Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][C@H:5]2[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1ccccc1O[C@H]1CCCNC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3O[C@H]3CCCNC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (S)-3-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.59-7.48 (m, 2H), 7.44 (d, J=8.1, 1H), 7.40-7.35 (m, 2H), 7.24 (d, J=8.3, 1H), 7.11-7.07 (m, 1H), 6.87 (s, 2H), 4.73-4.53 (m, 1H), 3.38-3.30 (m, 1H), 3.12-2.86 (m, 3H), 2.04-1.94 (m, 1H), 1.80-1.71 (m, 2H), 1.65-1.54 (m, 1H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:25])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>O1CCCC1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:25])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Br[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCCC1
Temperature: -25 °C

Procedure:
A solution of cyclohexyl magnesium bromide in ether (2.0 M, 3.10 mL, 6.25 mmol) (Aldrich) was added dropwise to a suspension of 6-chloroisatin (0.45 g, 2.5 mmol) (Crescent) in tetrahydrofuran (12.5 mL) with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 2 hours, 15% aqueous ammonium chloride solution (12.5 mL) was added and mixture was extracted with ethyl acetate. Ethyl acetate layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 30 minutes and filtered to give crude rac-6-chloro-3-cyclohexyl-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. (Yield 0.28 g, 43%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[C:17]4[CH3:23])=[CH:12][N:13]=2)=CC=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11]3[O:10][C:9]([NH2:8])=[N:13][CH:12]=3)[CH:15]=2)[NH:19][N:18]=1
Reactant: COc1ccc(CNc2ncc(-c3ccc4[nH]nc(C)c4c3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1n[nH]c2ccc(-c3cnc(N)o3)cc12
Temperature: 150 °C

Procedure:
A glass microwave reaction vessel was charged with N-(4-methoxybenzyl)-5-(3-methyl-1H-indazol-5-yl)oxazol-2-amine (196 mg, 587 μmol) and TFA (2.00 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 6 minutes. Toluene was added and the solvents were removed in vacuo to give the desired product. The residual material was treated with 2.0 M NH3 in MeOH and 1 N NaOH and the resulting precipitate was filtered to give a yellow solid which was used without further purification.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[N:18]1([CH2:24][CH:25]([OH:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([CH2:24][C:25](=[O:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(COc1ccccc1[N+](=O)[O-])CN1CCOCC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes,. stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl) -2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, quenched with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-[3-(4-morpholinyl) -2 -keto-1-propyloxy]nitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[N:6][CH:7]=1.[S-:24][C:25]#[N:26].[K+].BrBr>C(O)(=O)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C:13]1[CH:14]=[C:9]([O:8][C:5]2[N:6]=[C:7]3[S:24][C:25]([NH2:26])=[N:1][C:2]3=[CH:3][CH:4]=2)[CH:10]=[CH:11][C:12]=1[F:23])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)ccc1F
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl {5-[(5-aminopyridin-2-yl)oxy]-2-fluorophenyl}carbamate (3.00 g, 9.4 mmol) and potassium thiocyanate (3.93 g, 40 mmol) in acetic acid (40 mL) was added dropwise bromine (2.40 g, 15 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (3.20 g, 90%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([O:18][CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([O:18][CH2:19][C@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(-c2cccc(N)c2)c1
Yield: 148.3 %

Procedure:
To a solution of 3-aminophenylboronic acid (366 mg, 2.36 mmol, Aldrich Chem. Co.) and 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-pyridine (560 mg, 1.57 mmol) in toluene (10 mL) was added Pd(0) (58 mg) and Na2CO3 (5 mL of a 2M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate and chloroform. The organic extracts were dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate hexane 1:1 to afford to give the title compound (860 mg, 100% yield). MS (DCI/NH3) m/z 370 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.48 (s, 9h), 1.84-2.13 (m, 4H), 3.28-3.51 (m, 2H), 3.70-4.08 (m, 2H), 4.08-4.29 (m, 2H), 6.70-6.75 (m, 1H), 6.85-7.03 (m, 2H), 7.31-7.50 (m, 2H), 7.50-7.72 (m, 1H), 8.29 (d, J=3.0, 1H), 8.443 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1N.N(OC(C)(C)C)=O.[I:21]I>C(Cl)Cl>[I:21][C:4]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1I
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-methoxy-5-(trifluoromethyl)aniline (500 mg, 2.62 mmol) in CH2Cl2 (10 mL) was added t-butyl nitrite (467 μL, 3.93 mmol). The reaction was stirred for 5 min prior to addition of iodine (1.3 g, 5.24 mmol), and then heated at 70° C. for 2 h. The reaction was cooled, diluted with CH2Cl2 (10 mL), washed with sat. Na2S2O3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as a light yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.05 (d, J=2 Hz, 1H), 7.61 (dd, J=8.7, 1.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1.[F:20]C1C=C2C(C(C)=NN2)=CC=1.FC1C=CC=CC=1C#N>O>[Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([F:20])=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Reactant: Cc1n[nH]c2cc(F)ccc12
Agent: N#Cc1ccccc1F
Solvent: O
Product: N#Cc1ccccc1-n1nc(CBr)c2ccc(F)cc21
Yield: 61 %

Procedure:
In a similar manner to that described for the preparation of 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile except in Step 1 the mixture was diluted with H2O and in Step 2 the mixture was heated at reflux overnight, 6-fluoro-3-methyl-1H-indazole (2 g, 13.3 mmol) and 2-fluorobenzonitrile (1.73 mL, 16 mmol) were converted to the title compound (800 mg, 61%) as an off white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4-dichloro-benzenesulfonamide. LC: Tr 0.98 min, MS: 317.0 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45 (t, 1H), 6.11 (d, 1H), 6.72 (d, 1H), 6.92 (t, 1H), 7.59 (dd, 1H), 7.80 (d, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-aminophenylboronic acid according to the procedure of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A commercially available reagent of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionate (4.84 g, 15.6 mmol) was dissolved in N,N-dimethylformamide (39 mL), and 1-bromo-2-butyne (1.65 mL, 18.8 mmol) and potassium carbonate (3.25 g, 23.5 mmol) were then added at room temperature. After stirring at 60° C. for 6 hours, and the reaction solution was cooled to room temperature. 1-Bromo-2-butyne (0.55 mL, 6.28 mmol) was added at room temperature, and the mixture was then stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and potassium carbonate (0.433 g, 3.13 mmol) was then added. After stirring at 60° C. for 4.5 hours, the reaction solution was cooled to room temperature. Water (70 mL) was added, and the mixture was then extracted twice with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous solution (30 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 5.02 g (13.9 mmol, yield 89%) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH:7]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: Cc1ccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)cc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.180 mmol), intermediate 42.1, and 4-methylbenzyl alcohol (90 mg; 0.721 0 mmol), example 77 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CC(C)=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH2:19])=[S:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Product: NC(=S)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 ml, THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28˜7.26 (m, 1H), 7.15˜7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:16](=[O:17])[CH:11]2[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:19]1=[O:18]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
8.38 Parts of 2,4-difluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid. The mixture was stirred for two hours. The mixture was refluxed for 20 hours and the resulting product was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized twice from 70 parts of methanol at -40° C to yield 10.2 parts of white crystals of 2-(2,4-difluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 117°-123° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][N:15](C(=O)C)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[OH:1][NH:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:27]([CH3:26])(=[O:29])=[O:28])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccc2cc(C(=O)NO)sc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(Cc1ccccc1)Cc1ccc2cc(C(=O)NO)sc2c1

Procedure:
The title compound was prepared in procedures similar to those described for the preparation of 6-[(acetyl-benzyl-amino)-methyl]-benzo[b]thiophene-2-carboxylic acid hydroxyamide. Methanesulfonyl chloride was used instead of acetic anhydride for the preparation of this title compound. 1H NMR (DMSO-d6, 200 MHz) δ 11.46 (brs, 1H), 9.29 (brs, 1H), 7.90-7.76 (m, 3H), 7.36-7.16 (m, 6H), 4.43 (s, 2H), 4.33 (s, 2H), 2.99 (s, 3H). MS (EI): cal'd 389.1 (M−H−), exp 389.2 (M−H−).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CCOCC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([Cl:6])[CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CNc1cccc(Cl)c1
Reaction time: 6 h

Procedure:
A mixture of sodium bicarbonate (66 g), 3-chloroaniline (50 g) and methyl chloroacetate (51.5 ml) were stirred under nitrogen at 80°-100° for 6 h. Heating at 90° was continued overnight, and the mixture was then cooled and poured into ether (400 ml). The resultant suspension was stirred, chilled to 0°, the precipitated solid was filtered off and the filtrate was retained. The solid was dissolved in ethyl acetate (400 ml) and washed with water (2×200 ml), followed by dilute hydrochloric acid (200 ml). The organic phase was dried and concentrated in vacuo to give the title compound (16.4 g) as a solid, m.p. 75°-76°. The previously obtained filtrate was washed with dilute hydrochloric acid (200 ml), and the organic phase was separated, dried and concentrated in vacuo to give an oily solid. This was triturated with ether:hexane (1:1; 300 ml) and filtered off to give a further batch of the title compound (20 g).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>C1(C)C(C)=CC=CC=1>[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[NH2:1][C:25]1[C:24]([OH:23])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: [NH2-]
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Oc1cccnc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Nc1ncccc1O
Temperature: 25 °C

Procedure:
A mixture of 89.7 g (2.3 moles) of sodamide, 500 cc of xylene containing 0.1 cc of oleic acid and 95 g (1 mole) of 3-hydroxypyridine was placed in a Magne Drive as described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized with ammonia to 40 psig and to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated (158°-186°) for almost 5 hours, during which time hydrogen was evolved. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 250 cc of water. The temperature during the hydrolysis was 60° C. The aqueous phase was separated and neutralized to pH 7.0 with concentrated hydrochloric acid. It was extracted 3 times with 4-picoline. The picoline extracts were combined and distilled to give 39.3 g of recovered 3-hydroxypyridine and 40.6 g of 2-amino-3-hydroxypyridine boiling 223°-228° C. at 29 mm. The melting point of the 2-amino-3-hydroxypyridine, recrystallized from methanol-xylene, was 162°-163° C. The structure was confirmed by NMR and the IR spectrum was identical to the spectrum of 2-amino-3-hydroxypyridine found in Aldrich Library of Infrared Spectra, 2nd ed., p. 1157E. The yield of 2-amino-3-hydroxypyridine, based on 3-hydroxypyridine recovered, was 62.9%. This result significantly differed from the literature report by Levitt and Levitt, Chemistry and Industry, 1621 (1963) which reports the amination of 3-hydroxypyridine gave 2,6-diaminopyridine in good yield while also pointing out that 2-amino-3-hydroxypyridine should, in fact, not be obtained. This is not true of applicants' discovery. The recovered 2-amino-3-hydroxypyridine was found useful, for example, in preparing prostaglandin synthetase inhibitors as reported in Belg. Patent 830,786 (1975), in preparing antiinflammatory agents, analgesics and antipyretics as reported in Shen, et al., Ger. Offen. 2,330,109 (1974), and in preparing antibacterials as reported in Meszaros et al., Hung Teljes, 10,957 (1975). The 2-amino-3-hydroxypyridine was also found useful in the preparation of metalized azo dyes for dying wool, polyamide, and acrylic fibers as reported in Back and Buehler, Ger. Offen. Nos. 2,236,299 (1973) and 2,236,269 (1973).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32]([NH2:35])[CH2:33][CH3:34]>>[CH2:32]([NH:35][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:22])[CH2:33][CH3:34]
Reactant: CCCN
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: CCCNC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and propylamine. Colorless crystals (150 mg).