Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 4-fluorophenylboronic acid (210 mg, 1.50 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (233 mg, 81%). MS (CI/NH3) m/z 287 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.75-2.15 (m, 4H), 2.31-2.48 (m, 1H), 2.57 (s, 3H), 2.70-2.75 (m, 1H), 3.14-3.28 (m, 1H), 3.99-4.25 (m, 2H), 7.13-7.21 (m, 2H), 7.37 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 7.50-7.58 (m, 2H), 8.31 (d, J=3.0 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).
Reaction SMILES: CO[C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH2:35][CH2:34]2)[CH:4]=1.[CH3:48][O:49]C1C=CC(C(NC2C=C([N+]([O-])=O)C=CC=2C(NC2C=CC(OC)=CC=2)=O)=O)=C(OC2CCNCC2)C=1.COC1C=CC=CC=1C=O>>[CH3:48][O:49][C:33]1([O:32][C:5]2[CH:4]=[CH:3][CH:31]=[CH:30][C:6]=2[C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:13])=[O:8])[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])[CH2:35][CH2:34]1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OC2CCN(Cc3ccccc3OC)CC2)cc1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OC2CCNCC2)cc1
Agent: COc1ccccc1C=O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccccc2OC2(OC)CCN(Cc3ccccc3OC)CC2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E, 2-[4-methoxy-2-[1-(2-methoxybenzyl)piperidin-4-yloxy]benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (83 mg, 0.13 mmol, 86%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCC2)CC1(F)F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reaction time: 3 h

Procedure:
To a mixture of 5.5 g (0.0191 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1), 25 mL of dimethylformamide and 9.4 g (0.0287 mole) of cesium carbonate was added 10.9 g (0.0764 mole) of iodomethane. The mixture was stirred for 3 hours, then 80 mL of water was added and the solid collected by suction filtration to give 4.8 g of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1).
Reaction SMILES: [S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([O-:20])=O)(=[O:3])=[O:2].[NH2:21]O.Cl>CN(C=O)C>[S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([NH2:21])=[O:20])(=[O:2])=[O:3]
Reactant: NO
Reactant: O=C([O-])[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Step 5—Formation of N-hydroxy-1-[4-(4-fluorophenoxy) phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carbox-amide Methyl 1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate (1.11 g, 2.2 mmol) was dissolved in DMF (17 mls) to which was added 50% aqueous NH2OH (20 mls) and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into cold 1.0N HCl (100-120 mls) and extracted with EtOAc (4×). The combined EtOAc extractions were washed with 10% aqueous LiCl (4×), saturated NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc) and the resulting pure oil was dissolved in 1:1 acetonitrile:water and lyophilized to give N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxamide as a white solid (659 mg, 59%). LC/MS Calcd for [M+H]+ 509.1. found 509.1. 1HNMR (400 MHz, CD3OD): δ 7.69 (d, 2H, J=9.2 Hz), 7.04 (m, 4H), 6.95 (d, 2H, J=9.2 Hz), 4.30 (m, 1H), 3.76 (m, 1H), 3.50 (m, 7H), 3.10 (m, 4H), 2.90 (dd, 1H, J=13.2, 4.4 Hz), 2.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C@@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC[N:24](CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C@@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[NH2:24])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O[C@@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of (±)-trans-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclohexanol (390 mg, 1.27 mmol) in CH2Cl2 (6 mL) at 0° C. was treated successively with Et3N (350 μL, 2.53 mmol) and MeSO2Cl (194 μL, 2.53 mmol), stirred at 0° C. for 2 hours, and partitioned between CH2Cl2 and 10% NH4OH. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with brine, dried and concentrated. A solution of the residue in THF (3 mL) and 28–30 wt % NH4OH (1.2 mL) was stirred at 70° C. for 24 hours, allowed to cool to room temperature, and partitioned between EtOAc and 1 N NaOH. The aqueous phase was extracted with EtOAc and the extracts were washed with brine, dried and concentrated. Chromatography of the residue on alumina with 1:3 EtOAc:MeOH to 100% MeOH and a subsequent chromatography on alumina with 20:1 hexanes:EtOAc to 100% EtOAc followed by 3:1 EtOAc:MeOH to 100% MeOH gave the product (260 mg, 67%) as a tan oil which solidified upon standing: mp 69.1–70.4° C.; 1H NMR δ 1.03–1.34 (m, 6H), 1.37–1.52 (m, 1H), 1.57–1.77 (m, 5H), 1.92–2.05 (m, 3H), 2.48 (d, J=7.0 Hz, 2H), 2.45–2.64 (m, 3), 2.73 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 307 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[C:21]([F:28])[CH:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1F
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (29 mg, 33%), MS (ISP) m/z=347.5 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:18]1[CH2:21][CH:20]([C:22]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:18]2[CH2:21][CH:20]([C:22]([C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)([OH:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
The reaction mixture of 135 mg (0.44 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 105 mg (0.367 mmol) of 1-azetidin-3-yl-1-(3,5-difluorophenyl)-2,2-dimethylpropan-1-ol (3) and 230 uL (1.32 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was refluxed for 3 h. Then it was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl). Further elution of the column afforded the other racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[F:44]>>[Cl:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:41]=[CH:42][C:43]=1[F:44]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccc(F)c(Cl)c3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-chloro-4-fluorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:26][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:35]3[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:39]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12]1[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=[C:14]([NH2:25])[N:13]=1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CCN4CCOCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine (8.8 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (6.3 mg). LCMS (M+H)+: m/z=518.4.
Reaction SMILES: [NH3:1].C([Li])CCC.[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([O:16]C)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>CCCCCC.O1CCCC1>[C:27]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([NH2:1])=[O:16])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N
Reactant: COC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 25 parts by volume liquid ammonia in 22 parts dry tetrahydrofuran is added dropwise over a 5 minute period 10 parts by volume of a 2.3 M solution of butyl lithium in hexane under reflux under a dry ice condenser. Then, a solution of 3.9 parts methyl 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionate in 18 parts dry tetrahydrofuran is added dropwise, with stirring. After stirring the resulting mixture under reflux for 3 hours the dry ice condenser is removed, and the mixture stirred at ambient temperature for a further two hours. The solvents are then removed in vacuo. The residual gum is suspended in water and extracted with a 1:1 ether-benzene solution. The ether-benzene extract is separated, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo. The residue is triturated with 50 parts of n-pentane. The undissolved solid is filtered off, washed with n-pentane and air dried to give a white powder. This powder is recrystallized from a mixture of benzene and petroleum ether to afford, as white needles, 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionamide. This compound melts at about 192°-194° C. and is represented by the following structural formula. ##STR12##
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>CN(C)C(=O)C>[CH:29]1([C:32]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[CH:6][N:5]3[CH:28]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Yield: 31.3 %

Procedure:
In the same manner as in Example 9-2 and using N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (300 mg, 0.797 mmol), cyclopropanecarbonyl chloride (72.0 μL, 0.797 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (111 mg, 31%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[N:24]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])=[N+:25]=[N-:26].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@H:11]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:24]=[N+:25]=[N-:26])[O:12][C@@H:13]1[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=NCCOCCOCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCN=[N+]=[N-])O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
This protocol was modified to synthesis 5β exclusively. Briefly, compound 2 (1.0 g, 3.03 mmol) and alcohol 4 (1.60 g, 9.11 mmol) were dissolved in anhydrous DCM (20 mL), followed by addition of dried 4 A° MS (0.4 g) and reaction mixture stirred at room temperature for 20 minutes under N2. CSA (camphor sulphonic acid, 0.615 g, 9.0 mL, 9.1 mmol) was added at room temperature and 8 hours, followed by heating to 45° C. for 24 hours. The reaction mixture was cooled to room temperature, neutralized with Et3N (0.2 mL, pH 7.5), diluted with DCM (100 mL) and extracted using saturated NaHCO3 solution. The organic layer was washed with water, brine and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue purified by silica gel column chromatography using DCM:EtOAc:MeOH (8.0:1.5:0.5) to obtain compound 5β (1.15 g, 85%). The spectral data matched with above compound 5β.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.C([O:33][C:34](=O)[CH2:35][NH:36][CH:37]([CH3:39])[CH3:38])C.O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:12]=[CH:11][C:10]([N:9]4[C:34](=[O:33])[CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[C:8]4=[O:30])=[CH:15][CH:14]=3)[CH2:17][CH2:18]2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)CNC(C)C
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)CN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 5 parts of phenyl[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 3 parts of ethyl[(1-methylethyl)amino]acetate, 1 part of N,N-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. The warm solution was saturated with water and allowed to cool. The solution was poured onto water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from methylbenzene, yielding 3.7 parts (73%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 193.7° C. (38).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:24]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(OCC)(=O)C>[Pt]=S.CO>[NH2:24][C:4]1[C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:23])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[CH2:12][CH2:13]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3[N+](=O)[O-])CC2)n1
Agent: S=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
A round bottom flask is charged with 5% platinum sulfide on carbon (0.200 g, 0.039 mmol). The flask is evacuated and refilled with argon three times. To the flask is added 1-[4-(5-chloro-3-nitro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (1.10 g, 2.90 mmol) as a solution in a 1:1 mixture of ethyl acetate:methanol (100 mL). The mixture is placed under an atmosphere of hydrogen and stirred for 5 h at room temperature. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.67 g of 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone as a white solid in 66% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11](C)([O-])[CH3:12].[K+].BrC(C)C>CS(C)=O.[Cl-].[Na+].O>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:12])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Solvent: O
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (6.00 g, 49.1 mmol) in DMSO (100 mL) was added potassium t-butoxide (6.34 g, 56.5 mmol) and the resulting mixture was stirred for 20 mins. A sample of 2-bromopropane (7.25 g, 59 mmol) was added and the reaction was stirred for 18 hrs. It was then diluted with brine (100 mL) and extracted with ethylacetate (3×125 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 10:90) to afford 4.61 g (57%) of 3-isopropoxybenzaldehyde as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]([OH:27])=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[CH3:30][NH2:31]>C(O)C>[O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]([NH:31][CH3:30])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(=O)O)c2c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 36-1 by using N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine in Example 14-2) and a solution of methylamine in ethanol. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90-7.82 (m, 2 H), 7.77 (d, J=7.58 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.52 Hz, 1 H), 7.51-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.26 (dd, J=8.46, 1.64 Hz, 1 H), 7.15 (t, J=5.94 Hz, 1 H), 5.86 (s, 1 H), 5.00 (brs, 2 H), 3.90 (d, J=5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.62 (d, J=4.55 Hz, 3 H), 2.37 (s, 3 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].I[CH:19]([OH:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:21][CH2:19][CH2:20][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: CC(O)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCO)NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 27.9 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (3.30 g, 12.2 mmol) in N,N-dimethylformamide (50 ml) was added iodoethanol (1.4 ml, 18.0 mmol) and cesium carbonate (390 mg, 1.20 mmol). The solution was heated to 85° C. for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography (30% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (1.01 g, 3.40 mmol, 26%). 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 6H), 2.0-2.1 (m, 2H), 2.47-2.51 (m, 2H), 2.72 (m, 2H), 3.70 (m, 2H), 4.7 (s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 298 [M+H]+, 320 [M+Na]+.