Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NCc2cccnc2)c1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a stirred mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), 3-pyridinecarboxaldehyde (32.3 ml, 0.342 mmol), and acetic acid (65.5 ml, 1.14 mmol) in anhydrous methanol (4 ml) under nitrogen was added sodium cyanoborohydride (21.5 mg, 0.342 mmol) and the mixture was stirred for 3 h. The mixture was quenched with saturated aqueous K2CO3 (0.5 ml) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.1162 g (93%) of the title compound as a yellow solid; mp 284-287° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.13 (3H, s), 4.34 (2H, d, J 6.1 Hz), 6.39 (1H, t, J 6.1 Hz), 6.64-6.68 (3H, m), 7.17 (1H, t, J 7.7 Hz), 7.35 (1H, dd, J 7.9, J′4.9 Hz), 7.42 (2H, d, J9.0 Hz), 7.77 (1H, dt), 8.11 (2H, d, J 9.0 Hz), 8.44 (1H, m), 8.51 (1H, s), 8.61 (1H, s), 12.34 (1H, br s); MS (ES+) m/z 442/444[MH]+, 221/222[(M2H)/2]+. Anal. found: C, 67.08; H, 4.50; N, 15.54. C25H20ClN5O.0.3H2O requires: C, 67.13; H, 4.64; N, 15.66%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1>C(O)(C(F)(F)F)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)cc3)cc12
Yield: 6.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (100 mg, 0.176 mmol) was deprotected in TFA/methanol (3/3 ml). This afforded 5 mg (152% yield) of the titled compound after purification by preparative HPLC along with one more isomer Example 91. 1H NMR (CD3OD, 300 MHz): δ 8.51 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.72-7.67 (m, 2H), 7.51 (s, 1H), 7.42-7.34 (m, 3H), 7.06-6.87 (m, 3H), 5.46 (s, 2H), 3.61-3.51 (m, 2H), 3.21-3.13 (m, 2H), 3.02-2.94 (t, 1H), 2.37 (s, 3H), 2.15-2.11 (m, 2H), 2.02-1.89 (m, 2H). MS: m/z=466.2 (M+1), HPLC: 89.39% in method B.
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(Br)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.090 g, 0.47 mmol) and 4-bromoaniline (0.080 g, 0.47 mmol) in chloroform (3.0 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=1.O1CCOCC1.Cl>>[CH2:24]([O:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: CCOc1ccc(N)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.49 mmol), 5-amino-2-ethoxypyridine (Combi-Blocks, Inc., San Diego, Calif.), 1,4-dioxane (0.75 mL, 8.8 mmol), (Aldrich, St. Louis, Mo.) and 2 N aqueous HCl (0.24 mL, 0.49mmol) were added to a 50 mL round-bottomed flask. The suspension was stirred at 100° C. overnight. The crude product was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 20% methanol in dichloromethane to give 4-(2-(6-ethoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine LCMS (API-ES) m/z 324 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.80 (br. s., 1H); 8.83 (br. s., 1H); 8.27 (d, J=4.11 Hz, 1H); 8.26 (d, J=4.11 Hz, 1H); 8.11 (br. s., 1H); 7.82 (dd, J=2.93, 1.56 Hz, 1H); 8.81 (d, J=4.11 Hz, 1H); 6.92 (br. s., 1H); 6.86 (d, J=9.39 Hz, 1H); 4.28-4.37 (m, 2H); 2.44 (br. s., 3H); 1.33 (t, J=7.04 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]2[C:30]3[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=3[NH:24][C:23]([CH3:35])=[C:22]2[C:36]#[N:37])[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.N1C=CC=CC=1.[CH2:44]([S:47](Cl)(=[O:49])=[O:48])[CH2:45][CH3:46]>ClCCl>[C:36]([C:22]1[CH:21]([C:4]2[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[C:2]([NH:1][S:47]([CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])[CH:3]=2)[C:30]2[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=2[NH:24][C:23]=1[CH3:35])#[N:37]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc(OC)c2)c(OCC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(NS(=O)(=O)CCC)c(OCc2cccc(OC)c2)c(OCC)c1
Reaction time: 17 h

Procedure:
To a solution of 4-[3-amino-5-ethoxy-4-(3-methoxy-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (220 mg) and pyridine (106 μl) in dichloromethane (5 ml) was added propane-1-sulfonyl chloride (94 mg). After stirring for 17 h, the mixture was diluted with dichloromethane and extracted with water and sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Reaction SMILES: [Br:1][C:2](=[O:7])[CH:3](Cl)[CH2:4][CH3:5].[NH:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Br:1][C:2](=[O:7])[CH:3]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:8][C:9](=[O:10])[CH2:11][CH2:12]2)[CH2:4][CH3:5]
Reactant: O=C1CCc2ccccc2N1
Reactant: CCC(Cl)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(C(=O)Br)c1ccc2c(c1)CCC(=O)N2

Procedure:
A solution of α-bromobutanoyl chloride (78.9 g) in methylene chloride (50 ml) is added to a stirred mixture of 3,4-dihydrocarbostyril (31.3 g) and aluminum chloride (59.6 g) in methylene chloride (300 ml). The reaction mixture is stirred at reflux for about 3.5 hours, cooled, poured into a mixture of ice and water, resulting in the formation of a white precipitate which is filtered, washed with water, dried, and recrystallized from isopropanol, affording the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.[CH3:28][CH2:29][C:30](Cl)=[S:31].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:28][CH2:29][C:30]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12)=[S:31]
Reactant: CCC(=S)Cl
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=S)CC)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 11.34 g (0.026 mol) of 7-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml of acetone is added dropwise a solution of 3.66 g (0.029 mol) of methylthioacetyl chloride in 52 ml of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The aqueous phase is passed down a XAD-7 resin column and the product-containing fractions are combined, treated with Amberlite IR-120H ion-exchange resin and lyophilized to yield the title compound.
Reaction SMILES: N[C:2]1([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[CH2:6][S:5][CH:4]=[N:3]1.[OH-].[Na+].C[N:26]1C=CN=C1.CO>O1CCCC1>[NH2:26][C:4]1[S:5][CH:6]=[C:2]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: Cn1ccnc1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C1(N)CSC=N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 261.6 %

Procedure:
Ethyl 2-(4-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1 N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[CH:38]=[C:37]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=4)[N:39]([CH3:43])[CH:38]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 106B) (160 mg, 0.557 mmol) in N,N-dimethylformamide (3.21 mL) was added saturated aqueous bicarbonate solution (1.07 mL) followed by bis(triphenylphosphine) palladium dichloride (21.06 mg, 0.030 mmol). The mixture was heated to 70° C. for 2 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. LCMS TFA(+) m/z 602.99 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[N+:19]=[N-].[Na+].O>S(=O)(=O)(O)O.C(O)(=O)C>[N:8]([C:7]1[C:6]([Cl:5])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=1[Cl:17])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (3.2 g) in concentrated sulphuric acid (22 ml) was added dropwise with cooling to a solution of 2,6-dichloro-4-trifluoromethylaniline (9.3 g) in glacial acetic acid (48 ml). The mixture was stirred at room temperature for half an hour and then cooled to 0°-5°. A solution of sodium azide (2.6 g) in the minimum volume of water was added dropwise with cooling and the mixture stirred at 0°-5° for 1 hour and then at room temperature overnight. The mixture was poured into ice/water, extracted with dichloromethane and the extract worked up in conventional manner to give 1-azido-2,6-dichloro-4-trifluoromethylbenzene, as a red oil. A solution cf this oil (25.6 g) and 2-propyn-1-ol (40 ml) in xylene (80 ml) were stirred under nitrogen and heated under reflux overnight. The mixture was cooled and the solvent was evaporated under reduced pressure. Trituration of the residue with light petroleum (bp 30°-40°) gave a crude material which was purified by filtration through silica to give [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl]methanol, m.p.123°-125°.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[CH3:17]I>CN(C=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:10]([OH:16])=[N:11][C:12]([S:15][CH3:17])=[N:13][CH:14]=1)(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1c[nH]c(=S)[nH]c1=O
Reactant: CI
Solvent: CN(C)C=O
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
N-(1,1-Dimethylethyl)-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinesulfonamide (30.69 g, 116.7 mmol) was dissolved in DMF (300 mL) and methyliodide was added (8.72 mL, 140 mmoles) and the mixture was stirred at ambient temperature for 24 hours. An additional quantity of methyliodide (2.5 mL) was added and the reaction stirred an additional 24 hours. A final addition of methyliodide (2.0 mL) was made followed by another 24 hours of stirring to complete the reaction. The DMF was removed under reduced pressure, the residue was suspended in water (300 mL), sodium carbonate was added until the solution was neutralized, then the pH was adjusted to 8 with sodium hydroxide pellets. The aqueous solution was filtered, extracted with three 150 mL portions of ethyl acetate. The pH of the aqueous portions was adjusted to 3 with 37% HCl, the white solid that precipitated out was filtered, washed with water, and dried in a vacuum oven to yield 20.16 gm (72.78 mmol, 62%) of product which was used as is in the next step. An analytical sample crystallized from ethanol/water, had a m.p. 225.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH:28]=O)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:33])[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:28][NH:33][CH2:30][CH2:31][CH3:32])([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:26])([CH3:27])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCN
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCNCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.4 %

Procedure:
A slurry of ethyl 2-(tert-butoxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (172 mg, 0.42 mmol) and propylamine (40 μL, 0.49 mmol, 1.3 equiv) in 1,2-dichloroethane (3 mL) was treated with sodium triacetoxyborohydride (352 mg, 1.66 mmol, 4 equiv). Acetic acid (2 drops, ca 3-5 equiv) was added and the mixture stirred at room temperature for 17 hours then 60° C. for 1 hour. Once the reaction was complete, saturated aqueous sodium bicarbonate was added and the solution was extracted with dichloromethane. The organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by flash chromatography (0-60% ethyl acetate in hexane) gave ethyl 2-(tert-butoxycarbonylamino)-2-((propylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as an oil (66 mg, 34%). 1H NMR (CDCl3, 400 MHz) δ 4.16 (m, 2H), 3.5-3.3 (m, 2H), 3.2 (br m, 2H), 2.9 (m, 1H), 1.8-1.6 (m, 4H), 1.5-1.4 (m, 2H), 1.38 (s, 9H), 1.36-1.3 (m, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.18 (s, 12H), 1.05 (m, 1H), 0.75 (t, J=7.4 Hz, 3H), 0.68 (t, J=7.5 Hz, 2H). ESI+ MS: obsd m/z 457 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(Cl)(Cl)[Cl:15]>>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][C:10]=1[Cl:15]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-4-aminophenylacetate (20 g, 112 mmol) was dissolved in chloroform (300 ml) and treated with N-chlorosuccinimde (14.92 g, 112 mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-45%) in hexane to give the title compound as a orange oil (10.12 g, 47.4 mmol). LC/MS: Rt=2.59, [MH]+ 214.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([NH:20][NH2:21])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([C:12]2[N:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]3=[N:21][N:20]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1nccc2ccccc12
Solvent: CCO
Product: c1ccc(-c2nnc3c4ccccc4ccn23)cc1
Yield: 3.3 %

Procedure:
To a solution of 1-chloro-isoquinoline (4 g, 24.45 mmol) in ethanol (50 ml) was added benzoic acid hydrazide (4 g, 29.34 mmol) and the mixture was stirred at reflux temperature for 16 hrs. The reaction mixture was cooled and the precipitate was filtered off and recrystallised from ethanol (50 ml) affording 1.9 g of impure (NMR) tile compound. The filtrate was purified by silicagel chromatography using a mixture of ethyl acetate/heptane (1:2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 0.2 g (3%) of the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=O)[O:9][N:8]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:15]([C@@H:13]2[CH2:14][C@@H:12]2[C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)=[O:17])[CH2:28][CH2:29]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Reaction time: 24 h
Yield: 19 %

Procedure:
Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.139 g) and N,N′-carbonyldiimidazole (0.110 g) in dichloromethane was stirred under nitrogen for 1 hour. 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198 g), and triethylamine (0.121 g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to leave Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide (0.054 g) as a white solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 2-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C23H17F3: Calcd: C, 78.84 H, 4.89; Found: C, 78.65 H, 4.96. HPLC (ISO80-10M)) t=16.67 min (99%).
Reaction SMILES: [CH3:1][SH:2].C[O-].[Na+].Br[CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:11]>CO>[CH3:12][C:9]([CH3:13])([CH2:10][F:11])[C:8](=[O:14])[CH2:7][S:2][CH3:1]
Reactant: CC(C)(CF)C(=O)CBr
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)C(C)(C)CF
Temperature: 20 °C
Reaction time: 12 h
Yield: 77.3 %

Procedure:
40 g (0.83 mol) of methylmercaptan were passed into 150 ml of methanol at -20° C. A solution of 45 g (0.83 mol) of sodium methylate in 200 ml of methanol was then added dropwise to the same temperature. 154 g (0.78 mol) of 1-bromo-3,3-dimethyl-4-fluoro-butan-2-one were now added dropwise at 0° C. The mixture was stirred for a further 12 hours at 20° C., the inorganic precipitate was filtered off and the filtrate was distilled. 99 g (77% of theory) of 3,3-dimethyl-4-fluoro-1-methylthio-butan-2-one of boiling point 86° C./10 mm Hg were obtained. ##STR30##
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][CH3:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CSc1ccccc1N=C=O
Product: CSc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 60.9 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-methylthio phenylisocyanate(3.24 mmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H)+.