Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (CDCl3) mixture of rotamers δ 10.20 (1H, br), 8.56 and 8.52 (1H, s), 7.38 and 7.10 (1H, s), 7.16-7.09 (2H, m), 7.04-6.98 (2H, m), 5.21 and 4.98 (2H, s), 4.11 (2H, s), 3.74-3.50 (10H, m), 3.34 and 3.32 (3H, s), 3.18 and 2.97 (3H, s), 1.22 and 1.23 (3H, t, J=7 Hz); HRMS calcd for C26H31FN4O6+H+: 515.2306. Found: 515.2293.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Product: O=c1cc(N2CCN(Cc3cc([N+](=O)[O-])ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-nitro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-nitrobenzaldehyde. Mass spectrum (ES) MH+=332.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].N1C=CC=CC=1.CC1C=CC(S(OCC23CCC(C4SC(C)=NC=4C4C=CC=CC=4)(CC2)OC3)(=O)=O)=CC=1>C(Cl)Cl.[OH-].[Na+].CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:27]([C:29]1[CH:34]=[C:33]([CH:32]=[CH:31][CH:30]=1)[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)#[N:28]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(Oc2cccc(C34CCC(CCOCC(=O)O)(CC3)CO4)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (7F; 29 mg, 0.080 mmol), (3-cyanophenyl)boronic acid (24 mg, 0.160 mmol), TEA (0.2 mL, 1.44 mmol), pyridine (0.2 mL, 2.473 mmol), Cu(OAc)2 (16 mg, 0.088 mmol), 4A Molecular sieves (200 mg) in DCM (1 mL) was stirred under air at rt for 3 days. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (5 mL) and 1N aq. HCl (5 mL). The organic phase was washed with water (5 mL×5), dried (MgSO4), and concentrated in vacuo to provide the crude 3-cyanophenoxyphenyl t-butyl ester intermediate. This material was taken up in 1N aq. NaOH in MeOH (1 mL) and stirred at rt for 2 h, then was concentrated in vacuo. The residue was acidified to pH=5 with 1N aq. HCl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The crude material was purified by preparative LC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% TFA; Mobile Phase B: 95:5 MeCN:water with 0.1% TFA; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (17 mg, 0.040 mmol, 50% yield) as a clear oil. LCMS [M−H]+=406.1; 1H NMR (DMSO-d6) δ: 7.62-7.55 (m, 2H), 7.47 (d, J=2.6 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (dt, J=5.9, 2.8 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.09 (s, 1H), 6.92 (dd, J=8.0, 2.4 Hz, 1H), 3.96 (s, 2H), 3.75 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 2.12-1.99 (m, 2H), 1.87-1.74 (m, 2H), 1.72-1.57 (m, 4H), 1.40 (t, J=6.8 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-phenoxybenzoate (0.067 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water and 2-propanol were added to the residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.053 g of 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-phenoxybenzoic acid as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][O:12][C:11](=[O:15])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:12][CH2:13][CH2:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1)[CH2:10][C:11]([NH:19][NH2:20])=[O:15]
Reactant: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-(3-Trifluoromethylphenyl)tetrahydropyran-2-one (2.5 g) was dissolved in ethanol (10 mL), and hydrazine monohydrate (4.96 mL) was added at room temperature. The mixture was stirred at 80° C. for 4.5 hours and then concentrated under reduced pressure. The resulting oil was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride five times. After drying over magnesium sulfate, concentration under reduced pressure and purification by silica gel column chromatography (amino silica gel, mobile phase:ethyl acetate/heptane=0 to 50%→methanol/ethyl acetate=10%) gave the title compound (1.55 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.S(Cl)([Cl:18])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)Cc1cc([N+](=O)[O-])cc(Cl)c1Cl

Procedure:
By the method of Example 1, Step E, 18.27 grams (0.073 mole) of 2,3-dichloro-5-nitrophenylacetic acid and 80 mL of thionyl chloride were reacted in 400 mL of carbon tetrachloride, yielding 20.90 grams of 2,3-dichloro-5-nitrophenylacetyl chloride. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][NH:12][C:13]1[NH:23][C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32][CH3:33])=[C:27]([Br:34])[CH:26]=3)[C:17]([N:19]=[CH:20][CH:21]=2)=[O:18])[N:14]=1.I[CH3:36]>CN(C=O)C.C1COCC1>[CH3:11][NH:12][C:13]1[N:23]=[C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:26]=[C:27]([Br:34])[C:28]([O:32][CH3:33])=[C:29]([Br:31])[CH:30]=3)[C:17]([N:19]([CH3:36])[CH:20]=[CH:21]2)=[O:18])[N:14]=1
Reactant: CI
Reactant: CNc1nc2c(Cc3cc(Br)c(OC)c(Br)c3)c(=O)nccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1nc2ccn(C)c(=O)c(Cc3cc(Br)c(OC)c(Br)c3)c-2n1
Temperature: -78 °C
Yield: 43.6 %

Procedure:
Sodium bis(trimethylsilyl)amide (1 M in THF, 24 μL, 0.0240 mmol) was added dropwise to a solution of ceratamine B from Example 12 (formula (IIIB); R1=methyl) (12.1 mg, 0.0266 mmol) in DMF:THF (1:1, 0.27 mL) at 0° C. The reaction mixture was cooled to −78° C. and iodomethane (2.1 μL, 0.0346 mmol) was added dropwise followed by warming to −10° C. The reaction was quenched by the addition H2O (2 mL), and was extracted with EtOAc (6×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford crude ceratamine A (formula (IIIA); R1=methyl). Purification by flash chromatography (C-18 reverse-phase silica, 70% MeOH:H2O) yielded pure ceratamine A (formula (IIIA); R1=methyl) (5.4 mg, 0.0116 mmol, 43%) as a yellow solid. The major tautomer was characterized: 1H NMR (400 MHz, DMSO) δ 8.68 (m, NH), 7.74 (d, J=9.9 Hz, 1H), 7.66 (s, 2H), 6.42 (d, J=9.9 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.07 (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 175.6, 169.7, 164.1, 160.5, 151.4, 142.9, 140.2, 133.1, 121.3, 116.6, 100.4, 60.3, 43.7, 35.0, 29.2; HRMS (ESI) m/z calcd for C17H17Br2N4O2: 466.9713. found: 466.9701. These data from synthetic ceratamine A are consistent with data reported for natural products.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=2)[CH:10]=1)[CH3:2].[NH2:26][NH2:27]>CC#N>[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23]3[C:20]([C:21]([NH2:22])=[N:26][NH:27]3)=[CH:19][CH:18]=2)[CH:10]=1)[CH3:2]
Reactant: CC[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Reactant: NN
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(NC)n1
Yield: 28.5 %

Procedure:
4-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.464 g, 1.359 mmol) was taken up in CH3CN (5 mL) followed by the addition of hydrazine (0.171 mL, 5.44 mmol) and Hunig's (1.899 mL, 10.87 mmol) in a 20 mL microwave vial. The reaction was irradiated at 150° C. for 1 hour. The reaction mixture was then concentrated and the resulting residue was purified using reverse phase HPLC (5-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution (2×) that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (137 mg) as a white fluffy powder. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, 3H), 1.60-1.82 (m, 2H), 2.83 (d, J=4.0 Hz, 3H), 3.10 (d, J=2.3 Hz, 1H), 3.43 (d, J=2.5 Hz, 1H), 3.52 (dd, J=11.5, 2.9 Hz, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.89 (dd, J=11.2, 3.2 Hz, 1H), 4.03 (q, J=7.1 Hz, 1H), 4.14-4.26 (m, 1H), 4.29-4.38 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.97 (bs, 1H), 11.50 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(O[I:15](OC(=O)C)[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=O)C.[F:29][B-:30]([F:33])([F:32])[F:31].C1([I+]C2C=CC=CC=2)C=CC=CC=1.F[B-](F)(F)F.[Na+]>C(Cl)Cl>[F:29][B-:30]([F:33])([F:32])[F:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I+:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)OI(OC(C)=O)c1c(C)cc(C)cc1C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c([I+]c2ccc(Cl)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
4-Chlorophenylboronic acid (3.0 g, 8.2 mmol), methylene chloride (82 ml) and boron trifluoride ethyl ether complex (1.29 g, 9.1 mmol) were charged and cooled to 0° C. A solution of diacetoxy(2,4,6-trimethylphenyl)iodine (III) (3.0 g, 8.2 mmol) synthesized in (i) in methylene chloride (82 ml) was added dropwise, and the reaction was carried out at 0° C. for 1.5 hours. A saturated aqueous solution of sodium fluoroborate (18.1 g, 164.8 mmol) was added dropwise, and the mixture was extracted with addition of water and methylene chloride. The organic layer was dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by recrystallization to give the title compound (3.36 g, 93.5%).
Reaction SMILES: [C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 101.4 %

Procedure:
To a solution of (2R,5S)—N′-acetyl-6-(benzyloxy)-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 213 (0.20 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)—N′-acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 214 (0.15 g, 99%) as a colorless foam.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[C:1]([CH2:3][NH:4][C:5](=[O:6])[C@@H:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)C[C@H](Nc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C[C@H](Nc1ccc(-c2ccc(N3CCNCC3)cc2)cc1)C(=O)NCC#N

Procedure:
To tert-butyl 4-{4′-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate (122 mg, 0.242 mmol) in dry TB (5 mL) under dry nitrogen was gradually added a total of 10 equivalents of MeSO3H (160 μL, 2.42 mmol) over a period of 5 days in portions of 1–2 equivalents at a time. Aqueous sat. NaHCO3 was added carefully and the product was extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1.5/13.5/85) to afford (2S)-N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]amino}pentanamide. MS (+ESI): 406.9 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[OH-].[Na+]>CC(C)=O>[CH3:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCN3CCOCC3)cc2c1=O
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (885 mg) was dissolved in acetone (50 ml), sodium iodide (45 mg) and potassium carbonate (4.14 g) were added followed by 4-(2-chloroethyl) morpholine hydrochloride (1.68 g). The resultant mixture was stirred at 60° C. for 18 hours. 2N NaOH (9.4 ml) was added and stirred for 20 minutes, cooled and the insoluble material removed by filtration. The filtrate was concentrated, acidified to pH 1 with concentrated hydrochloric acid and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[7-(2-morpholin-4-ylethoxy)-1-oxoisoquinolin-2(1H)-yl]benzoic acid as an oil (720 mg); NMR Spectrum: (DMSOd6) 2.00 (s, 1H), 2.60 (m, 4H), 2.80 (m, 2H), 3.18 (m, 4H), 3.75 (m, 2H), 6.40 (d, 1H), 6.80 (d, 1H), 7.03 (d, 1H), 7.20 (m, 1H), 7.40 (d, 1H), 7.75 (m, 3H); Mass Spectrum: M+H+ 409.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:29]COCC>CN(C)C=O.[Ag]=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:29])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-hydroxy-pyrazolidine-1-carboxylic acid benzyl ester, 28, (2.55 g, 7.91 mmol) is dissolved in dimethylformamide (40 mL). Methyl iodide (1.97 mL, 31.6 mmol) is added followed by silver oxide (3.67 g, 15.8 mmol). The flask is cover with foil and stirred overnight in the absence of light. The reaction mixture is poured into ether (150 mL). The mixture is stirred vigorously at room temperature and filtered through a pad of Celite. The filtrate is washed with water (2×150 mL) and brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.58 g (97% yield) of the desired product as a yellow, clear oil.
Reaction SMILES: [I:1]I.Br[C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1>>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:4]=1[I:1]
Reactant: O=C(Nc1nc(-c2ccco2)c(Br)s1)c1ccccc1
Reactant: II
Product: O=C(Nc1nc(-c2ccco2)c(I)s1)c1ccccc1
Yield: 55.9 %

Procedure:
In a manner similar to that in Example 92, by using iodine (26.3 g, 104 mmol) in place of DMF and using N-[5-bromo-4-(2-furyl)thiazol-2-yl]benzamide (10.3 g, 29.6 mmol) obtained in Step 1 in place of Compound h, the entitled Compound n (6.56 g, 56%) was obtained as a white solid.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[C:15]1(N2CCOCC2)[CH2:19][CH2:18][CH2:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[C:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)=[N:13]1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@H](c2noc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (0.900 g, 4.10 mmol) and 4-cyclopentenylmorpholine (1.23 ml, 8.19 mmol) in dichloromethane (21 ml) was added triethylamine (0.714 ml, 5.12 mmol) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvent was evaporated. The residue was redissolved in 6 M aqueous hydrogen chloride solution (20.5 ml) and stirred at reflux for 4 h. After cooling to room temperature the reaction mixture was poured on ice, basified with 2 M aqueous sodium hydroxide solution (80 ml) and washed with two 50-ml portions of ethyl acetate. The combined organic layers were extracted with two 50-ml portions of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2-3 by addition of concentrated hydrochloric acid and extracted with three 100-ml portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (50 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.060 g, 6%) as off-white solid. MS m/e: 234 ([M−H]−)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ccc2c(Br)cccc21
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 51 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of n-butyllithium in pentane (28.8 ml) over 30 minutes and stirred for 30 minutes. The mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) added with ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was acidified with 5 N aqueous hydrochloric acid under ice cooling and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 52, 3.17 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (80.0 mg) obtained in Step A of Example 141 in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 24.6 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 3-bromopentane (93.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (51.8 mg).