Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:55][CH2:54][O:53][CH2:52]C1>>[C:8]([C:6]1[N:7]=[C:2]([C:14]2[CH:15]=[CH:16][CH:55]=[C:54]([O:53][CH3:52])[C:13]=2[C:12]#[N:11])[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: C1COCCO1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2nc(C(N)=O)c(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)nc2N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (220 mg), neopentyl glycol ester 2-cyano-3-methoxyphenylborate (164 mg), and tetrakistriphenylphosphine palladium (0) (39 mg), dioxane (8.8 mL) was added a 2 M aqueous sodium carbonate solution (836 μL), followed by stirring at 100° C. for 3 hours under an argon atmosphere. After leaving to be cooled, the mixture was subjected to liquid separation by the addition of ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-(2-cyano-3-methoxyphenyl)-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (208 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([F:18])=[CH:13][CH:12]=2)=[O:7])C.Cl>CO>[F:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:17]2
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2ccc(F)cc2c1

Procedure:
3 N aqueous sodium hydroxide (5 mL, 15 mmol) was added to a solution of 6-fluoro-quinoline-3-carboxylic acid ethyl ester (2.2 g, 10 mmol) in methanol (50 mL). A heavy precipitate developed, and the mixture was diluted with an additional 50 mL of methanol to facilitate stirring. The mixture was stirred for 3 hours, then neutralized with of 1N hydrochloric acid (15 mL). The methanol was evaporated in vacuo, and the slurry diluted with water. The product was collected by filtration and washed with water, to give the product, 1.76 g (92%) as a colorless solid. MS: m/z 192.1 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35]>>[CH3:36][C:31]1[C:30]([CH2:29][N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1noc(C)c1CCl
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(C)c1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-(chloromethyl)-3,5-dimethylisoxazole, to give the desired product as a white solid (66%).
Reaction SMILES: C([C:3]([OH:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:4]1[N:8](C)[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)#N.[OH-].[Na+]>CCOCC>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]([C:4]2[NH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2)=[O:22])=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(C(O)(C#N)c2ccc(C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)[nH]1
Yield: 93.6 %

Procedure:
Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-methylpyrrole-2-acetate (0.161 g, 0.540 mmoles) was dissolved in 30 ml of ether and shaken with 10 percent NaOH, washed with brine and dried over MgSO4. Evaporation of the ether yielded 0.130 g (86.1 percent) of methyl 1-5-(4-methylbenzoyl)pyrrole-2-acetate, mp 118°-120°. The IR was identical to an authentic sample of methyl 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C:9]1([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 1,4-dibenzylpiperazine-2-carboxylate (35.4 g, 0.1 mol) in THF(200 mL) cooled to −78° C. was added dropwise LDA (64 mL, 1.8 M). The reaction was stirred at −78° C. for 1 h then MeI (7.2 mL, 0.11 mol) was added. The reaction was allowed to slowly warm to RT then quenched with sat'd NH4Cl. Water (200 mL) was added and the residue was extracted with EtOAc (200 mL). The EtOAc layer was washed twice with water then the solvent was removed in vacuo. Silica gel chromatography provided ethyl 1,4-dibenzyl-2-methylpiperazine-2-carboxylate (compound 10A) 14.91 g. HPLC RT: 2.42 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:353.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)(=[O:27])=[O:26])[CH2:21][CH2:20]1>>[F:41][C:38]([F:39])([F:40])[C:33]([C:15]1[CH:16]=[C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:13][CH:14]=1)([OH:42])[C:34]([F:37])([F:36])[F:35]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: COc1cccc(-c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)c1

Procedure:
Following the procedure outlined for Example 69, 3-methoxyphenylboronic acid (26.4 mg, 0.173 mmol, Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-methoxy-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, J=4.9, 1.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.49 (d, J=1.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.28 (dd, J=4.9, 3.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 3.81 (s, 3H), 2.95 (br. s, 8H). m/z (ESI, +ve ion) 580.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.34 μM; GK-GKRP EC50 (LC MS/MS)=1.82 μM.
Reaction SMILES: C([N:8]1[CH2:31][C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[O:11][CH:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([CH2:31][NH:8][CH2:9][CH:10]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:11]3)[CH2:17][CH2:16]2)=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccccc2)O3)ccc1OC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccccc2)O3)ccc1OC(C)C
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
To (10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (264 mg, 0.53 mmol), ammonium formate (167 mg, 2.65 mmol), palladium (30 mg, 0.03 mmol) (10% on carbon) was added methanol (5 mL) and the reaction mixture was stirred at 75° C. for 40 minutes. The reaction mixture was cooled, filtered over celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1:1 sat. aq. NaHCO3/25% aq. NaOH, dried over MgSO4, filtered and concentrated in vacuo to give (4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone (170 mg, 79%), which was used directly without further purification in the next step. ESI-MS m/z calc. 408.5. Found 409.7 (M+1)+; Retention time: 1.24 minutes (3 min run)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[F:13][CH:14]([F:34])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)(=O)C>[F:34][CH:14]([F:13])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[C:32]4[C:3]([OH:10])([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:33][C:31]=4[NH:30][N:29]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(C2CCN(c3ccc(OC(F)F)cc3)CC2)n[nH]1
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(OC(F)F)cc4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
Ethyl trifluoroacetoacetate (5.64 mL, 38.5 mmol) was added to a solution of 3-{1-[4-(difluoromethoxy)phenyl]piperidin-4-yl}-1H-pyrazol-5-amine (2.97 g, 9.63 mmol) produced in Reference Example 72 in acetic acid (52 mL), and the mixture was stirred at 60° C. for 3 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure, followed by azeotropy with toluene twice. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: hexane/ethyl acetate=100/0-0/100 (gradient)] and further purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-40/60 (gradient)] to obtain the title compound (1.84 g, yield: 43%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:7]=[C:8]1/[C:9](=[O:21])[C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]=2[CH2:19][CH2:20]/1.[ClH:22].C(O)C>[Pd].ClCCl.CO>[ClH:22].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[CH2:20][CH2:19][C:11]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[C:9]1=[O:21]
Reactant: Cc1[nH]cnc1/C=C1\CCc2sc3ccccc3c2C1=O
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2sc3ccccc3c2C1=O

Procedure:
A mixture of (E)-3,4-dihydro-2-[(5-methyl-1H-imidazol-4-yl) methylene]-1(2H)-dibenzothiophenone (599 mg), 2N hydrochloric acid (2 ml) and ethanol (50 ml) was hydrogenated at atmospheric pressure and room temperature using a 10% palladium on charcoal catalyst (60 mg) for 20 h. The suspension was warmed on a steam bath for 10 min and then filtered. The filtrate was evaporated to give an oil which was purified by FCC eluting with System A (100:10:1) to give a solid. A solution of this solid in a mixture of dichloromethane (20 ml) and methanol (5 ml) was treated with a slight excess of ethereal hydrogen chloride. The solution was evaporated to give the title compound (449 mg), m.p. 266°-269°, t.l.c. (System A 100:10:1) Rf 0.3.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: N#Cc1cc2nc(Cl)ccc2n1Cc1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C#N)n2Cc2ccccc2)n1
Temperature: 100 °C

Procedure:
A degassed mixture of 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile (0.12 g, 0.45 mmol, from Step 3), di-tert-butyl hydrazine-1,2-dicarboxylate (0.12 g, 0.54 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (35 mg, 0.045 mmol, Aldrich) and Cs2CO3 (0.18 g, 0.54 mmol, Aldrich) in toluene (2.5 mL) was heated at 100° C. for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, filtered to remove solids, and the solvent was removed in vacuo. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded purified product. Yield: (0.14 g, 67%).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[C:11]=1[C:12]([OH:14])=[O:13].C(N(CC)C(C)C)(C)C>C1COCC1>[F:9][C:10]1[CH:18]=[C:17]([O:19][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH:16]=[C:15]([F:20])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1c(F)cc(O)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)c(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
tert-Butyl(chloro)dimethylsilane (6.42 g, 42.6 mmol) was added to a solution of 2,6-difluoro-4-hydroxybenzoic acid (3.09 g, 17.8 mmol) in THF (50 mL), followed by the addition of N,N-diisopropylethylamine (9.19 mL, 51.5 mmol) over 5 min. After stirring at rt for 10 min the solution was concentrated in vacuo. Purification by gradient column chromatography, eluting with 10-50% solvent A in solvent B (A=DCM, B=DCM:MeOH:AcOH 95:5:1) yielded 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzoic acid (615 mg). This material was dissolved in THF (20 mL), borane-THF complex (1.0M in THF, 6.4 mL, 6.4 mmol) was added and the solution stirred at rt for 4 h. Further borane-THF complex (1.0M in THF, 6.4 mL, 6.4 mmol) was added and the solution stirred at rt for 18.5 h before concentration in vacuo. Purification by gradient column chromatography, eluting with 0-10% EtOAc in iso-hexane yielded 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzyl alcohol (470 mg). The title compound (533 mg, 0.90 mmol) was subsequently prepared from 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzyl alcohol (356 mg, 1.30 mmol) and (IntA1) (289 mg) using the methods of (77).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:31]>>[IH:31].[IH:31].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COCCOCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Product: COCCOCCn1c(N2CCCNCC2)nc2ccccc21

Procedure:
Hydrolyze 4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.73 g, 1.73 mmol) with hydroiodic acid (57%, 5 mL) for 1 hour as described in Example 113 to provide 2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazole dihydroiodide (0.73 g).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[CH2:27][CH:26]([C:25]3[CH:28]=[CH:29][C:22]([NH2:21])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:12][CH:11]=1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Reactant: C=Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C2CC(c3ccc(OC(F)(F)F)cc3)=NO2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-chlorosuccinimde (0.634 mmol, 85 μL) and pyridine (4 μL) in 2.5 mL of chloroform was added p-trifluoromethoxybenzaldehyde oxime (130 mg, 0.634 mmol). The reaction was heated at 50° C. for 3 h. 4-Aminostyrene (0.793 mmol, 93 μL) was then added followed by a solution of triethylamine (0.666 mmol, 93 μL) dissolved in 0.5 mL of CHCl3 dropwise. The reaction was stirred at 50° C. for 3 h. The cooled solution was diluted with chloroform (15 mL) and washed with water (2×10 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 2:1 hexane/EtOAc solution as the eluent (Rf=0.18) to afford 4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine (125 mg; 61%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.2 Hz, 2H), 5.65 (dd, J=10.9, 8.9 Hz, 1H), 3.55-3.75 (bs, 2H), 3.67 (dd, J=16.8, 10.9 Hz, 1H), 3.30 (dd, J=16.8, 8.9 Hz, 1H); EIMS 322 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[Li+].[BH4-].C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CC(C)c1cc(Br)cc2c1NC(=O)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(Br)cc2cc[nH]c12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g, 0.17 mol) in THF (275 ml) at room temperature under a nitrogen atmosphere, was added, via syringe, 2.0 M solution of LiBH4/THF (215 ml) over 30 min. The reaction mixture was stirred at 90° C. for 1 hr, cooled, quenched with distilled water and 5% HCl, and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by elution from a silica gel column with hexane/EtOAc (9:1) to give (14.5 g, 36%) ofthe product. 1H NMR (300 MHz, CDCl3) δ 8.18 (b, NH), 7.62 (d, 1H), 7.21 (t, 1H), 7.16 (d, 1H), 6.51 (dd, 1H), 3.20 (m, 1H), 1.38 (d, 6H); ESI (+) MS m/e=239 (MH+), ESI (−) MS m/e=237 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]=3)[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of methyl 4-chloro-3-{[(3,5-dichloropyridin-2-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (3.58 g, 7.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63 g, 8.50 mmol), and triethylamine (1.2 mL) in tetrahydrofuran (30 mL) was stirred at 50° C. for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with tetrahydrofuran/ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (3.32 g, 7.73 mmol, 100%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccncc1C(O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (97 mg, ol) in THF (5 mL) at −78° C. was added 1.0 M phenylmagnesium bromide in THF (0.46 mL) and the reaction mixture stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by preparation TLC of silica gel with 10% methanol in dichloromethane to yield [3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-phenyl-methanone as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:28])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with diethylamine
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=O)[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.O.[NH2:32][NH2:33]>CO>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:24])[C:19]([NH:32][NH2:33])=[O:21])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](C)C(=O)OCC
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a stirred solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg, 2.34 mmol) in anhydrous MeOH (20 mL) cooled to −20 deg C. is added a solution of 50% wt hydrazine hydrate (0.15 mL, 2.36 mmol) in MeOH (10 mL) dropwise. The crude is allowed to warm to rt in 2 hrs and is stirred overnight. The crude white precipitate is filtered to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate (870 mg). HPLC retention time=1.70 minutes (condition A); MS 398.2 (M+1).