Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)cc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (0.54 g, 1.58 mmol) (from Example 1d supra) and aniline (0.67 g, 7.11 mmol) (Aldrich) was heated at 110° C. for 30 minutes. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude products was purified by flash column chromatography (silica gel) to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester as a white amorphous solid. (Yield 0.49 g, 68.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12](=O)[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][C:8]=1[OH:9].O.[NH2:23][NH2:24]>>[CH2:18]([O:17][C:15]([C:14]1[NH:24][N:23]=[C:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(O)c(OC)c1
Reactant: NN
Solvent: O
Product: CCOC(=O)c1cc(C=Cc2ccc(O)c(OC)c2)n[nH]1
Yield: 51 %

Procedure:
According to the procedure of Example 1, ethyl 6-(3-methoxy-4-hydroxyphenyl)-2,4-dioxo-5-hexenoate is reacted with hydrazine hydrate to afford ethyl-3-[β-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate in 51% yield, mp=99°-101° C.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:2].[N+:13]([O-])([OH:15])=[O:14]>>[CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)=[O:2]
Reactant: O=CNC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Product: O=CNC1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 1 h

Procedure:
2-Formylaminoindane (15 g) was added portionwise to fuming nitric acid (30 ml, density=1.5 g/ml) whilst keeping the temperature at between 0° and -5°. Stirring was continued for 1 hour at 0° before pouring the reaction mixture onto ice/water and extracting with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing hexane (20% down to 0%) and then methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to give the title compound, yield 7.7 g, m.p. 91°-92°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:35][C:34](=[O:36])[C:33]3([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:23]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:34]([C:33]1([NH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[O:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:36]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84 mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg (0.35 mmol) of 2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of toluene, and the mixture was heated under reflux overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 93 mg (59%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[CH:8][C:9]=2[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:4]=[N:3]1.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[CH:8][C:9]=2[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]([C:19]2[CH:20]=[CH:21][C:22]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:23][C:18]=2[CH3:17])=[N:3]1
Reactant: Cc1cc(-n2cccn2)ccc1B(O)O
Reactant: CCN(CC)c1cc(C)nc2cnn(C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)c1cc(C)nc2c(-c3ccc(-n4cccn4)cc3C)nn(C)c12
Temperature: 100 °C
Reaction time: 16 h
Yield: 7.2 %

Procedure:
A mixture of compound 13a (40 mg, 0.13 mmol), compound 2c (41 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), aqueous sodium carbonate (0.3 mL of a 2 M solution, 0.6 mmol), toluene (2 mL), and ethanol (2 mL) was heated at 100° C. with stirring for 16 hr in a sealed vial. The mixture was cooled, filtered, and purified by preparative HPLC to afford [1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-diethyl-amine (compound 13-1, 3.5 mg).
Reaction SMILES: [P:1]([O-:41])([O:32][CH:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N+:35]1([CH3:40])[CH3:39])([O:3][CH2:4][CH:5]([O:24]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[H][H]>C(O)C.[Pd]>[P:1]([O-:41])([O:32][CH:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N+:35]1([CH3:40])[CH3:39])([O:3][CH2:4][CH:5]([OH:24])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OC=C1CCC[N+]1(C)C)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OC=C1CCC[N+]1(C)C
Yield: 80.7 %

Procedure:
In 20 ml of ethanol was dissolved 162 mg of 2-Benzyloxy-3-hexadecyloxypropyl 1,1-dimethylpyrrolidinio-2-ylmethyl phosphate prepared in Example 7, and 20 mg of palladium(5%)-carbon (catalyst) was added to the resulting solution. The mixture was stirred overnight at 50° C. in a stream of hydrogen. The reaction liquid was cooled, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give 111 mg of 3-hexadecyloxy-2-hydroxypropyl 1,1-dimethylpyrrolidinio-2-ylmethyl phosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1.Cl[C:40]1C=C(C(NO)=N)C=CC=1C1N=C2OC(C)(C)CC(NC(=O)C(C)(C)C)C2=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:40]=[N:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(C(=O)NN)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1
Product: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-c4nnco4)cc3Cl)c(-c3ccc(Cl)cc3)cc21

Procedure:
The product was prepared using the procedures analogous to those described for Example 318 substituting tert-butyl [(4R)-7-[2-chloro-4-(hydrazinocarbonyl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]carbamate for N-[7-{2-chloro-4-[(hydroxyamino)(imino)methyl]phenyl}-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-2,2-dimethylpropanamide in Step B except without addition of boron trifluoride-diethyl etherate.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][CH3:30])=[CH:26][CH:25]=1>>[CH3:30][N:29]([CH2:28][C:27]1[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CNCc1ccc(C)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: Cc1ccc(CN(C)CCn2cnc(-c3cc(C(=O)O)ccn3)c2)cc1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-methyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.33 (3H, s), 2.61 (3H, s), 2.69 (2H, t, J=6 Hz), 3.80 (2H, s), 4.00 (1H, t, J=5.7 Hz), 4.13 (1H, t, J=5.8 Hz), 7.23 (2H, t, J=8.9 Hz), 7.44 (1H, m), 7.51 (1H, d, J=6.9 Hz), 7.52 (1H, s), 7.73 (1H, d, J=5.1 Hz), 8.24 (1H, m), 8.35 (1H, s), 8.76 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:50]3[CH2:51][CH2:52][CH:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:48][CH2:49]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CCCC1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(3-methanesulfonyl-propyl)-piperidine dihydrochloride (example 72) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4S [(M+H)+] 728.2799, observed 728.2797.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.BrBr.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 5 minutes. To the reaction liquid were then added 8.1 g of 4-benzylpyridine, 100 ml of methanol and 3.3 g of anhydrous sodium acetate, and the mixture was refluxed under heating for 5 hours. After refluxing the mixture, the reaction mixture was worked up in the same manner as described in Example 46, whereby 12.3 g (79.9%) of ifenprodil were obtained as white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].C1COCC1.CN(C=O)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>C1COCC1>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:36]([C:31]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=2)(=[O:38])=[O:37])[C:8]=1[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled stirring suspension of NaH (60% dispersion in mineral oil; 63 mg, 1.6 mmol) in THF (3 mL) is added a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (200 mg, 1 mmol) in 3:1 THF/DMF (4 mL). After 45 minutes, a solution of 3,4-dichloro-benzenesulfonyl chloride (214 μL, 1.4 mmol) in THF (3 mL) is added. After 10 minutes, the reaction mixture is added to ice/water and extracted with EtOAc. The organic layer is washed with brine and evaporated. The crude product is purified by flash chromatography (3:1 iso-hexane/EtOAc elution), to afford [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=413.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.[C:31]([Mg]Cl)#[CH:32]>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:31]#[CH:32])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1

Procedure:
To a solution of 3-[5-bromo-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step C (71 mg, 0.14 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.42 mL, 0.21 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[C:9]([N+:19]([O-])=O)=[CH:10][C:11](Br)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])C.[H][H]>C(O)(=O)C.[Pd]>[NH:7]1[C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:19][C:4](=[O:3])[C:5]1=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)NCCC3
Yield: 44.3 %

Procedure:
A solution of the product from Example 83 (1 g, 2.7 mmol) in 250 mL acetic acid was treated with 20% Pd/C (0.1 g) and shaken on a Parr apparatus under 52 psi hydrogen gas for 21 hours. After removal of the catalyst, the solvent was evaporated but gave negligible material. The catalyst/celite was washed two times with 1 N HCl, and the aqueous solution was basified with sodium bicarbonate. The precipitate was collected by filtration, dried and then recrystallized from methanol/dimethylformamide to give the title compound (0.26 g, 44% yield) mp>300° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1>C(O)CCC>[CH3:17][C:16]1[C:11]2[O:10][N:9]=[C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: Cc1cccc2c(Cl)noc12
Solvent: CCCCO
Product: Cc1cccc2c(N3CCNCC3)noc12
Reaction time: 6 h
Yield: 71.5 %

Procedure:
To a stirred and heated (90° C.) mixture of 120 parts of piperazine and 400 parts of 1-butanol were added dropwise 60 parts of 3-chloro-7-methyl-1,2-benzisoxazole. Upon complete addition, stirring was continued for 6 hours at reflux temperature. After cooling, the reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was solidified on standing, yielding 56 parts (71.5%) of 7-methyl-3-(1-piperazinyl)-1,2-benzisoxazole as a residue (int. 2).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2Br)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2N2CCNCC2)CC1

Procedure:
Boc protected piperazine (849 mg, 4.56 mmol) was dissolved in DCM (20 mL) and triethyl amine (2.54 mL, 18.2 mmol) was added. To the stirred solution, ortho-bromo benzoyl chloride (2 g, 9.11 mmol) was added via syringe under nitrogen. The system was stirred for about 12 hours at r.t. The reaction was washed with water, dried, filtered, and concentrated. The residue was subjected to chromatography on silica gel to give 1-Boc-4-(2-bromo-)-piperazine (1.48 g, 8.85 mmol) as a white foam. 1-Boc-4-(2-bromo-benzoyl)-piperazine was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 375.2 (M+1)
Reaction SMILES: [NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>COCCOC>[CH2:23]([N:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCCCS(=O)(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CCCCCS(=O)(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a cold solution (ice bath) of ethyl 6-(anilinosulfonyl)hexanoate (64b) (0.86 g, 2.88 mmol) in 1,2-dimethoxyethane (5 ml) a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol) and a solution of benzylbromide (0.49 g, 2.88 mmol) in 1,2-dimethoxyethane (3 ml) were added, and the resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with petroleum ether-tert-butylmethyl ether (3:2, v/v) as eluent to give the title compound (0.56 g, 50%) as an oil. 1H NMR (DMSO-d6, HMDSO), 8:1.16 (3H, t, J=7.0 Hz); 1.21–1.87 (6H, m); 2.27 (2H, t, J=6.6 Hz); 3.21 (2H, t, partially overlapped with a signal of H2O, J=7.6 Hz); 4.05 (2H, q, J=7.0 Hz); 4.89 (2H, s); 7.14–7.58 (10H, m).
Reaction SMILES: O=P(Cl)(Cl)Cl.[ClH:6].[Br:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N+:12]([O-])=[CH:13]2>>[Br:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[C:13]2[Cl:6]
Reactant: COc1ccc2c[n+]([O-])ccc2c1Br
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1Br
Temperature: 90 °C
Yield: 110.1 %

Procedure:
POCl3 (6.5 ml) was added to the 5-bromo-6-methoxyisoquinoline-N-oxide hydrochloride (1.22 g) and the mixture heated at 90° C. for 6 h. Excess POCl3 was removed in vacuo and the remaining solid washed with water, filtered and dried in vacuo to give 5-bromo-1-chloro-6-methoxyisoquinoline (1.26 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)o2)cc1
Yield: 95.7 %

Procedure:
A mixture of methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.600 g), 1 M aqueous sodium hydroxide solution (3.6 ml), tetrahydrofuran (6 ml) and ethanol (3 ml) was heated under reflux for 1.5 hrs. After cooling, 1 M hydrochloric acid was added to acidify the mixture. The crystals were collected by filtration to give 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.550 g, yield 95%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 284–286° C.