Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1CNC(=O)c1ccccc1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A solution of 4-(3-bromo-propoxy)-biphenyl (291 mg, 1.00 mmol; Preparation 12) and 3-[2-(benzoylamino-methyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (320 mg, 0.90 mmol; Preparation 21) in DMF (5 mL) was treated with K2CO3 (100 mg) and heated at 60° C. for 48 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organics were dried (Na2SO4), concentrated, and purified using silica gel chromatography (10-30% EtOAc/hexanes) to give 3-{2-(benzoylaminomethyl)-4-[3-(biphenyl-4-yloxy)propoxy]phenyl}propionic acid tert-butyl ester (450 mg). This material was treated with a mixture of CH2Cl2 (1.0 mL)/TFA (0.8 mL)/water (0.1 mL) at ambient temperature for 2 h. The reaction mixture was concentrated and dried under vacuum to afford the title product as a white solid (380 mg, 75%). MS (ES) m/e 510.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])(=[O:21])[NH2:2]
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(=O)c3ccccc3ccn2c1
Agent: Cl
Product: NC(=O)c1cc2c(=O)c3ccccc3ccn2c1
Temperature: 25 °C

Procedure:
2-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 2-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[C:11]3[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.O.O[Li].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:21]=[C:11]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(4-bromophenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (2.40 g, 7.0 mmol) was dissolved in THF (50 mL) and water was added (12 mL) followed by LiOH—H2O (877 mg, 20.9 mmol). The mixture was stirred overnight at room temperature and 1M HCl (ca 28 mL) was added. The mixture was extracted with EtOAc (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a crude white solid that was directly used into the next step. LCMS m/z 317.0, 319.0 (M+H)+, ret. time 2.62 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.CCN(CC)CC.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:19]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:7]1=[O:11])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NCc2cc(I)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)N1Cc2cc(I)ccc2C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-iodo-2,3-dihydroisoindol-1-one (3 g) in DMF (60 mL), were added N,N-dimethylaminopyridine (DMAP: 14 mg), Et3N (4.84 mL) and tert-butyl-diphenylsilyl chloride (9.0 mL). The mixture was stirred at 50° C. for 2 h. After cooling, saturated NaHCO3 aq. was added into the reaction mixture. Then it was extracted with EtOAc. The organic layer was washed with water and brine, then was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The trituration with Et2O followed by filtration gave compound aa2-1 (2.78 g) as a yellow amorphous solid.
Reaction SMILES: CS(O[CH2:6][C:7]1([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C:7]1([NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (1-(benzyloxycarbonylamino)cyclopropyl)methyl methanesulfonate (5 g, 16.7 mmol) in 100 mL of DMF was added NaN3 (3 g, 46.15 mmol) in one portion at room temperature. Then the reaction mixture was stirred at 70° C. for 16 hours. The mixture was poured into 400 mL of water, extracted with ethyl acetate (600 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated at 40° C. under reduced pressure to give a crude product as colorless oil, which was used in the next step without further purification MS: (M+H)+=247.2.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[N:25][C:26]#[N:27])C.[Li+].[OH-].Cl>C1COCC1.O>[CH3:35][O:34][C:31]1[N:30]=[CH:29][C:28]([C@@H:6]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[CH2:21][CH2:20][CH2:19][NH:18][C:17]=4[N:16]=3)[C:8]2=[N:25][C:26]#[N:27])[CH2:5][C:4]([OH:36])=[O:3])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=NC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCc3ccc4c(n3)NCCC4)C2=NC#N)cn1
Reaction time: 16 h

Procedure:
To a solution of the ester 1-3 (180 mg, 0.37 mmol) in THF (20 mL) and water (20 mL) at room temperature was added 1N LiOH solution (5 mL, 5 mmol) and the mixture stirred for 16 hr. The mixture was neutralized with 1N HCl and the solvent removed. Column chromatography of the residue (silica gel; CHCl3/EtOAc/MeOH 8:1:1) gave 1-4 as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[C:6]([C:8]1[C:9]([C:22]2[N:23]([CH3:30])[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)=[N:10][N:11]([CH3:21])[C:12]=1[NH:13][C:14](=[O:20])[C:15](OCC)=[O:16])#[N:7]>CO>[C:6]([C:8]1[C:9]([C:22]2[N:23]([CH3:30])[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)=[N:10][N:11]([CH3:21])[C:12]=1[NH:13][C:14]([C:15]([NH:2][OH:3])=[O:16])=[O:20])#[N:7]
Reactant: NO
Reactant: CCOC(=O)C(=O)Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1NC(=O)C(=O)NO

Procedure:
Separate solutions were prepared of 0.94 g. of hydroxylamine hydrochloride in 10 ml. of methanol, and 0.728 g. of potassium hydroxide in 5 ml. of methanol at the boiling point of methanol. Both solutions were then cooled to about 30°-40° C., and the potassium hydroxide solution was added with shaking to the hydroxylamine hydrochloride solution. After the addition, the flask containing the mixture was flushed with nitrogen so that the mixture was maintained in a nitrogen atmosphere while being cooled in an ice bath for about 5 minutes to insure complete precipitation of the potassium chloride. The potassium chloride was filtered off and the filtrate diluted with about 50 ml. of methanol. To this methanolic solution, there was then added 2.3 g. (0.0067 mole) of N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]oxamic acid, ethyl ester, and the mixture was stirred for about 3 hours at ambient room temperature. A precipitate formed which was filtered off. The solid so collected was refluxed in methanol and the solid which did not dissolve was collected on a filter. The solid weighed about 0.3 g. and had a melting point of about 179°-180° C. The solid was identified by NMR spectrum and elemental analyses as N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]-N'-hydroxyoxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]4[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-isopropyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=603.7)=97%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14]
Reactant: O=c1oc(CO)c(Br)c2ccccc12
Reactant: OB(O)c1ccccc1F
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: [Cs+]
Product: O=c1oc(CO)c(-c2ccccc2F)c2ccccc12
Yield: 33 %

Procedure:
The title compound was made in a similar way as that of the intermediate B2 using 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.6 g, 2.352 mmol), 2-fluorophenylboronic acid (0.494 g, 3.53 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and Cs2CO3 (0.77 g, 2.35 mmol) to afford the title compound (0.21 g, 33%).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (52 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 53%).
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[CH:19]=O)=[O:15])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26].CC(C)([O-])C.[K+]>C1COCC1.CCOCC>[CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:27][C:25]#[N:26])[CH:21]=[C:22]([CH3:24])[CH:23]=2)=[O:15])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:2])[CH3:3]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=O)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzaldehyde (2.26 g, 6.89 mmol) and diethyl cyanomethylphosphonate (1.14 ml, 7.03 mmol) in anhydrous THF (15 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (0.85 g, 7.58 mmol). After stirring for 1 hr., the mixture was further stirred for 4 hr. at room temperature. The reaction mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 1.56 g (65%) of a white solid. m.p. 144-145° C.; 1H NMR (300 MHz, CDCl3) δ 1.19 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 3.39 (1H, d, J=16.8 Hz), 7.49 (1H, s), 7.69 (1H, s), 7.75 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(#N)C>[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][N:30]1[CH2:2][C:3]2[C:8](=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=2)[C:9]1=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN1Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Methyl 6-bromomethyl-3-nitrobenzoate (430 mg, 1.64 mmol), N-glycyl-3(R)-methyl-β-alanine benzyl ester hydrochloride 2-4 (611 mg, 2.13 mmol) and triethylamine (0.68 mL, 4.92 mmol) were stirred in acetonitrile (10 mL) for 16 hours. The solution was poured into 1N HCl and extracted with EtOAc (3×), washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography eluting with EtOAc afforded 2-6 as a solid. Rf (silica; EtOAc)=0.45. ##STR60## N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-β-alanine (2-7)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([CH2:24]O)[CH:21]=[C:20]([Cl:26])[C:3]=1[O:4][CH:5]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:24][C:22]1[CH:23]=[C:2]([Cl:1])[C:3]([O:4][CH:5]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:20]([Cl:26])[CH:21]=1
Reactant: CCOC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccc2c(c1)OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a magnetically stirred solution of 0.206 g (0.52 mmol) of the product of step A dissolved in 2 mL methylene chloride was added 0.162 g (0.62 mmol) of triphenylphosphine followed by 0.205 g (0.62 mmol) of carbon tetrabromide at 0° C. The reaction mixture was held at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was then concentrated in vacuo and the residue was applied to a silica gel flash chromatography column and eluted with 15% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.220 g (92%) yield of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CC(=O)OCC>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:19])[CH2:17][O:18][CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1COCC(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of compound 3f (6.6 g, 20 mmol) in dry THF (100 mL) was added NaH (60%, 960 mg, 24 mmol) in small portions at 0° C. and stirred for 1 hr. Then compound 3b (5 g, 22 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and extracted with EA (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by CC eluting with PE:EA=9:1 to give 3g as a white solid (3.2 g, 34% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:17])([F:16])[CH2:11][S:12](Cl)(=[O:14])=[O:13].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]([F:17])([F:16])[CH2:11][S:12]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:14])=[O:13]
Reactant: COC(C)(C)CCO
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)(C)CCOS(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (0.4 g, 3.4 mmol) and TEA (0.2 g, 2 mmol) in CH2Cl2 (6 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.12 g, 0.66 mmol). The solution was stirred at rt for 1 h. The organics were extracted with CH2Cl2 (25 mL) and washed with 0.1 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product as an oil (0.086 g, 50%). 1H NMR (400 MHz CDCl3) δ 4.41 (t, 2H, J=7.3 Hz), 3.87 (q, 2H, J=8.8 Hz), 3.14 (s, 3H), 1.94 (t, 2H, J=7.3), 1.16 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2coc3ccccc23)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COc1ccc(-c2c(C(=O)c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
When 3-p-methoxyphenylbenzofuran was acylated with p-chlorobenzoyl chloride as described in the procedure of Example 1, 2-p-chlorobenzoyl-3-p-methoxyphenylbenzofuran was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:7]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:5]=1[NH2:21].[C:23](Cl)(Cl)=[O:24]>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:7]([C:17]([F:19])([F:20])[F:18])=[CH:6][C:5]=1[N:21]=[C:23]=[O:24]
Reactant: COC(=O)c1cc(Oc2cccnc2)c(C(F)(F)F)cc1N
Reactant: O=C(Cl)Cl
Product: COC(=O)c1cc(Oc2cccnc2)c(C(F)(F)F)cc1N=C=O

Procedure:
300 mg of 2-amino-5-(pyridin-3-yloxy)-4-trifluoromethyl-benzoic acid methyl ester are treated with phosgene according to the procedure described in example 74, yielding 291 mg of 2-isocyanato-5-(pyridin-3-yloxy)-4-trifluoromethyl-benzoic acid methyl ester as a brownish oil. 1H-NMR (CDCl3): 8.50 br s, 1H; 8.40 s, 1H; 7.60 s, 1H; 7.50 s, 3H; 3.95 s, 3H.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[C:6]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[CH2:2]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOCC
Product: C=CCCN1CCN(c2ccccc2)CC1
Yield: 74.8 %

Procedure:
A mixture of 4-bromobut-1-ene (8.68 g) and 1-phenylpiperazine (35.7 g) is heated to reflux in diethyl ether (100 mL) for 2 hours. The mixture is filtered and the filtrate is extracted with 2N hydrochloric acid (150 mL). The extracts are washed with diethyl ether (150 mL) and basified with 25% sodium hydroxide. The aqueous layer is extracted with diethyl ether (3×100 mL), the extracts dried over MgSO4, filtered and evaporated to leave a brown oil. This oil is purified by MPLC on silica gel eluting with 5% methanol in dichloromethane to give 10.4 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[C:15]([CH3:16])[C:3]=12.[Cl-].[CH2:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O.C(=O)(O)[O-].[Na+]>C(#N)C>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:15]([CH3:16])[C:3]=12
Reactant: C=[N+]1CCOCC1
Reactant: CCOC(=O)c1cnc2scc(C)c2c1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)c(C)c2c1O
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A suspension of ethyl 4-hydroxy-3-methylthieno[2,3-b]pyridine-5-carboxylate (Preparation 26, 0.92 g) and 4-methylenemorpholin-4-ium chloride (1.57 g) in acetonitrile (40 mL) is heated to 60° C. for 4 h. The resulting suspension is allowed to cool to room temperature, poured into water, and adjusted to neutral pH with saturated aq. sodium bicarbonate. The solution is extracted with CH2Cl2 (3×100 mL). The combined organic layers are washed with brine (25 mL), dried (Na2SO4), and concentrated to afford 1.26 g of the title compound as a yellow solid. Physical characteristics. M.p. 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.64, 4.37, 3.70, 3.38, 2.51, 2.47, 1.35; MS (ESI−) m/z 335 (M-H). Anal. Found. C, 56.93; H, 6.10; N, 8.26; S, 9.34.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C@@H:7]1[CH3:19])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C@@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCNC[C@@H]1C
Reaction time: 12 h

Procedure:
A solution of 2.05 g (S)-2-Methyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-ethyl ester in 15 ml dichloromethane was treated with 11.2 ml TFA and the resulting solution stirred for 12 h. The solvents were removed in vacuum and the crude hydrotrifluoroacetate transformed to the free amine by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.70 g.