Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11]>O.C1COCC1>[Cl:4][C:5]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCOc1ccc(OC)cc1Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OCCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
A solution of LiOH.H2O (0.67 g; 16 mmol) in water (20 mL) was added to a solution of ethyl 3-(2-chloro-4-methoxyphenoxy)propionate (1.90 g; 7.3 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at RT overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated yielding 0.90 g (54%) of the sub-title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])(=[O:3])[CH3:2].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([C:18]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(=O)c1cccc(C)c1O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C)c1OC(=O)C1CCCCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Acetyl-6-methylphenol (3.0 g) was dissolved in pyridine (15 ml) and to the solution was added dropwise cyclohexanecarbonyl chloride (3.08 g) with stirring at room temperature. After stirring for 4 hours, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with water, diluted hydrochloric acid and then water and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain the title compound (5.2 g) as oil in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]3[N:16]=[CH:17][C:18](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1)#[CH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]3[N:16]=[CH:17][C:18]([C:21]#[C:20][C:22]4[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: OCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: CC(C)(O)c1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from [5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (example C.14 step 2) (193 mg, 0.5 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (80 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (97 mg, 46%). MS (ISP) 418.1 [(M+H)+]; mp 118-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15][C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:48](N2C=NC=C2)=[O:49])C=1>C1COCC1>[O:49]=[C:48]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[S:13][C:12]([N:14]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15][C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)=[N:11][N:10]=3)=[CH:3][C:2]=2[O:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc(N)c(O)c2)s1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc3[nH]c(=O)oc3c2)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
tert-Butyl (S)-1-(5-(3-hydroxy-4-aminophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (200 mg, 328 μmol) was dissolved in 50 mL THF in a round bottom flask. To this flask was added CDI (213 mg, 1312 μmol). The mixture was stirred at 70° C. for 16 hours. After removing the solvent under reduced pressure, the remaining residue was mixed with 100 mL EtOAc. The organic solution was washed with water, saturated ammonium chloride twice and dried over sodium sulfate. After removing the solvent, the desired product (140 mg, 67%) was obtained as a tan solid. LCMS (API-ES) m/z (%): 636.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.23 (s, 9H) 1.58 (s, 9H) 2.82-2.96 (m, 1H) 2.95-3.08 (m, 1H) 4.12-4.27 (m, 1H) 4.32-4.43 (m, 2H) 7.15-7.25 (m, 1H) 7.49 (d, J=8.02 Hz, 2H) 7.60 (d, J=7.83 Hz, 2H) 7.70 (dd, J=8.12, 1.47 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([F:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([Zn]I)[CH:27]=[CH:28][CH:29]=1>O1CCCC1.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:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: Fc1cccc([Zn]I)c1
Reactant: CC(=O)c1cc(F)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 11 %

Procedure:
A mixture of 7-acetyl-5-fluoroquinolin-8-yl trifluoromethanesulfonate (3.4 g, 10. mmol, from Example 53, Step 2) in tetrahydrofuran (10 mL) was degassed for 10 minutes, to which was added tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) and 0.5 M (3-fluorophenyl)(iodo)zinc in tetrahydrofuran (50 mL). The reaction mixture was heated at 65° C. overnight, and then cooled to room temperature. The reaction was quenched with sat. NaHCO3 solution. The mixture was filtered through a Celite pad. The filtrate was extracted with dichloromethane. The combined organic layers were wash with brine, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 30% ethyl acetate in hexane) to give the desired product (0.32 g, 11%). LCMS calculated for C17H12F2NO (M+H)+: m/z=284.1; Found: 284.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([CH3:17])[N:16]=1)[C:8](N(OC)C)=[O:9])[CH:2]([CH3:4])[CH3:3].[CH2:18]1COCC1>C[Mg]Br.CCOCC>[CH2:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:18])[CH:14]=[C:15]([CH3:17])[N:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (410 mg, 1.74 mmol) in THF (10 mL), methyl magnesium bromide (1.17 mL of a 3 M solution in ether, 3.47 mmol) is added at 5° C. The mixture is stirred at 5° C. for 1.5 h. The reaction is quenched by adding NH4Cl. The mixture is diluted with EA (50 mL), washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (280 mg) as a colourless oil. LC-MS: tR=0.84 min; 1H NMR (CDCl3): δ 0.96 (d, J=6.5 Hz, 6H), 2.08-2.20 (m, 1H), 2.62 (s, 3H), 2.65 (s, 3H), 2.74 (d, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.42 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1CC#N.[C:10]1([CH3:19])[C:11]([C:16](Cl)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16]([C:11]2[C:10]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:5][CH:4]=[CH:3]1
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cccn1C

Procedure:
-2-acetonitrile: To a solution of 24 g. (0.20 mole) of 1-methylpyrrole-2-acetonitrile and 30.92 g. (0.20 mole) o-toluoyl chloride in 200 ml. methylene chloride (cooled externally to -20°C.) is added dropwise 23.4 ml. (0.20 mole) of stannic chloride. After the addition is complete, the yellow mixture is permitted to come to room temperature. The mixture is then poured into ice-dilute hydrochloric acid. The two phases are separated. The organic phase is washed consecutively with N,N-dimetyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution; dried over magnesium sulfate; and the product, 1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, is separated from the residual oil by chromatography. The column is packed with acid washed alumina in hexane. The eluant is benzene. The product is found in the first compoundbearing fraction as determined by ultraviolet absorption at 260 mμ. The benzene is evaporated and the resultant solid is purified by recrystallization twice from methaol, m.p. 90°-92.5°C.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][N:2]1[C:14]([CH:16]1[CH2:21][CH2:20][N:19](C(OCC2C=CC=CC=2)=O)[CH2:18][CH2:17]1)=[O:15])=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.C>ClCCl>[NH:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)N2CCc3c([nH]c4ccccc34)C2)CC1
Solvent: ClCCl
Solvent: CO
Product: O=C(C1CCNCC1)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 18 h

Procedure:
32 g (76.65 mmol) of benzyl 4-[(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)carbonyl]-1-piperidinecarboxylate, 300 ml of methanol, 300 ml of dichloromethane and 9 g of palladinized charcoal (10% palladium) are introduced into a Parr apparatus, and a hydrogenolysis is performed under approximately 0.41 MPa for 18 h.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1.[N-:18]=[N+:19]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=1)=[N+:18]=[N-:19]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(N=[N+]=[N-])cc1
Yield: 92.2 %

Procedure:
Following the general procedure of Marchesini (J. Org. Chem. 49, p. 4287-4290, 1984), sodium nitrite (38 g, 0.56 mol) was slowly added to a stirred and cooled (0° C.) mixture of ethyl 4-aminophenylacetate (25 g, 0.14 mol) in 700 mL of TFA. After the addition was complete, the reaction was stirred at 0° C. for another 0.5 hour and then sodium azide (27 g, 0.42 mol) was slowly added over a period of 0.5 hours. The mixture was stirred for another 2 hours at 0° C. and then quenched with ice water and the product was extracted with EtOAc. The organic phase was washed with water, dried over magnesium sulfate, filtered, concentrated to yield 26.5 g (90%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ7.31 (d, J=8 Hz, 2H), 7.07 (d, J=7 Hz, 2H), 4.07 (q, J=7 Hz, 2H), 3.66 (s, 2H), 1.17 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.[CH2:24]([CH:26]([CH2:29][CH3:30])[CH:27]=O)[CH3:25].C(O)(=O)C.C([BH3-])#N>CO>[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@H:2]2[CH2:1]1)[CH3:25]
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Reactant: CCC(C=O)CC
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)CN1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 42 (35 mg, 0.1 mmol) in methanol (0.5 mL) was added a solution of 2-ethylbutanal (20 mg, 0.2 mmol) in methanol (0.5 mL). To this solution was added acetic acid (30 μL, 0.5 mmol) followed by MP-cyanoborohydride resin (136 mg). The resulting mixture was shaken at 50° C. overnight and then filtered. The filtrate was concentrated. The residue was dissolved in 1:1 methanol:dimethyl sulfoxide and purified by HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to afford the title compound. 1H NMR (500 MHz, pyridine-d5/D2O) δ ppm 0.82 (t, 6 H, J=7.48 Hz), 1.24-1.36 (m, 4 H), 1.42-1.54 (m, 2 H), 1.83-1.91 (m, 1 H), 2.14-2.29 (m, 6 H), 2.36 (m, 1H), 2.84 (m, 2H), 2.93 (s, 1 H), 3.01 (m, 1H), 4.21 (m, 1H), 7.67 (t, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 8.36 (d, 1H, J=8 Hz), 8.48 (s, 1 H), 10.02 (d, 1H, J=8 Hz); MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]([NH:18][C:22]2[CH:21]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)Nc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 60 °C
Yield: 73 %

Procedure:
2-Chloro-4-aminobenzonitrile (305.2 mg, 2 mmol) and carbonyldiimidazole (324 mg, 2 mmol) were combined in a reaction vial, and THF (3 mL) was added. The resulting mixture was heated overnight at 60° C., and the product, 1,3-bis-(3-chloro-4-cyano-phenyl)-urea was isolated by filtration and washed with several portions of 1N HCl to provide 220 mg (73% yield). This intermediate (200 mg, 0.6 mmol) was dispersed in DMF (2 mL) in a microwave vial, and a solution of 3-aminomethyl-N-(3-dimethylaminomethyl-benzyl)-benzamide (200 mg, 0.7 mmol), prepared in a fashion analogous to 3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide (Example 3), in DMF (1 mL), was added. The vial was sealed and heated in a microwave at 150° C. for 70 min. The reaction mixture was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing 76 mg of product which was contaminated with the aniline by-product. To remove the aniline, the mixture was dissolved in a solution of methanol/acetonitrile (20/80, 10 mL) and divided into 10 portions each of which were loaded directly onto a Varian 50 mg SCX cartridge. Each cartridge was washed with 2×2 mL acetonitrile and 2×2 mL methanol, then treated with NH3 in methanol (7N, 2 mL) to elute the pure title compound (60 mg, 18.4% yield), MS analysis electrospray, 462 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CNC(=O)C(=NOC)c1cccc(Cl)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1cccc(Cl)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.12 g, 3.0 mmol) was added to a solution of 3-chloro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.43 g, 1.68 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.44 g, 1.87 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about two hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 0.72 g crude oil. The oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-chloro-benzeneacetamide (430 mg) as an oil. (95% E isomer; 5% Z isomer).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)(=[O:29])=[O:28]
Reactant: FC(F)(F)COc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (13.48 g, 50 mmol) was dissolved in DCM (500 mL) and cooled to 0° C. Triethylamine (29 mL, 0.2 mol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.2 mL, 55 mmol). The reaction was then allowed to warm to room temperature and stir overnight, before being quenched by the addition of water. The layers were separated, and the organic phase dried (MgSO4), filtered and concentrated. The residue was recrystallised from hot ethanol to give pure 1-(methylsulfonyl)-4-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (3.3 g, 18%).
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([Cl:13])=[O:12])=[C:9]([I:14])[C:8]([NH2:15])=[C:7]([I:16])[C:3]=1[C:4]([Cl:6])=[O:5].[C:17](Cl)(=[O:19])[CH3:18].O>CC(N(C)C)=O>[I:1][C:2]1[C:3]([C:4]([Cl:6])=[O:5])=[C:7]([I:16])[C:8]([NH:15][C:17](=[O:19])[CH3:18])=[C:9]([I:14])[C:10]=1[C:11]([Cl:13])=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 8 h
Yield: 99 %

Procedure:
To 2,4,6-triiodo-5-amino-isophthalic acid dichloride (150 g; 0.252 mole) in DMAC (300 ml) is added acetyl chloride (80 ml; 4 times the theoretical amount). The mixture is stirred overnight in an ice-water bath. It is then poured over water (1.5 liter). The resulting material is then filtered and washed twice with water, after which it is dried in an oven at 45° C, to give 159 g of product (i.e., in a yield of 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][C:36]1[N:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][C:36]3[N:37]([CH3:41])[CH:38]=[CH:39][CH:40]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: Cn1cccc1CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1cccc1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hr with a stream for nitrogen bubbling through it. A solution of 2-(2-aminoethyl)-1-methylpyrrole (5.40 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added and the mixture was stirred at room temperature under nitrogen overnight. The solvent was evaporated under reduced pressure and the resulting oil was triturated in water (100 ml) which caused a solid to form. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Water was added to the cloud point. Upon cooling, a solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 4.31 g (63%) of title compound, mp 171°-172.5° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])C.S(=O)(=O)(O)O>O>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])(=[O:11])[CH3:10]
Reactant: CCOC(CCCNC(C)=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NCCCC=O

Procedure:
Dissolve 5 gms. of 4-acetamidobutyraldehyde diethyl acetal in 75 ml. of distilled water and 5 ml. of 1 N sulfuric acid. Allow the solution to stand at room temperaure until the hydrolysis is complete as determined by thin layer chromatography. Neutralize the solution with sodium bicarbonate then saturate the solution with sodium chloride and extract with chloroform. Distill the combined chloroform extracts to a residue comprising 4-acetamidobutyraldehyde, which can be used without further purification in the following procedure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@:19]1([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:18][C@@:19]2([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)=[O:17])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)O)c1
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cncc(NC(=O)OC(C)(C)C)c2)CCOC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A suspension of 5-tert-butoxycarbonylamino-pyridine-3-carboxylic acid (2.5 mmol) in 20 mL tetrahydrofuran was combined with N,N-carbodiimidazole (2.75 mmol) and stirred for 15 minutes at ambient temperature. Then a solution of n-butyl(S)-3-amino-tetrahydrofuran-3-carboxylate (2.5 mmol) in 4 mL tetrahydrofuran was added and the reaction mixture was stirred further overnight. Then the solvent was distilled off and the crude product thus obtained was purified by chromatography (silica gel; dichloromethane with 1-25% ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].[I-].[Na+]>CS(C)=O.O>[C:21]([O:24][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:7]1[CH:6]=[C:5]([CH:19]=[O:20])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])(=[O:23])[CH3:22]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCC(C)(C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 100 °C
Reaction time: 10 h
Yield: 52.1 %

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 1d, 0.45 g) in dimethylsulfoxide (10 mL) was treated with sodium acetate (0.343 g) under nitrogen. The resulting mixture was stirred at 100° C. for 10 h. Sodium iodide (1 eq) was added and the reaction heated at 120° C. for 30 h. The reaction mixture was diluted with water (250 mL) and the solid filtered off and dried to afford the subtitle compound (0.25 g) as a solid.