Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH:14]=[CH:15][CH:16]=1.Cl>CCCCCCC>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][CH2:19][CH2:20][OH:21]
Reactant: Brc1cccc(C2OCCO2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCCCCCC
Product: OCCOCc1cccc(Br)c1
Temperature: 25 °C

Procedure:
A solution of DIBAL-H in heptane is added under an inert atmosphere to a cooled (−78° C.) solution of 2-(3-bromophenyl)-1,3-dioxolane in hexanes. The reaction mixture is stirred until no starting material is seen by TLC. Aqueous HCl (1N) is added to the reaction mixture while warming to room temperature. The product is extracted with EtOAc. Combined organic layers are dried over anhydrous MgSO4, and concentrated under reduced pressure to give 2-(3-bromobenzyloxy)ethanol.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:13]1([CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:22].[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].N#N>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[O:22]=[C:11]1[C:10]2[C:19](=[CH:20][CH:21]=[C:8]([C:29]3[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=3)[C:23]#[N:24])[CH:9]=2)[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:12]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CC2(CCOCC2)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC32CCOCC2)c1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
To a 10 mL CEM microwave test tube was charged with Cs2CO3 (147 mg, 0.45 mmol), PdCl2(PPh3)2 (20 mg, 0.028 mmol), 5-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-1,4′-pyran]-3(2H)-one (51 mg, 0.18 mmol), 3-cyanophenylboronic acid (35 mg, 0.24 mmol), dioxane (3 mL) and H2O (0.1 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 100° C. for 10 min. The reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-30%) to give 42 mg of 3-(3-oxo-2,2′,3,3′,5′,6′-hexahydrospiro[indene-1,4′-pyran]-5-yl)benzonitrile as white solid. MS ESI+ve m/z 304 (M+H)30.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:32]2[C:27]([C:26]([F:37])([F:36])[F:25])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[CH3:24])=[O:23]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: OB(O)c1cccnc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 33.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.034 g, 0.0001 mol), [2-(trifluoromethyl)-3-pyridyl]boronic acid (Combi-Blocks, 0.038 g), bis(triphenylphosphine)palladium(II) dichloride (0.007 g), Na2CO3 (0.032 g), and isopropanol-water (1 mL, 3:1). The mixture is heated at 80° C. for 16 hr. The mixture is concentrated, taken up in EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite, and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.015 g, 33% yield). LCMS m/z=454.6 [M+H]+, tR=2.52 min. (compound same as Example 284)
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[C:12]1([C:2]2[C:3]([NH2:11])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1cc2c(cc1Br)OCO2
Product: Nc1cc2c(cc1C1=CCCCC1)OCO2

Procedure:
The title compound was prepared by Suzuki coupling of 6-bromo-benzo[1,3]dioxol-5-ylamine (Bioorganic & Medicinal Chemistry (2002), 10(11), 3395-3400) and cyclohexen-1-ylboronic acid according the procedure Example 44, step (g). Mass spectrum (ESI, m/z): Calcd. for C13H15NO2, 218.1 (M+H), found 218.1.
Reaction SMILES: O[CH:2]1[CH2:6][S:5][C:4]2=[C:7]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)=[N:9][N:3]12.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>C(COC)OC.C(OCC)(=O)C>[N+:16]([C:12]1[CH:11]=[C:10]([C:8]2[C:7]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:4]3[S:5][CH:6]=[CH:2][N:3]3[N:9]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=[N+]([O-])c1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
3-Hydroxy-6-(3-nitrophenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole (1 g, 2.938 mmol) was dissolved in dimethoxyethane (15 mL) under nitrogen atmosphere. Trifluoroacetic anhydride (0.8 mL, 5.664 mmol, 2 eq) and triethylamine (0.41 mL, 2.938 mmol, 1 eq) were added and the mixture was stirred at room temperature for 3 days. The solution was then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (eluant: DCM/MeOH 97:3) to give 417 mg (44%) of 6-(3-nitrophenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:19]([CH3:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[CH3:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:14]([CH3:21])=[CH:15][C:16]([NH:17][C:28](=[O:29])[NH:27][C:25](=[O:26])[C:24]3[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=3[Cl:22])=[CH:18][C:19]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Temperature: 70 °C
Yield: 74.5 %

Procedure:
To a solution containing 3.0 g of 4-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3,5-dimethylaniline in 40 mL of toluene under an atmosphere of nitrogen and heated to 70° C. (internal) was slowly added a solution containing 2.7 g of 2-chlorobenzoyl isocyanate in 5 mL of toluene. The resulting mixture was heated at 70° C. for 1/2 hour. The reaction mixture was cooled to 0° C. and filtered. The collected solid was washed with toluene and then hexane. It was dried under vacuum to afford 3.58 g of a white solid, mp. 224°-226° C. NMR (DMSO-d6): 1.7-2.2 (m, 10H, contains singlet at 2.03), 2.7-3.0 (m, 4H), 6.07 (d, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 7.4-7.7 (m, 4H), 10.38 (S, 1H), 11.20 (S, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2nccc(N3CCC(O)C3)c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-ol (7.67 g, 31.3 mmole), triethylamine (8.73 mL, 63 mmole) and catalytic amount of 4-dimethylaminopyridine dissolved in DCM (100 mL) and cooled to 0° C. The solution was degassed with argon. Methanesulfonyl chloride (2.9 mL, 37.6 mmole) was added dropwise over 30 minutes. The reaction was stirred under argon for 30 minutes at 0° C. and then stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified on column chromatography (silica, 1-5% MeOH in chloroform). The solvent was removed in vacuo to afford the title compound as a white solid (7.0 g, 69%): LC-MS (ES) m/z 324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1>C1COCC1.[Pd]>[NH2:13][C:4]1[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)OC(CO)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(c1)CC(CO)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (5-methyl-7-nitro-2,3-dihydrobenzofuran-2-yl)methanol (7c) (2.3 g, 0.011 mol) and Pd/C (230 mg, 10%) in THF (30 mL) was introduced H2 and stirred at ambient temperature for 12 h. The mixture was filtered through celite and concentrated to give the title compound (7d) as a solid. MS-ESI (m/z): 180 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Product: CCOC(=O)c1cc(-c2cncnc2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) and 5-Pyrimidineboronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a white solid, MS (ISP): m/e=244.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]1([CH3:35])[CH:25]=[CH:24][C:23]([C:26]([NH:28][C@H:29]([CH:33]=O)[CH:30]([CH3:32])[CH3:31])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]3[CH2:19][CH2:18][N:17]([CH2:33][CH:29]([NH:28][C:26](=[O:27])[C:23]4[CH:22]=[CH:21][C:20]([CH3:35])=[CH:25][CH:24]=4)[CH:30]([CH3:31])[CH3:32])[CH2:16][CH2:15]3)[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2(C3CCNCC3)OCCO2)cc1Cl
Reactant: Cc1ccc(C(=O)N[C@H](C=O)C(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(CN2CCC(C3(c4ccc(Cl)c(Cl)c4)OCCO3)CC2)C(C)C)cc1
Yield: 52.3 %

Procedure:
A solution of 4-[2-(3,4-dichlorophenyl)-[1,3]dioxolan-2-yl]piperidine (0.21 g, 0.7 mmol), N-p-toluoyl valinaldehyde (0. 17g, 0.764 mmol), sodium triactetoxy-borohydride (0.22 g, 1.04 mmol) in methylene chloride (20 mL) was stirred overnight under argon. After concentrating the reaction mixture, the residue was stirred with ethyl acetate and dilute aqueous potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude was flash chromatographed on flash silica gel with 1% methanol/methylene chloride (containing 1% ammonia) to give N-(1-{4-[2-(3,4-dichlorophenyl)-[1,3 ]dioxolan-2-yl]piperidin-1-yl-methyl}-2-methylpropyl)-4-methylbenzamide (0.187g, 0.366 mmoles).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@@H:5]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:36])[CH:26]=2)[C:14]1=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.O.[OH-].[Li+].C(O)(=[O:44])C>O1CCOCC1.O>[C:22]([C:19]1[N:18]=[C:17]2[N:13]([C@@H:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:4][C:3]([OH:2])=[O:38])[C:14](=[O:37])[N:15]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=4[CH3:34])[N:27]([CH3:36])[CH:26]=3)[C:16]2=[CH:21][CH:20]=1)(=[O:44])[NH2:23]
Reactant: CC(=O)O
Reactant: COC(=O)C[C@H](c1ccc(F)cc1)n1c(=O)n(Cc2cn(C)c3cc(C)cc(C)c23)c2ccc(C#N)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](CC(=O)O)c4ccc(F)cc4)c4nc(C(N)=O)ccc43)cn(C)c2c1
Reaction time: 24 h
Yield: 13 %

Procedure:
To a stirred solution of (R)-3-[5-cyano-2-oxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl]-3-(4-fluoro-phenyl)-propionic acid methyl ester (0.17 g, 0.33 mmol) in dioxane (10 ml) and water (3 ml) was added lithium hydroxide monohydrate (70 mg, 1.66 mmol). The reaction was stirred for 24 hours after which time it was diluted with water and acidified using acetic acid. The resulting precipitate was collected via filtration and washed with water. The remaining solid was purified via preparative TLC (2×1 mm silica gel plates, 5% MeOH/Dichloromethane) to afford 22 mg (13%) of the title compound. LCMS, M++1, m/z: 516.20.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[Br:24].[CH:25]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Br:24][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:31](=[O:32])[CH2:30][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:8]([CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])[CH:7]=[CH:6]2
Reactant: COC(=O)c1ccc(Cn2ccc3cc(Br)c(N)cc32)c(OC)c1
Reactant: O=C(O)CC1CCCC1
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)c(NC(=O)CC4CCCC4)cc32)c(OC)c1
Yield: 60 %

Procedure:
Using a similar procedure to that described in Example 185, but starting from methyl 4-(6-amino-5-bromoindol-1-ylmethyl)-3-methoxybenzoate (GG) and cyclopentylacetic acid, methyl 4-[5-bromo-6-cyclopentylacetamidoindol-1-ylmethyl]-3-methoxybenzoate was obtained in 60% yield as an off-white solid; partial NMR: 1.6 [br m,8H,(CH2)4 ], 3.8 (s,3H,OCH3), 3.9 (s,3H,OCH3), 5.3 (s,2H,NCH2), 6.4 (dd,1H,H3 -indole), 7.1 (d,1H,H2 -indole), 7.7 (br, 1H,NH), 7.8 (s,1H,H4 -indole), 8.5 (br s,1H,H7 -indole).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(=O)(O)[O-:11].[Na+].[Br-].[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.C(O)(C)C>[O:9]=[C:5]1[N:4]([CH2:3][C:2]([OH:11])=[O:1])[CH2:8][CH2:7][O:6]1
Reactant: O=C1OCCN1CCO
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C(O)CN1CCOC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (0.575 g, 4.38 mmol) in acetone (40 ml) was added 15% aqueous sodium bicarbonate (12 ml) to give a white slurry, which was then cooled to 0° C. (JOC 2003, 68, 4999-5001). Sodium bromide (0.090 g, 0.88 mmol) and TEMPO (0.014 g, 0.09 mmol) were added and the resulting mixture was stirred for 10 minutes followed by the addition of trichloroisocyanuric acid (2.03 g, 8.76 mmol) in four equal portions added every five minutes. The pale yellow slurry was warmed to 25° C. and stirred for an additional 12 hours to yield a yellow solution. Iso-propanol (3 ml) was added and the mixture was stirred for 45 minutes to give a white slurry, which was filtered through a Celite® cake. The filtrate was concentrated in vacuo, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (30 ml). The aqueous phase was acidified with 4N HCl until pH ˜2 and then put on for continuous extraction with methylene chloride (˜100 ml) for 16 hours. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to yield (2-oxo-oxazolidin-3-yl)-acetic acid (0.445 g, 70%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[C:25]([CH:34]=O)[CH:24]=1)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[C:25]([CH2:34][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 79.3 %

Procedure:
Compound 53 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 48 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and methanesulfonyl chloride gives the title compound in 48% yield as a tan solid, mp 210.7° C. 1H NMR (CDCl3) δ 2.72-3.58 (br m, 7H), 6.49 (s, 1H), 6.74 (s, 1H), 6.96-7.49 (m, 12H); MS (ES) 398 (M+Na), 374 (M−H). HPLC shows 98% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Yield: 76.9 %

Procedure:
The product of Example 2, Step C, 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (3.25 g, 6.93 mmol) and (trimethylsilyl)acetylene (1.10 mL, 7.78 mmol) were combined in triethylamine (17 mL). Dichlorobis(triphenylphosphine)-palladium(II) (0.120 g, 0.017 mol) and cuprous iodide (0.033 g, 0.17 mmol) were added and the resultant solution was stirred at ambient temperature for 22 hours. The reaction mixture was adsorbed onto Celite® for 20 mm and was filtered, washing with ethyl acetate. The filtrate was concentrated to a thick oil, further diluted with ethyl acetate (100 mL) and washed with aqueous citric acid (2 M, 2×25 mL), water, and brine. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford a tan-colored solid. Recrystallization from heptane-ethyl acetate afforded 2-(2-chloro-4-trimethylsilanylethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (2.34 g, 76% yield) as a grey-colored solid: 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1 H), 8.95 (s, 1 H), 7.53 (d, J=1.7 Hz, 1 H), 7.47 (m, 1 H), 7.32 (m, 1 H), 7.27 (dd, J=8.4, 1.8 Hz, 1 H), 6.72 (dd, J=8.0, 6.6 Hz, 1 H), 4.73 (t, J=5.5 Hz, 1 H), 3.87 (apparent t, J=4.7 Hz, 2 H), 3.57 (m, 2 H), 0.21 (s, 9H); MS (APCI+)=439.1; MS (APCI−)=437.1.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:10]([C:19]([NH2:21])=[O:20])=[CH:11][C:12]2[C:17](C=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1C=CC=CC=1>>[C:5]([O:4][C:1]1[C:10]([C:19]([NH2:21])=[O:20])=[CH:11][C:12]2[C:17]([CH:2]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:7])[CH3:6]
Reactant: NC(=O)c1cc2ccccc2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2ccccc2cc1C(N)=O
Temperature: 25 °C

Procedure:
Acetic anhydride (19.2 ml, 200 mmol) was added to a solution of 18 (29.95 g, 160 mmol) in pyridine (32 ml, 400 mmol) and the mixture was maintained at room temperature for 30 minutes. The solid was filtered off, washed with acetone and dried (MgSO4), generating 27.06 g (74%) of 19 as pale yellow crystals, mp 201°-202° C. (lit. 203°-205° C.).
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]([OH:27])=O)(=[O:3])[NH2:2].[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: NCC1CCOCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCC1CCOCC1

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-tetrahydro-2H-pyran-4-ylmethanamine similar to as described in Example 2 to afford 6 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(tetrahydropyran-4-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 471 (M)+. NMR (400 MHz, DMSO) δ 11.30 (t, J=5.4 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.05-4.97 (m, 2H), 4.59-4.51 (m, 2H), 3.91-3.74 (m, 3H), 3.19 (t, J=6.0 Hz, 2H), 1.82-1.67 (m, 1H), 1.67-1.58 (m, 2H), 1.49 (s, 6H), 1.32-1.18 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]([CH3:17])=[CH:4][C:3]=1[NH:18]C(=O)C.[ClH:22]>>[ClH:22].[ClH:22].[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]([CH3:17])=[CH:4][C:3]=1[NH2:18]
Reactant: CC(=O)Nc1cc(C)c(OCCN2CCOCC2)cc1C
Agent: Cl
Product: Cc1cc(OCCN2CCOCC2)c(C)cc1N

Procedure:
The mixture of N-[2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (11.4 g, 39 mmol) in 3N aq.HCl (100 mL) was refluxed for 2 h and then concentrated under reduced pressure. The residue was lyophilized to give 2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)aniline dihydrochloride as gray solid quantitatively.