Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(NC(C2C(C(F)(F)F)=CC([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=CN=2)=O)=CC=1C(=O)NC1CC1.Cl[C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([C:54](=[O:59])[NH:55][CH:56]3[CH2:58][CH2:57]3)[CH:48]=2)=[O:45])=[CH:36][N:35]=1.FC(F)(F)CO>>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:44]([C:37]2[CH:36]=[N:35][C:34]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:39][C:38]=2[C:40]([F:43])([F:42])[F:41])=[O:45])=[CH:48][C:49]=1[C:54](=[O:59])[NH:55][CH:56]1[CH2:58][CH2:57]1
Reactant: O=C(NC1CC1)c1cc(NC(=O)c2ncc(OCC(F)(F)F)cc2C(F)(F)F)ccc1Cl
Reactant: O=C(NC1CC1)c1cc(NC(=O)c2cnc(Cl)cc2C(F)(F)F)ccc1Cl
Solvent: OCC(F)(F)F
Product: O=C(NC1CC1)c1cc(NC(=O)c2cnc(OCC(F)(F)F)cc2C(F)(F)F)ccc1Cl

Procedure:
Analogously to the preparation of (Ib-2), N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-5-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)pyridine-2-carboxamide is synthesized from 2-chloro-N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-4-(trifluoromethyl)pyridine-5-carboxamide and 2,2,2-trifluoroethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:33][CH:34]([CH3:36])[CH3:35])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:33][CH:34]([CH3:36])[CH3:35])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of methyl {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetate (1.6 g, 3.2 mmol) in tetrahydrofuran (5 ml)-methanol (5 ml) was added 1N aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was acidified with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetic acid (1.3 g, yield 85%) as pale-yellow crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:20])[C:16]([CH3:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH3:20])[C:16]([CH3:19])=[N+:17]([O-:9])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Br)cnc1C
Solvent: ClCCl
Product: Cc1cc(Br)c[n+]([O-])c1C

Procedure:
m-Chloroperbenzoic acid (71.42 g) in dichloromethane (11) was added dropwise to a stirred solution of 5-bromo-2,3-lutidine (70.0 g) over I hour. After 23 hours the solution was cooled to 15° and ammonia gas bubbled through to give a white precipitate, which was filtered off. The filtrate was washed with 5% aqueous sodium sulphite, dried, and stripped to give 5-bromo-2,3-lutidine-N-oxide, 61.78 g, m.p. 80°-2°, from ethyl acetate.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>O.CCOCC.C([O-])(O)=O.[Na+]>[C:1]([NH:8][CH2:9][CH2:10][CH:11]=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCC=O
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirring solution of 3-(Boc-amino)-1-propanol (25 mL, 0.144 mol) in water saturated DCM (1.0 L) was added Dess-Martin reagent (99.2 g, 233.9 mmol) and the reaction mixture was stirred for 1 hour. The reaction was then diluted with ether (1.0 L), followed by a solution of Na2S2O3 (250 g) in 80% NaHCO3 (450 g in 1.0 L H2O). The reaction was stirred vigorously for 30 minutes until two layers formed, the top layer was clear. The reaction was filtered to remove the precipitated solids and the aqueous layer was extracted with ether (1.0 L). The organic layer was washed with sat. NaHCO3 (1.0 L), H2O (1.0 L), and brine (1 L), dried over Na2SO4 and concentrated to a clear oil. The crude oil was dissolved in EtOAc: hexanes (1:1 v/v, 1.0 L) and filtered through a short silica gel column to yield the desired N-Boc-3-amino-propanal (21.7 g, 0.125 mol, 85.6% yield): 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1 H, CHO), 4.85 (bs, 1 H, NH), 3.36-3.42 (m, 2 H, CH2), 2.67 (t, 2 H, CH2), 1.39 (s, 9 H, (CH3)3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:10]2[O:12][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(O)C(C)(C)O
Reactant: N#Cc1ccc(B(O)O)cc1F
Solvent: C1CCCCC1
Product: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Temperature: 40 °C
Yield: 85.6 %

Procedure:
A suspension of the crude 3-fluoro-4-cyanophenyl boronic acid (9.2 Kg, 55.8 mol) in cyclohexane (150 L) was treated with pinacol (13.2 Kg, 111.6 mol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 40° C. for 4 h. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was cooled down to room temperature before being washed with water (2×75 L). The organic layer was then dried over magnesium sulfate (MgSO4) and concentrated under the reduced pressure to afford 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 11.8 Kg, 13.8 Kg theoretical, 85.6% yield) as a light yellow solid. For 19: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (t, 1H, J=7.00 Hz), 7.62 (m, 2H), 1.29 (s, 12H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[N:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:40][CH:39]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, light yellow solid (93 mg, 75%), MS (ISP) m/z=497.4 [(M+H)+], mp 205° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (20 mg) was dissolved in trifluoroacetic acid (20% in dichloromethane, 1.5 mL) and stirred for 20 min at room temperature. The reaction was concentrated and the resulting residues loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The amine was eluted with 2M ammonia in methanol and concentrated. The unprotected piperidine was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) and sodium cyanoborohydride (2.4 mg) and one drop of acetic acid. The reaction was stirred at room temperature for 1 h. The reaction was concentrated. The resulting residue was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL), stirred for 5 min, and concentrated. The resulting residue was purified by preparative HPLC to afford the title compound. 1H-NMR (CD3OD, 500 MHz) δ 8.05 (m, 1H), 7.78 (m, 1H), 7.44 (m, 2H), 7.22 (m, 0.75H), 7.13 (m, 1.8H), 7.03 (m, 0.6H), 5.34 (s, 0.3H), 5.27 (s, 0.7H), 3.69 (m, 4H), 3.47 (m, 4H), 2.55-3.00 (m, 7H), 2.00-2.55 (m, 2.5H). Mass spec.: 446.24 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)(=[O:16])=[O:15])[CH:10]([CH3:26])[CH2:9]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[NH2:23])(=[O:16])=[O:15])[C@H:10]([CH3:26])[CH2:9]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CC1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N)c1
Yield: 53.9 %

Procedure:
A solution of 4-(4-Fluoro-2-trifluoromethyl-phenyl)-2-methyl-1-(3-nitro-benzenesulfonyl)-piperazine (330 mg, 0.8 mmol) and a catalytic amount of 10% Pd/C in EtOAc (25 mL) was stirred under H2 (1 atm) at ambient temperature for two hours, after which the reduction was judged complete by TLC. The H2 removed under vacuum, and the reaction mixture was filtered through celite, and rinsed with EtOAc (3×25 mL), and the filtrate was concentrated in vacuo, affording 180 mg of the desired sulfonamide in >95% purity (62% yield). HRMS: calcd for C18H19F4N3O2S+H+, 418.12068. found ([M+H]+), 418.12119.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C.C(OCC)C>[CH2:17]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (1.96 g, 9 mmol), 1-butylbromide (1.46 ml, 13.5 mmol) and potassium carbonate (1.86 g, 13.5 mmol) in ethanol (20 ml) was refluxed for 18 hours. After cooling to ambient temperature acetone (5 ml) and diethyl ether (5 ml) was added to the reaction mixture, followed by filtration and evaporation of the filtrate in vacuo. The crude product was subjected to column chromatography using a mixture of chloroform and methanol (7/1) containing 1% concentrated ammonium hydroxide as eluent and 1-butyl-3-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one was eluted first followed by 1-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one contaminated with the di-butylated product. The last product was recrystallized from ethanol and 1-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one was isolated as a white crystalline compound, which was dissolved in a small amount of methylene chloride whereafter oxalic acid was added. The formed 1-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one oxalate was collected by filtration, white crystals, m.p. 209-214° C. 1-butyl-3-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one as an oil was dissolved in a small amount of methylene chloride and oxalic acid was added. Only a yellow syrup of this product was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH:26]([CH3:30])[NH:25]1.C(N(CC)CC)C.[OH-].[Na+]>C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH:26]([CH3:30])[NH:25][CH:24]([CH3:23])[CH2:29]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CC1CNCC(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CC(C)NC(C)C2)c2nccc(C)c2c1
Yield: 83.6 %

Procedure:
A mixture of 5.5 g (0.015 mole ) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 3.4 g (0.03 mole) of 2,6-dimethylpiperazine in 80 ml of benzene was heated under reflux for 21 hr, treated with 2 ml of triethylamine, and heated for an additional 4 hr. The mixture was allowed to cool, diluted with water and toluene, and made strongly basic with 50% sodium hydroxide solution. The organic layer was washed, dried and concentrated to dryness in vacuo. Recrystallization from hexane containing a little toluene afforded 5 g (83%) of the title compound, mp 94°-96°.
Reaction SMILES: C([O:5][C:6](=O)[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)([F:9])[F:8])(C)(C)C.[NH3:18]>CO>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([F:9])([F:8])[C:6]([NH2:18])=[O:5])=[N:11][CH:12]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(Br)cn1
Solvent: CO
Product: NC(=O)C(F)(F)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (300 mg, 0.974 mmol) is dissolved in 7M ammonia in methanol (5 mL) and the mixture is stirred at ambient temperature for 3 days. The mixture is evaporated to dryness to give the title (240 mg). 1H-NMR (400 MHz, DMSO-d6) 7.70 (d, 1H), 8.05 (bs, 1H), 8.3 (d, 1H), 8.40 (bs, 1H), 8.85 (s, 1H). m/z (Cl) 251+253 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][C:36]([S:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[O:29][CH:30]=1.[I-].[K+]>CC(=O)CC>[CH3:1][C:2]1[CH:3]=[C:4]([O:17][CH2:25][C:26]2[N:27]=[C:28]([CH:31]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39][C:40]([F:43])([F:41])[F:42])=[CH:35][CH:34]=3)[O:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Cc1cc(O)ccc1COCCn1ccnn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Cc1cc(OCc2coc(C=Cc3ccc(SC(F)(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 201 mg (0.86 mmol) 3-methyl-4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol and 169 mg (0.52 mmol) cesium carbonate in 10 ml 2-butanone was stirred at 60° C. for 30 minutes, then 275 mg (0.86 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole and 143 mg (0.86 mmol) potassium iodide were added and stirring was continued overnight. After evaporation, the residue was mixed with aqueous NaOH (1N) and extracted with ethyl acetate. The combined extracts were dried, evaporated and the product purified on silica (ethyl acetate) to yield 280 mg (63%) of the title as a white solid melting at 102° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].Cl>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:25]
Reactant: CCNCC
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: CCN(CC)CCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Yield: 12 %

Procedure:
The procedure of Example 5 was followed starting with (D) of Example 5 (2.5 g, 7.6 mmol) and using diethylamine in place of dibutylamine to produce 0.32 g (12% yield) of the named compound as the HCl salt, mp 219°-220° C. IR(KBr): 3400, 1600 cm−1. MS: 365(MH+). 1H NMR (CDCl3): δ 8.25-6.82 (m, 10H), 4.02 (t, J=5.4 Hz, 2H), 3.14 (m, 6H), 1.99 (m, 4H), 1.36 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28]CNC[CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28][CH2:1][N:2]([CH2:4][C:5]4[C:13]5[C:8](=[N:9][CH:10]=[CH:11][CH:12]=5)[NH:7][CH:6]=4)[CH2:3][CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Solvent: Cc1ccccc1
Product: c1cnc2[nH]cc(CN3CCN(c4ccc5[nH]ccc5c4)CC3)c2c1
Yield: 31.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.23 g, 1.33 mmol) and 1-(5-indolyl)piperazine (0.27 g, 1.34 mmol) in toluene (20 ml) was heated at reflux for 16 h under nitrogen. The mixture was allowed to cool and the solid present collected. Purification by flash chromatography, eluting with 90:8:1 dichloromethane/methanol/ammonia, twice gave the title compound (0.14 g, 32%) as a white solid. Recrystallisation from methanol afforded needles, m.p. 232.5°-233° C.; (Found: C, 72.14; H, 6.29; N, 21.07. C20H21N5. 0.1H2O requires C, 72.09; H, 6.41; N, 21.02%); δH (DMSO-d6) 2.56 (4H, m, 2×piperazinyl CH2), 3.02 (4H, m, 2×piperazinyl CH2), 3.69 (1H, s, CH2N), 6.27 (1H, m, 3'-H), 6.83 (1H, dd, J 8.8, 2.1 Hz, 6'-H), 6.97 (1H, m, 2'-H), 7.05 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.22 (2H, m, 4'-H, 7'-H), 7.38 (1H, d, J 2.1 Hz, 2-H), 8.06 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.4 Hz, 6-H), 10.77 (1H, br s, NH), and 11.46 (1H, br s NH); m/z (CI+, NH3) 322 (M+1)+.
Reaction SMILES: [Mg].Cl[CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1.CN(CCN(C)C)C.[Si:21]([O:28][C@H:29]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])/[CH:30]=[N:31]/[S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+].II>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH2:3][C@@H:30]([NH:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[C@H:29]([O:28][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: CC(C)(C)S(=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: ClCc1ccc2c(c1)OCO2
Agent: CN(C)CCN(C)C
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N[C@H](Cc1ccc2c(c1)OCO2)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 63.2 %

Procedure:
To a slurry of magnesium turnings (1.09 g, 44.8 mmol) in 5 mL of THF was added iodine (0.0650 g, 0.256 mmol), followed by a solution of 5-(chloromethyl)benzo[d][1,3]dioxole (6.55 g, 38.4 mmol) in 30 mL of THF. After 1 minute, the exothermic reaction mixture was placed in an ice bath for 1 minute and then stirred at ambient temperature for 1 hour. TMEDA (7.68 ml, 51.2 mmol) was added to the reaction and the mixture was cooled to −78° C. for 5 minutes at which point a solution of (E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (5400 mg, 12.8 mmol) in 25 mL THF was added via a syring pump over 15 minutes. The reaction was allowed to warm to RT over the course of 2 hours then stirred at RT for an additional hour. The mixture was diluted with ethyl acetate (100 mL) and poured in saturated ammonium chloride (250 mL). The aqueous layer was extracted with ethyl acetate (2×250 mL) and the combined organic layers were washed with water and then brine and dried over Na2SO4. The organic colvents were filtered, concentrated under reduced pressure and the crude material was purified by silica gel to provide N-((2R,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3,4-bis(tert-butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide (4.51 g, 63.1% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].Cl.[CH3:29][O:30][CH2:31][C:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:36][CH2:35][C:32]4([CH2:31][O:30][CH3:29])[CH2:34][CH2:33]4)=[O:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: COCC1(CN)CC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Agent: Cl
Product: COCC1(CNC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)CC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 1-[1-(methoxymethyl)cyclopropyl]methanamine monohydrochloride similar to as described in Example 2 to afford 11 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-[[1-(methoxymethyl)cyclopropyl]methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 471 (M)+. 1H NMR (400 MHz, DMSO) δ 11.34 (t, J=5.3 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.09-4.88 (m, 2H), 4.67-4.44 (m, 2H), 3.25 (s, 4H), 1.49 (s, 5H), 0.63-0.30 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2]
Reactant: Clc1cnccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Temperature: 90 °C
Yield: 75.3 %

Procedure:
A mixture of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.25 g, 1.0 mmol), cesium carbonate (0.65 g, 2.0 mmol) and 2-chloropyrazine (0.17 g, 1.5 mmol) in DMF (3 mL) was heated to 90° C. for 3 hr. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/PE=1/2) on silica gel to give the title compound as a light yellow solid (0.25 g, Yield: 76.7%). MS (ESI) m/z=333 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH:25][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN)O4)CC2)cc1
Product: CCCC(=O)NCC1(C)Cc2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2O1
Yield: 61.8 %

Procedure:
By using 1-{5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methaneamine (110 mg, 0.278 mmol) synthesized in Example 108 and butyryl chloride (32 mg, 0.304 mmol), the reaction was carried out in the same manner as Example 137 to synthesize 80 mg of the title compound (yield 68%). Melting point was 140 to 142° C.