Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[C:6]2[CH3:16].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[N:8]([CH3:20])[CH:7]=[C:6]2[CH3:16]
Reactant: CI
Reactant: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
A solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (900 mg, 4 mmol) in 7 ml DMF was cooled to zero degrees C, and sodium hydride (104 mg, 4 mmol, 95% powder) was added. The reaction mixture was stirred 15 minutes at zero degrees C, and then iodomethane (270 ul, 4 mmol) was added. The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. The reaction mixture was then cooled to 0° C., quenched by adddition of 1 N NH4Cl, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 75% ) as a solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:20][C:19]4([C:21]([O:23]CC)=[O:22])[CH:15]([CH2:16][CH2:17][CH2:18]4)[CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.O>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH:13]3[CH2:20][C:19]4([C:21]([OH:23])=[O:22])[CH:15]([CH2:16][CH2:17][CH2:18]4)[CH2:14]3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C12CCCC1CC(N1CCC(c3ccccc3)CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C12CCCC1CC(N1CCC(c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of ethyl 2-(4-phenylpiperidin-1-yl)octahydropentalene-3a-carboxylate (1.85 g, 5.42 mmol) in THF (35 mL) was added a solution of sodium hydroxide (2.16 g, 54.2 mmol) in water (35 mL). The reaction mixture was stirred at ambient temperature for about 18 h. The solvent was removed under reduced pressure and the crude product was extracted into DCM (3×20 mL). The combined organic phases were washed with water (3×50 mL) and dried over MgSO4. Concentration in vacuo gave 2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalene-3a-carboxylic acid (1.70 g) that was used in the next step without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[CH3:20])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>CCCCCC.[Li]CCCC.C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([CH3:20])=[CH:12][CH:13]=[C:14]([O:16][CH2:17][O:18][CH3:19])[C:15]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1C1(O)CCC1
Reaction time: 2 h
Yield: 13.7 %

Procedure:
To a solution of tert-butyl-[[5-(methoxymethoxy)-2-methyl-phenyl]methoxy]-dimethyl-silane (Intermediate 174, 0.3 g, 1 mmol) in hexane (5 ml), BuLi (1.6M in hexane, 0.9 ml, 1.4 mmoli) was added at room temperature. The reaction mixture was stirred for 2 h and then added dropwise at −30° C. to a suspension of CeCl3 (0.37 g, 1.5 mmoli) in dry THF (5 ml) that was previously stirred at room temperature overnight. After 45 min at −30° C., cyclobutanone (0.07 g, 1 mmoli) dissolved in THF (1 ml) was added. The reaction was stirred at the same temperature for and then quenched with ammonium chloride (20 ml) and extracted with Ethyl Acetate (2×20 ml). Combined organic layers were dried over Na2SO4 and evaporated under vacuum to afford a colorless oil that was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 75:25 as eluents affording the title compound (0.05 g) as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(3,5-difluorophenyl)acetic acid were treated as in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.73-7.76 (m, 1H), 7.47-7.50 (m, 2H), 7.37-7.40 (m, 2H), 7.09-7.22 (m, 3H), 3.77 (s, 2H), 2.42 (s, 3H); MS (APCI+) M/Z 406 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](OC(ON=C(C#N)C(OCC)=O)=O)[CH:11]([CH3:13])[CH3:12].C(N(CC)CC)C.C(OCC)(=O)C>O>[C:1]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)c1ccccc1
Yield: 95.5 %

Procedure:
A mixture comprising benzoic acid (1.22 g), ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (2.42 g), triethylamine (1.4 ml) and ethyl acetate (20 ml) is stirred at room temperature for 1 hour and then admixed with water. The ethyl acetate layer is separated and treated as in Example A to give isobutyl benzoate (1.7 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](OC(OCC)OCC)C>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2nnco2)cc1
Yield: 57 %

Procedure:
A stirred solution of 4-fluorobenzohydrazide (4.2 g, 27.2 mmol) in triethylorthoformate (27 mL) was heated at 140° C. for 5 h. The reaction was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (100-200 mesh; using 12% ethyl acetate in hexane) to afford 2-(4-fluorophenyl)-1,3,4-oxadiazole [Polshettiwar, Tetrahedron Letters, 49:879-883 (2008)] as off-white solid (2.5 g, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.08 (dd, 2H), 7.19 (dd, 2H); LC-MS m/z calculated for [M+H]+165.04. found 165.00.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[SH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: COC(=O)CCS
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCSc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (2.60 g, 0.014 mole) and methyl 3-mercaptopropionate (1.92 g, 0.016 mole) in DMF (10 mL) was added anhydrous K2CO3 (2.07 g, 0.016 mole). After stirring at ambient temperature for 16 hr, the reaction was quenched with ice water. The precipitated product was collected by suction filtration, washed well with water, and dried in vacuo to give a bright yellow solid (3.65 g, 97%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH2:30]>>[CH3:29][NH:30][C:26]([C:23]1[CH:24]=[CH:25][C:17]2[C@@H:16]3[C@H:21]([CH2:20][CH2:19][C:18]=2[CH:22]=1)[N:12]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:11])[CH2:13][CH2:14][CH2:15]3)=[O:28]
Reactant: CN
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: CNC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 75 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): tR=1.91 min; Mass spectrum (ESI+): m/z=389 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][NH:6][CH2:7]2.Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][N:6]([C:13]1[CH:18]=[N:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CN1C2CNCC1COC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 112h (800 mg, 5.6 mmol) and 5-bromo-2-nitropyridine (1.37 g, 6.86 mmol) in DMSO (50 ml) was added Cs2CO3 (5g) and t-BuNH4I (cat.). The reaction mixture was stirred at 120° C. overnight. Then it was cooled to room temperature, and extracted with EtOAc (300 ml). The organic layer was washed with water (3×100 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to get crude product, which was purified through a silica gel column eluting with DCM:MeOH=100:1 to 50:1 to give 112i as a yellow solid (850 mg, 72%) MS: [M+H]+: 265
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.CCOC(C)=O>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:4][CH:5]=2)[CH:10]=1)=[O:22]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(4-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in dry DMF, morpholine (5 equiv.) was added at 0° C. and reaction mixture was stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography/preparative HPLC to give the desired compound (15% yield). LCMS: 515.25 (M+1)+; HPLC: 99.80% (@ 254 nm) (Rt; 5.168); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 10.01 (bs, 1H), 8.94 (bs, 1H), 8.39 (s, 1H), 8.35 (d, J=7.6 Hz, 2H), 8.18 (s, 1H), 7.68 (d, J=7.2 Hz, 2H), 5.90 (s, 1H), 5.30 (m, 1H), 4.44-4.41 (m, 4H), 3.98 (m, 2H), 3.63-3.60 (m, 2H), 3.37-3.30 (m, 2H), 3.16 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.4 Hz, 6H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[C:6]([Cl:14])[CH:5]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][OH:29])[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](=[N:28]/[O:29][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=2[Cl:14])/[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(OCCBr)c(Cl)c1
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Product: C/C(=N\OCCOc1ccc(C(=O)O)cc1Cl)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared as white solid (0.334 g, 53%) from 4-(2-bromo-ethoxy)-3-chloro-benzoic acid methyl ester and 1-(4-tert-butyl-phenyl)-ethanone oxime using a procedure similar to that of step 1 of example 6. mp=167.1-168.8° C.; mass spectrum (+APCI, M+H) m/z 390. 1H NMR (400 MHz, DMSO-d6); δ 12.95 (bs, 1H), 7.89 (d, 1H), 7.84 (dd, 1H), 7.57 (d, 2H), 7.39 (d, 2H), 7.29 (d, 1H), 4.45 (m, 4H), 2.13 (s, 3H), 1.29 (s, 9H). Elemental analysis: Calcd. for C21H24ClNO4: C, 64.69; H, 6.20; N, 3.59, Found: C, 64.50; H, 6.28; N, 3.57.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:44]3[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methylsulfonyl-piperazine (Aldrich) to give the title compound. LC-MS: 671.2 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30][N:31]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14]([NH:31][OH:30])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 0.204 g (0.49 mmol) of 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, 0.079 g (0.58 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.112 g (0.84 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and stirred at room temperature for 1 h. Then added 0.3 mL of 50% aqueous hydroxylamine and stirred for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH/CH2Cl2 to provide 0.077 g (36%) of the desired product as a white solid. Electrospray Mass Spec: 435.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:7]([N+:15]([O-:17])=[O:16])[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:18](=[O:20])[CH3:19])[C:3]1=[C:7]([N+:15]([O-:17])=[O:16])[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Product: CC(=O)N1CCN(C)C1=C(Sc1ccccc1)[N+](=O)[O-]

Procedure:
20 ml of acetic anhydride and 1.26 g of 1B were heated together at 100° for 1 hour. The resulting mixture was cooled on an ice-bath and filtered to give 1, as a yellow crystals, m.p.: 191°-193° (with decomposition).
Reaction SMILES: [OH-].[Na+].[C:3]1([NH:9][CH:10]([CH:16]([OH:18])[CH3:17])[C:11]([O:13]CC)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOCC.O.O.CO>[C:3]1([NH:9][CH:10]([CH:16]([OH:18])[CH3:17])[C:11]([OH:13])=[O:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(Nc1ccccc1)C(C)O
Agent: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: CCOCC
Product: CC(O)C(Nc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-bromo-3-hydroxybutanoate (10 g) and 15 ml of HMPT is added 13.2 g of aniline. The reaction is stirred at RT for 3 days and then taken up in ether followed by washing with dilute sulfuric acid, pH 3, and water. The ether phase is dried over magnesium sulfate and evaporated to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is saponified using 1.6 g of sodium hydoxide, 40 ml of methanol and 20 ml of water with stirring overnight at RT. The acid 2-phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium carbonate (2.12 g) at 35° for a few hours and worked up using ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[CH2:10][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:8][CH2:7][C:6]=2[NH:5][C:4]1=[O:22].C(O)(C(F)(F)F)=O>C([SiH](CC)CC)C>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:10]2)[NH:5][C:4]1=[O:22]
Reactant: COc1ccc(CC2CCC3=C(C2)CC(CO)C(=O)N3)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Yield: 67.4 %

Procedure:
3,4,5,6,7,8-Hexahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (6.75 g) (prepared according to Example 17) was suspended in triethylsilane (35 ml) and TFA (17.25) ml was added with rapid stirring. When tlc (SiO2 /EtOAc) showed no starting material remained, the stirring was stopped and the reaction mixture separated into two layers. The lower (TFA) layer was added to a saturated solution of sodium carbonate and this organic solution was extracted into dichloromethane, dried (MgSO4) and evaporated. The residue (9.4 g) was purified in several fractions to give 3,4,4a,5,6,7,8,8a-octahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (mixed isomers 4.58 g). This product was purified by chromatography on a "Dynamax" 60A Si 21×250 mm column using 0.25% NH4OH, 1.8% MeOH in dichloromethane as mobile phase. A flow rate of 21.6 ml/min was used and injections of 10 ml of 10 mg/ml of product in mobile phase were made. The material eluting at 20.1 minutes was collected and recrystallised from ethyl acetate to give the title compound (0.2 g) mp 196°-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: Fc1ccc(N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008 mol), 4fluorophenyl isothiocyanate (1.45g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.31 g (71%), m.p. 146°-148 ° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17]C(C)(C)C)=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.Cl.C(Cl)(=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:17])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 35.8 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) of (+)-N,N-dimethyl-8-(tert-butoxycarbonyl)amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.100 gm (0.56 mMol) of isonicotinoyl chloride hydrochloride, 0.036 gm (36%) of the title compound were recovered in two crops from toluene/hexane by the procedure described in Example 24.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[Br:7].CN([CH:15]=[O:16])C.O.O.C(O)(=O)C(O)=O>CCOCC.O.CCOC(C)=O>[Br:7][C:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][C:2]=1[CH:15]=[O:16]
Reactant: Brc1oc2ccccc2c1Br
Reactant: CN(C)C=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1oc2ccccc2c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
2,3-Dibromobenzofuran (1.37 g, 5.0 mmol) is dissolved in Et2O (20 ml) in a dry flask under nitrogen and cooled to −78° C. t-Butylithium (6.47 ml, 11.0 mmol) is added drop-wise, and the chilled solution is stirred 1 h. DMF (0.45 ml, 5.75 mmol) is dissolved in Et2O (5 ml) and also added dropwise, and the mixture is stirred at −78° C. for another 4 h. The reaction is warmed to rt, whereby oxalic acid dihydrate (1.26 g, 10.0 mmol) and water (5 ml) are added. The reaction continued stirring at rt for 2 days and is then diluted with water (25 ml) and EtOAc (35 ml). The layers are allowed to separate, and the aqueous is extracted with EtOAc (1×35 ml). The organics are combined, dried over Na2SO4, filtered, and concentrated to an orange oil that solidified upon standing. The crude material is chromatographed over 100 g slurry-packed silica, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 628 mg (56%) of 3-bromo-1-benzofuran-2-carbaldehyde as a yellow crystalline solid. HRMS (FAB) calcd for C9H5BrO2+H: 224.9552, found 224.9555.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=O)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(CC2=NC(C)(C)CO2)cc1[N+](=O)[O-]

Procedure:
A mixture of 2-amino-2-methyl-1-propanol, 7.2 g (0.05 mol), (Aldrich Chemical Company) and 4-methoxy-3-nitrobenzeneacetic acid, 16.7 g (0.079 mol), (Journal of the American Chemical Society, Vol. 70, pp. 2837-2843, (1948)) is refluxed overnight in xylene, 100 ml, under a water separator. The mixture is diluted with toluene, filtered, washed with an aqueous solution of potassium bicarbonate and water. The organic layer is separated and evaporated. The resulting gum is chromatographed over silica gel and eluted with ethyl acetate to give 7.6 g of 4,5-dihydro-2-[(4-methoxy-3-nitrophenyl)methyl]-4,4-dimethyloxazole after recrystallization from hexane; mp 88°-90° C.