Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:31]1([CH2:34][NH2:35])[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][NH:35][C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH2:33][CH2:32]1
Reactant: NCC1CC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC1CC1)O2
Yield: 73 %

Procedure:
Following the amide coupling procedure described in protocol A, 502 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 356 mg CDI (2.20 mmol) and 158 mg cyclopropanemethylamine (2.22 mmol produced 445 mg of N-(cyclopropylmethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a clear colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[NH:10][C:11]1[C:12]2[C:19]3[CH2:20][CH2:21][NH:22][CH2:23][C:18]=3[S:17][C:13]=2[N:14]=[CH:15][N:16]=1.Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[NH:10][C:11]1[C:12]2[C:19]3[CH2:20][CH2:21][N:22]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:23][C:18]=3[S:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Oc1ccc(Cl)c(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)ccc4Cl)c23)C1

Procedure:
The compound was synthesized in analogy to Example 122 from 4-chloro-3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 70A (100 mg, 0.27 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (63 mg, 0.38 mmol) to yield 17 mg (13%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH:5]=1.[C:18](Cl)([CH3:21])([CH3:20])[CH3:19]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:18]([CH:5]1[CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:9][C:4]1=[O:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)OC1=CCC(c2ccccc2)CC1
Reactant: CC(C)(C)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CC(c2ccccc2)CCC1=O
Temperature: -45 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
Trimethyl-(4-phenyl-cyclohex-1-enyloxy)-silane (7.27 mmol) and tert-butyl chloride (7.85 mmol) are introduced first in dichloromethane under nitrogen and cooled to −45° C. A solution, also cooled to −45° C., of titanium tetrachloride (7.63 mmol) in dichloromethane (3.6 ml) is added, and stirring is continued for 3 hours at this temperature. The reaction mixture is diluted with dichloromethane and washed with ice water. The organic phase is dried over sodium sulphate and the solvent is removed in a vacuum. Column chromatography (ethyl acetate/heptane 1:4) of the residue produces the title compound (250 mg) in a yield of 15% (Angew Chem Int Ed Engl 1978, 17, 1, 48-49). 1H NMR (ppm, CDCl3): 7.35 (5H); 3.15 (1H); 2.55 (1H); 2.4 (3H); 2.25 (1H); 2 (1H); 1.8 (1H); 1.05 (9H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:15][CH:16]([NH2:24])[CH2:17][CH2:18][CH2:19][C:20](O)([CH3:22])[CH3:21].Cl>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:24])[CH3:15])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(N)CCCC(C)(C)O
Reactant: CCCCCCCCc1ccccc1
Agent: Cl
Product: CCCCCCCCc1ccc(C(C)(C)CCCC(C)N)cc1

Procedure:
6-(4-n-Octylphenyl)-6-methyl-2-heptylamine b0.26 162°-6° was prepared following the procedure of Example 3 from n-octylbenzene and heptaminol hydrochloride.
Reaction SMILES: C(O[C:4](=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](OCC)=[O:8])[CH3:5])C.Cl.[CH:18]([NH2:20])=[NH:19].[OH-].[K+].C(O)(=O)C>C(O)C.O.C(OCC)(=O)C>[OH:8][C:7]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH3:5])[N:20]=[CH:18][N:19]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)ncnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of diethyl malonate (4.8 mL), triethyl orthoacetate (17 mL), acetic anhydride (0.11 mL) and zinc chloride (1.2 g) was stirred at 140° C. To the mixture was added acetic anhydride (0.11 mL) each after 30, 90 and 120 minutes, and then stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−7/3) to give diethyl 2-(1-ethoxyethylidene)malonate (5.02 g). To a solution of diethyl 2-(1-ethoxyethylidene)malonate (4.13 g) in ethanol (15 mL) were added formamidine hydrochloride (1.73 g) and a solution of potassium hydroxide (2.21 g) in water (7.5 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized by adding acetic acid. To the mixture was added ethyl acetate (30 mL), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (1.5 g).
Reaction SMILES: O=[CH:2][C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+].Cl>CN(C=O)C.COC(OC)OC.C(O)(=O)C.CO>[CH2:25]([NH:30][CH2:2][C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC(C=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)CNCC(CNC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A mixture of tert-butyl 3-oxo-2,2-diphenylpropylcarbamate (0.10 g, 0.307 mmol) in DMF (4 mL) and trimethylorthoformate (4 mL) was treated with neopentylamine (0.054 g, 0.615 mmol), sodium triacetoxyborohydride (0.098 g, 0.461 mmol) and acetic acid (2 drops) and the reaction was stirred at 23° C. overnight. LC/MS shows only formation of the imine. The reaction was then treated with sodium borohydride (0.050 g, 1.32 mmol) and methanol (˜2 mL) and stirred at 23° C. for 30 minutes. The reaction was acidified with 1N HCl and washed with diethyl ether. The aqueous phase was basified with sat. aq. sodium bicarbonate, extracted with diethyl ether (3×) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude tert-butyl 3-(neopentylamino)-2,2-diphenylpropylcarbamate (0.055 g, 45%) as an oil. 1H NMR (400 MHz, CDCl3) δ: 0.82 (9H, s), 0.92-0.96 (2H, m), 1.42 (9H, s), 2.35 (2H, s), 3.47 (2H, s), 3.86 (2H, d, J=4.80 Hz), 7.15 (1H, br s), 7.17-7.26 (6H, m), 7.28-7.34 (4H, m). HPLC ret. time (Condition A): 2.68 min. LC/MS (M+H)+: 397.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)=[N:12][N:11]=[N:10]1.Br[C:31]1[S:40][C:39]2[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34][C:33]=2[CH:32]=1.C([O-])(O)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:29][C:15]1[N:16]=[CH:17][C:18]([C:31]2[S:40][C:39]3[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34][C:33]=3[CH:32]=2)=[CH:19][C:14]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:10]=[N:11][N:12]=1
Reactant: CCOC(=O)N1CCc2cc(Br)sc2CC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2cc(-c3cnc(N)c(-c4nnnn4-c4cccc(F)c4F)c3)sc2CC1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.50 g, 6.3 mmol), ethyl 2-bromo-4,5,7,8-tetrahydrothieno[3,2-d]azepine-6-carboxylate (1.91 g, 06.3 mmol), and NaHCO3 (15.6 mL, saturated solution in H2O) in N,N-dimethylformamide (83 mL) was degassed with a nitrogen stream for 20 min. To this mixture was added [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (460 mg, 0.6 mmol) and the reaction was stirred in a microwave for 10 min at 120° C. The resulting crude mixture was diluted with ethyl acetate (300 mL) and filtered. The filtrate was washed with H2O (2×150 mL) and brine (1×150 mL), concentrated under reduced pressure, and purified via silica gel chromatography to provide ethyl 2-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-4,5,7,8-tetrahydrothieno[3,2-d]azepine-6-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1>>[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1)(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)C(=O)Nc1ccccc1I
Product: CC(C)C(=O)Nc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared by Procedure W and Scheme AF using N-(2-iodophenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 245.1 (M−100)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[C:26]([F:39])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1Cl>CC(C)CO.C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([F:39])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1[O:23][CH2:19][CH:14]([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)CO
Product: CC(C)COc1ncc(-c2nc(-c3ccc(OCC(=O)O)c(F)c3)no2)cc1Cl
Temperature: 130 °C

Procedure:
Lithium bis(trimethylsilyl)amide (225 μl; 1 M; 0.22 mmol) was added to a solution of tert-butyl {4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-fluorophenoxy}acetate (66.04 mg; 0.15 mmol) in 2-methyl-1-propanol (1.50 mL) and THF (2 mL). The resulting mixture was heated at 130° C. for 10 min in the microwave. A mixture of the desired product and the isopropyl ester was isolated. NaOH (5N solution; 5 eq; 0.15 mL) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and washed with HCl 1N, brine and dried over MgSO4. After evaporation of the solvents, the title product was isolated as white solid (51 mg; 81%). 1H NMR (DMSO-d6, 300 MHz) δ 13.25 (br s, 1H), 8.91 (d, J=2 Hz, 1H), 8.57 (d, J=2 Hz, 1H), 7.90-7.86 (m, 2H), 7.32 (t, J=9 Hz, 1H), 4.91 (s, 2H), 4.27 (d, J=6 Hz, 2H), 2.12 (m, 1H), 1.02 (d, J=6 Hz, 6H). LC/MS (Method B): 420.3 (M−H)−. HPLC (Method A) Rt 5.29 min (Purity: 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[N:7]([C:21]1[N:22]([C:26]2[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([O:35]CC3C=CC=CC=3)=[CH:28][C:27]=2[O:43]CC2C=CC=CC=2)[N:23]=[N:24][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[OH:43][C:27]1[CH:28]=[C:29]([OH:35])[C:30]([CH:32]([CH3:34])[CH3:33])=[CH:31][C:26]=1[N:22]1[C:21]([N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[C:6](=[O:51])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:25][N:24]=[N:23]1
Reactant: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(O)cc1O
Reaction time: 1 h

Procedure:
A mixture of Pd(OH)2/C (0.02 mmol), [3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-(4-morpholin-4-yl-benzyl)-carbamic acid t-butyl ester (138 mg, 0.2 mmol) in EtOH (5 ml) was subjected to one atmosphere of H2 for 1 hour. The catalyst was filtered off through Celite® pad and ethanol was then removed under reduced pressure. The crude reaction mixture was used in the next reaction without any purification.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[OH:33][CH2:32][CH2:34][NH:35][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:16][CH:17]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1
Reactant: NCCO
Reactant: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CO)cn23)n[nH]1
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CNCCO)cn23)n[nH]1

Procedure:
The title compound was synthesized using N-(4-(2-(hydroxymethyl)-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-7-ylthio)phenyl)cyclopropanecarboxamide and ethanol amine using the procedure described in Example 283. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.32 Hz, 4H) 1.82 (dt, J=12.44, 6.28 Hz, 1H) 2.11 (s, 3H) 2.83-2.92 (m, 2H) 3.53-3.62 (m, 2H) 4.01 (s, 2H) 4.90 (s, 1H) 5.86 (s, 1H) 6.47 (s, 1H) 7.53 (d, J=8.08 Hz, 2H) 7.75 (d, J=7.83 Hz, 2H) 8.26 (s, 1H) 10.36 (s, 1H) 10.48 (s, 1H) 12.12 (s, 1H); ESI-MS: m/z calc'd for C23H26N8O2S 478.57; found 479.4 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([C@@H:8]([NH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)(C)C.[Pd]>[CH:2]1([C@@H:8]([NH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)CN[C@@H](C(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)CN[C@@H](C(=O)O)C1CCCCC1
Yield: 201.4 %

Procedure:
Benzyl (2R)-2-cyclohexyl-2-[(2-ethoxy-2-oxoethyl)amino]ethanoate hydrochloride (40 g, 0.1 mol, from step (b) above) dissolved in iso-propyl alcohol (320 mL) was hydrogenated in the presence of 5% Pd/C (2 g, 50% aq.) for 3 h at 30° C. After removal of the catalyst by filtration, the filtrate was neutralised with tetrabutylammonium hydroxide and the pH was adjusted to 5.2. To rid the resultant of water, the suspension was evaporated and washed repeatedly with iso-propylalcohol and dried to yield 49 g (94%) of the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccccc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 25.6 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), phenylboronic acid (13.2 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis (triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered. and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (10 mg, 0.023 mmol, 25% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.97 (br. s., 1H), 10.16 (t, J=5.56 Hz, 1H), 7.69 (d, J=7.33 Hz, 2H), 7.55 (dd, J=11.62, 1.52 Hz, 1H), 7.51-7.43 (m, 3H), 7.38-7.42 (m, 1H), 7.35 (t, J=7.96 Hz, 1H), 5.34 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (sept, J=6.82 Hz, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7](/[CH:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[N+:1]([C:4]1[O:8][C:7]([CH2:9][NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Yield: 81.7 %

Procedure:
5-[1-(4-[(E)-1-(5-Nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9a, 0.38 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10a, 315 mg, 82%).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH3:13])[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][C:15]1([CH3:36])[CH:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([OH:35])=[CH:20][CH:21]=2)[O:16]1>>[CH2:2]([N:9]([CH2:10][CH2:11][O:35][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:24][C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:21][CH:20]=1)[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Product: CN(CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1)Cc1ccccc1
Yield: 49 %

Procedure:
Reaction of N-benzyl-N-(2-chloroethyl)methylamine hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound (49%) as a colourless oil, The hydrochloride salt had m.p. 112°-115° C. decomposed.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](/[C:22](=[CH:12]/[C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[C:6]3[CH3:11])/[C:23]#[N:24])=[O:25])=[CH:19][CH:20]=1
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Product: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(Cl)cc3)cc12

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 500 mg (2.81 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 566 mg (3.09 mmol) 3-(4-chlorophenyl)-3-oxopropanenitrile to yield 830 mg (66% of th.) of the crude product (76% purity) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:28])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[OH:28])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-{1-[2-(4-fluorophenyl)-2-oxo-ethyl]-piperidin-3-ylmethyl}-urea (23 mg, 48 μmol) in methanol (1.0 mL) was treated with sodium borohydride (4.5 mg, 120 μmol) and the mixture was stirred at room temperature. After 3 hours and again after 5 hours, additional sodium borohydride (ca. 2 mg) was added. After a total of 7 hours, water (0.5 mL) was added, and the mixture was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonia, to provide a white glassy solid (21 mg, 91%). This material was a 1:1 mixture of epimers at the hydroxyl group. 1H NMR (300 MHz, CDCl3) δ8.25+8.16 (2s, 1H), 7.75+7.70 (2s, 1H), 7.54 (s, 1H), 7.30 (m, 2H), 7.05 (s, 1H), 7.00 (t, J=9 Hz, 2H), 6.21+6.13 (2 bt, 1H), 4.71 (m, 1H), 4.15+4.14 (2 s, 3H), 3.3-3.1 (m, 3H), 3.0-2.7 (m, 3H), 2.60 (q, J=8 Hz, 2H), 2.5-2.3 (m, 3H), 2.3-2.1 (2m, 1H), 1.9-1.5 (m, 4H), 1.20+1.19 (2 t, J=8 Hz, 3H) Mass spec (ES+) m/z 482.4 (M+H+).