1) irradiating a reaction product of glycine (a) and phthalic anhydride (b) with microwaves to produce 2-(1,3-dioxoisoindolin-2-yl)acetic acid (compound 1);
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1.[Si:14]([O:31][CH2:32][CH2:33][CH:34]=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1.O>[Si:14]([O:31][CH2:32][CH2:33][CH:34]([OH:35])[CH2:6][C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1)([C:27]([CH3:29])([CH3:30])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Reactant: CC1=NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)COC(CC(O)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)=N1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
5.2 ml of a solution of 1.6M n-butyllithium in hexane was added dropwise to a solution of 940 mg of 2,4,4-trimethyl-2-oxazoline in 20 ml of tetrahydrofuran with stirring, at -78° C. The resulting mixture was stirred at -78° C. for 1 hour. After this time, 2.00 g of 3-tert-butyldiphenylsilyloxy-1-propanal [prepared as described in Can. J. Chem., 71, 695 (1993)] in 10 ml of tetrahydrofuran was added to the reaction mixture whilst stirring, maintaining the temperature at -78° C. Stirring was continued at -78° C. for 15 minutes, then the reaction mixture was brought to room temperature and stirred for 30 minutes. At the end of this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate fraction was washed with water, dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a mixture of 50% v/v ethyl acetate and hexane as the eluent, to afford 2.18 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[CH3:33])[CH:3]=1.[Cl-].C[Zn+].[CH3:37]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[F:32][C:30]1[CH:29]=[CH:28][C:27]([CH3:33])=[C:26]([C:4]2[CH:3]=[C:2]([CH3:37])[N:7]=[CH:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=2)[CH:31]=1
Reactant: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CN1CCN(C)C1=O
Agent: C[Zn+]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(F)ccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-(6-chloro-4-(5-fluoro-2-methylphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.055 g, 110 μmol, example 253) in THF (1.5 mL) were added methylzinc(II) chloride (82.4 μL, 165 μmol), 1,3-dimethyl-2-imidazolidinone (DMI) (0.3 mL) and PEPPSI-IPr (1.49 mg, 2.2 μmol, CAS RN 905459-27-0) and the clear solution was stirred at 50° C. for 2 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 100:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 98:2). Colorless foam (0.022 g; 41%). MS (ESI): m/z=481.12 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(OCC)(=O)C.O>[OH-].[Na+]>[CH3:14][S:15]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)On1nnc2ccc([N+](=O)[O-])cc21
Yield: 70.7 %

Procedure:
1-Hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g) is dissolved in 1 N aqueous sodium hydroxide (40 ml). To the solution is added dropwise methanesulfonyl chloride (5.6 g) with stirring under ice-cooling and thereto are added ethyl acetate (100 ml) and water (100 ml). The mixture is stirred at room temperature for 1 hour. To the reaction mixture is added ethyl acetate (50 ml) and the insoluble materials are filtered off. The ethyl acetate layer is dried over magnesium sulfate-charcoal. After drying, the layer is concentrated so as to be about 30 ml and thereto is added n-hexane (about 30 ml) and the mixture is allowed to stand. The precipitated crystals are separated by filtration and dried to give 1-methanesulfonyloxy-6-nitro-1,2,3-benzotriazole (7.3 g; 72%), melting point: 115°-116° c. The product is dissolved in ethyl acetate and treated with charcoal and thereto is added n-hexane to give faint yellow flakes melting point: 117°-118° C.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)O
Product: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 47 %

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-trifluoromethylphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield=47% (purification by flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 79° C. IR (nujol): 3280, 1740, 1690, 1640, 1620 cm-1 1H NMR (CDCl3 /TMS): 7.70 (s, 1H); 7.55 (AB, 2H, J=8 Hz); 7.45 to 7.20 (m, 7H); 6.95 (t, 1H, J=6 Hz); 5.15 (s, 2H); 3.90 (s, 2H); 3.40 (q app., 2H, J app.=6 Hz.); 2.65 (t, 2H, J=5 Hz); 2.30 (s, 3H). Microanalysis: C23H22O4NSF3Calc. % C=59.35 H=4.76 N=3.01 Found. % C=59.17 H=4.73 N=2.87
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:30]2[CH2:34][CH:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][O:16][CH:17]2[CH2:22][O:21][C:20]3=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:19]3[CH2:18]2)[CH2:10][CH2:9]1.[N+](C1N=C2N(C=1)CC(OCC(O)=O)CO2)([O-])=O.FC1C=C(N2CC(CNC(=O)C)OC2=O)C=CC=1N1CCNCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:30]2[CH2:34][C@H:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][O:16][C@@H:17]2[CH2:22][O:21][C:20]3=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:19]3[CH2:18]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCN(C(=O)COC4COc5nc([N+](=O)[O-])cn5C4)CC3)c(F)c2)C(=O)O1
Agent: CC(=O)NCC1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO[C@@H]4COc5nc([N+](=O)[O-])cn5C4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
N-[3-(3-Fluoro-4-{4-[2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperazin-1-yl}-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. A mixture of (2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetic acid (53 mg, 0.22 mmol), N-[3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (73 mg, 0.228 mmol) (prepared as described by Barbachyn et al, U.S. Pat. No. 5,547,950) and TBTU (114 mg, 0.35 mmol) is dissolved in DMF (5 ml) and treated with Et3N (0.122 ml, 0.88 mmol) and stirred at room temperature for 12 hours. The mixture was diluted with EtOAc and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC to give 13 mg (10%) of the titled product as a tan solid. ESI MS m/z 562 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=11.6 Hz, 1H), 7.44 (s, 1H), 7.21-7.02 (m, 1H), 7.00-6.85 (m, 1H), 5.99-5.92 (m, 1H), 4.76-4.67 (m, 2H), 4.44-4.22 (m, 4H), 4.05-4.01 (m, 1H), 3.79-3.44 (m, 4H), 3.49 (s, 2H), 3.10-2.62 (m, 4H), 2.02 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]2([OH:84])[CH2:83][CH2:82][CH2:81][CH2:80]2)=[C:73]([CH3:85])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]4([OH:84])[CH2:80][CH2:81][CH2:82][CH2:83]4)=[C:73]([CH3:85])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 30 mg, 0.129 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.4 mg, 0.018 mmol), potassium phosphate (55 mg, 0.258 mmol) and water (0.2 mL) were added to a solution of 1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol (Example 34-(2); 42.2 mg, 0.086 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (27.2 mg, 62%).
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12]C)=[O:11])=[CH:4][C:3]1=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([OH:12])=[O:11])=[CH:4][C:3]1=[CH2:19]
Reactant: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C1C=C(Oc2cc(C(=O)O)ccc2OC)C1(F)F

Procedure:
A solution of methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate (1.39 g) in methanol (22 mL) is treated with a solution of potassium carbonate (0.83 g) in water (8 mL) and the solution is heated at 60°-70° C. for 8 hours, cooled and evaporated. The residue is dissolved in water (30 mL), extracted with diethyl ether (50 mL) and acidified to pH 4 by treatment with glacial acetic acid. The precipitated solid is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and concentrated, to give 3-(4,4-difluoro-3-methylene-cyclobut-1-enyloxy)-4-methoxybenzoic acid, in the form of a white solid, m.p. 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1.[N:22]([O-:24])=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:22]([O-:24])=[O:23])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1
Reactant: O=N[O-]
Reactant: O=C(Nc1cncc2[nH]c3ccc(Cl)cc3c12)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
N-(6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (125 mg, 0.4 mmol, 1 equiv.) was dissolved in 2 ml TFA and NaNO2 (541 mg, 7.84 mmol, 2 equiv.) was added in one portion. The solution was stirred at room temperature for 4 hr. Volatiles were removed by rotovap, and the resulting oily orange solids were suspended in water, neutralized with a saturated aqueous sodium bicarbonate solution and filtered to give 132 mg (92%) of N-(6-chloro-8-nitro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cc(O)c(O)c(Br)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a vigorously stirred suspension of 3-bromo4-hydroxy-5-methoxy-benzaldehyde (15.20 g, 65.8 mmol), AlCl3 (9.65 g, 72.4 mmol) in CH2Cl2 (100 mL) at 0° C. with exclusion of moisture was added pyridine (22.90 g, 290 mmol, 23.4 mL) to keep the temperature below 32° C. The resulting clear dark solution was heated to reflux for 24 hours and cooled to RT. The mixture was poured into a slurry of 1 N HCl and ice. The CH2Cl2 layer was removed and the aqueous suspension was extracted with ether till clear. The combined ether layers were dried over anhydrous magnesium sulfate, filtered and evaporated to a volume of approximately 200 mL and cooled to 0° C. for 2 hours. The resulting suspension was collected by filtration and dried under high vacuum to give 10.12 g of 3-bromo-4,5-dihydroxybenzaldehyde (71%) as a tan solid. 1H NMR (500 MHz; CDCl3): δ 7.18 (s, 1H); 7.37 (d, J=2.0 Hz, 1H); 8.48 (brs, 1H); 9.40 (brs, 1H); 9.56 (s, 1H).
Reaction SMILES: [N:1]([CH:4]([CH2:7][N:8]=[N+:9]=[N-:10])[CH2:5][OH:6])=[N+:2]=[N-:3].[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)(Cl)Cl>[N:1]([CH:4]([CH2:7][N:8]=[N+:9]=[N-:10])[CH2:5][O:6][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:7][N:8]=[N+:9]=[N-:10])=[O:17])=[N+:2]=[N-:3]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: [N-]=[N+]=NCC(CO)N=[N+]=[N-]
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NCC(COC(=O)CCCCC(=O)OCC(CN=[N+]=[N-])N=[N+]=[N-])N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
8.52 g (0.06 Mole) 2,3-diazidopropanol in 20-ml dry CCl4 is added dropwise to 5.49 g (0.03 Moles) adipyl chloride in 30-ml dry CCl4 while the temperature is held below 20° C. At the end of the addition, the cooling bath is removed and the temperature is allowed to rise to 25° C. The reaction mixture is allowed to stir at ambient temperature for 18 hours under a slow flow of nitrogen to purge HCl produced in the reaction. At the end of this period the reaction mixture is washed with H2O, dilute bicarbonate solution, and a final H2O wash. The resultant colorless solution is stripped of solvent to yield 9.8 g (83%) colorless oil nD25 1.5050, d425 1.258; infrared spectrum is consistent with the expected structure. Elemental analysis for nitrogen gives 42.01%, theoretical is 42.62%.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1)(=[O:23])=[O:22]
Reactant: Cc1nc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(OS(C)(=O)=O)nc(C(Cl)(Cl)Cl)n1
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-4-methyl-6-trichloromethyl-[1,3,5]triazine (1.14 g, 5.0 mmol; J. Amer. Chem. Soc. 1956, 178, 2447) and triethylamine (0.51 g, 5.5 mmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0° C. and stirred for 1 h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (CI) 291, 293 (MH+).
Reaction SMILES: [OH:1][C:2]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([F:12])[CH:10]=2)[N:5]([C:14]([NH2:16])=[O:15])[C:4]1=[O:17].[CH3:23][N:24]([CH3:35])[C:25](=[O:34])[CH2:26][O:27][C:28]([O:30][CH:31](I)[CH3:32])=[O:29]>CC(C)=O>[C:14]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:12])=[C:8]([Cl:13])[CH:7]=2)[C:3](=[C:2]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[O:1][CH:31]([O:30][C:28]([O:27][CH2:26][C:25]([N:24]([CH3:23])[CH3:35])=[O:34])=[O:29])[CH3:32])[C:4]1=[O:17])(=[O:15])[NH2:16]
Reactant: NC(=O)N1C(=O)C(=C(O)c2cccs2)c2cc(F)c(Cl)cc21
Reactant: CC(I)OC(=O)OCC(=O)N(C)C
Solvent: CC(C)=O
Product: CC(OC(=O)OCC(=O)N(C)C)OC(=C1C(=O)N(C(N)=O)c2cc(Cl)c(F)cc21)c1cccs1
Reaction time: 90 h
Yield: 8.7 %

Procedure:
The tetrabutylammonium salt of 3-[hydroxy-(2-thienyl)methylene]-6-chloro-5-fluoro-2,3-dihydro-2-oxo-1H-indole-1-carboxamide (6.25 g) and N, N-dimethyl-(1-iodoethoxy)carbonyloxyacetamide (5.55 g) were combined in 60 mL of acetone, and the solution stirred for 90 hr. at 20° C. The precipitate present was removed by filtration and dried in vacuo. The solids were chromatographed on silica gel, eluting with 90:10 chloroform:acetone. Fractions containing the title product were combined and evaporated. The residue was slurried with a small amount of ethyl ether and filtered to give 820 mg of yellow solid, mp 194.5°-195.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N=CC1C=CC=CC=1O)C1C=CC=CC=1>>[CH2:12]([N:19]=[CH:4][C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccccc1C=NCc1ccccc1
Product: COc1ccc(O)c(C=NCc2ccccc2)c1

Procedure:
This compound was prepared from 2.7 g of 2-hydroxy-5-methoxy-benzaldehyde, 2.3 mL of benzylamine and 0.03 g of p-toluenesulphonic acid using the procedure described for 64a. Yield: 4.3 g (oil).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[C:11]([C:12]([OH:14])=O)=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH:9]=[C:8]([CH3:23])[N:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:21]([C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([CH3:23])[N:7]=[C:6]([CH3:5])[C:11]=2[C:12](=[O:14])[NH:32][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(-c2cccc(C#N)c2)c(C(=O)O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C#N)c2)c(C(=O)NCCN2CCOCC2)c(C)n1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of thionyl chloride (0.29 g) in methylene chloride (5 ml) was added N,N-dimethylformamide (0.18 g) at 10° C. and the mixture was stirred at the same temperature for 1 hour. Thereto was added 2,6-dimethyl-4-(3-cyanophenyl)-3-pyridinecarboxylic acid (0.505 g) at 10° C. and the mixture was stirred at ambient temperature for 1 hour. To the resulting mixture was added dropwise a solution of 2-morpholinoethylamine (0.62 g) in methylene chloride (2 ml) at 10° C. The mixture was stirred at the same temperature for 1.5 hours, diluted with methylene chloride (10 ml) and a saturated aqueous solution of sodium bicarbonate (10 ml). The separated organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and methanol (25:1 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was tritulated with diethyl ether to give 4-(3-cyanophenyl)-2,6-dimethyl-3-(2-morpholinoethylcarbamoyl)pyridine (0.33 g).
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(O)C(C(O)=O)=CC1=2.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[C:25]([Br:32])=[C:24]([OH:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2.[CH3:38][O:39][CH2:40]Cl>>[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[C:25]([Br:32])=[C:24]([O:33][CH2:38][O:39][CH3:40])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Reactant: COCCl
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J). Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L and Compound M serve as reagents in accordance with Formula 6. The hydroxy group of Compound M is protected for further transformations with methoxymethyl chloride (MOMCl) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-carboxylic acid (Compound N).