Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:28]([F:29])=[C:27]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]=1[F:37])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:1][C:4]1[C:28]([F:29])=[C:27]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]=1[F:37]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(N=[N+]=[N-])c(F)c3o2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(N)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3.50 g (6.80mmol) of 7-azido-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 93 (1) was suspended in 120 mL of tetrahydrofuran, 1.96 g (7.48 mmol) of triphenylphosphine was added and the mixture was stirred at room temperature for 2 hours. To this was added 50 mL of 1N hydrochloric acid and the mixture was further stirred for 10 hours. The mixture was adjusted to pH 9 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (chloroform-chloroform:methanol=40:l) to give 2.83 g of 7-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 85%).
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH:12]([OH:21])[C:13]2[S:17][C:16]3=[CH:18][N:19]=[CH:20][N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.C(OCC)(=O)C>ClCCl.CN(C=O)C.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>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11]([CH:12]([OH:21])[C:13]4[S:17][C:16]5=[CH:18][N:19]=[CH:20][N:15]5[CH:14]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CNc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4cn5cncc5s4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (30.7 mg) is added to a solution of 51.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) described in Example 16-a) and 0.057 ml of N-methylaniline in a mixture of 2.0 ml of dry dichloromethane and 0.5 ml of DMF, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. Ethyl acetate (10 ml) is added thereto, and the resultant precipitate is further washed twice with 5 ml of ethyl acetate and dried in vacuo to give a yellow powder. This powder is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 0.83 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:3]
Reactant: CC(O)c1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(O)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 3-(1-hydroxyethyl)phenol (7 g), 2-chloromethylquinoline (9 g), potassium carbonate (7 g) and potassium iodide (0.3 g) in acetone (75 ml) was refluxed overnight. The reaction mixture was poured into water, and then thoroughly extracted with ethyl acetate (3×30 ml). The organic extract was washed with NaOH solution (1N), water, brine, and then dried over MgSO4. All volatiles were removed to obtain a dark brown liquid, which was chromatographed on silica gel (12% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid.
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6]
Reactant: COc1ccc(-c2nc(-c3ccccc3)n(CCCCCCCC(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Boron tribromide (0.7 ml) was added to a suspension of 1-(7-carboxyheptyl)-4,5-bis(4-methoxyphenyl)-2-phenylimidazole (0.7 g) in anhydrous dichloromethane (20 ml ) and the reaction was stirred at room temperature for 1 h. Boron tribromide (0.3 ml) was added and the reaction was stirred at reflux for 2 h and at room temperature for 20 h. Water was carefully added to the cooled reaction mixture and the resulting yellow precipitate was collected. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethanol and water gave 1-(7-carboxyheptyl)-4,5-bis-(4-hydroxyphenyl)-2-phenylimidazole (0.44 g, 67%) as a cream solid, m.p 135°-7°; Found C, 3.97; H, 6.38; N, 5.98%; C29H30N2O4 requires: C, 74.02; H, 6.42; N, 5.95%.
Reaction SMILES: CO[Na].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)=[O:6].[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.C(O)(=O)C>CO.O>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH:4]=[CH:21][C:23]2[CH:32]=[CH:31][CH:30]=[C:25]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=2)[CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CO[Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C=CC(=O)c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To CH3ONa (0.45 g, 0.0082 mol) stirring in 20 ml of dry CH3OH at 10° C. was added 3-benzyloxyacetophenone (5.0 g, 0.019 mol) and methyl 3-formylbenzoate (3.12 g, 0.019 mol). A heavy precipitate formed almost immediately, and the mixture was diluted with 20 ml CH3OH, warmed to room temperature and stirred for 18 hours. Glacial acetic acid (3 ml) was added and the mixture poured into 300 ml H2O. Title product was recovered by filtration, air dried and purified by chromatography on silica gel gradiently eluted with 49 to 39:1 toluene:ethyl acetate, 4.97 g of solid; MS 372.2 (M+); 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.95 (s, 3H), 5.14 (s, 2H), 7.2-7.9 (m, 13H), 8.06 (dt, 1H), 8.3 (s, 1H); TLC Rf 0.7 (49:1 CHCl3 :isopropanol).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([OH:30])=[O:21])=[CH:11][CH:12]=1)([OH:3])=[O:19]
Reactant: COC(=O)c1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C(=O)O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C19H20O7 [M+Na]+: 383.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:13]3[S:14][CH2:15][CH2:16][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O1CCOCC1.O.[Cl-].[NH4+]>O.C(OCC)(=O)C.[Zn]>[N:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)=[N:11][N:12]3[CH2:16][CH2:15][S:14][C:13]=23)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
6-(3-Nitro-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole (150 mg, 0.463 mmol) was suspended in a 5:1 dioxane/water mixture (3 mL). Zinc powder (121 mg, 1.852 mmol, 4 eq) was added, followed by ammonium chloride (247 mg, 4.63 mmol, 10 eq) and the mixture was heated to 100° C. and stirred at the same temperature for 2 hours. The reaction mixture was then allowed to cool to room temperature and diluted with water and ethyl acetate. The aqueous phase was basified by adding solid Na2HPO4 and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried and concentrated to dryness. 100 mg of 3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine were obtained as off-white solid (73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)COc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-diamino-N-quinolin-2-yl-benzamide (770 mg, 2.77 mmol) and (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester (615 mg, 2.77 mmol) in DMSO (10 mL) was added Yb(OTf)3 (344 mg, 0.55 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:4) as eluent gave {3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester as a white solid. MS (m/z) 481.4 (M+1); 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (m, 3H), 8.04 (d, 1H), 7.92 (d, 2H), 7.75 (m, 2H), 7.54 (m, 1H), 6.80 (s, 2H), 4.78 (s, 2H), 3.81 (s, 3H), 2.17 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride (0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from ethyl acetate to yield 0.17 g (43%) of the title compound as a white solid mp 174°-175° C. HRMS m/e calculated for C22H22ClN3O: 379.1448. Observed m/e: 379.1465. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25]CC)=[O:24].[OH-].[K+]>CN(C=O)C.CO.O>[O:14]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:22][C:23]([OH:25])=[O:24])=[C:11]([Cl:12])[C:10]=2[Cl:13])[CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCc2cc(O)c(Cl)c(Cl)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A stirred mixture of 6-hydroxy-7,8-dichloro-1-tetralone (1 g., 0.0044 mole), potassium carbonate (10.69 g., 0.005 mole) and ethyl bromoacetate (0.84 g., 0.005 mole) in DMF (20 ml.) is heated at 60° C. for 11/2 hours. A solution of potassium hydroxide (0.45 g., 0.008 mole) in methanol (40 ml.) is added, the mixture is refluxed for one-half hour and then poured into water (ca. 500 ml.). Upon acidification a white powder separates. It is collected, washed with water, dried and crystallized from ethanol to obtain (1-oxo-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)-acetic acid (1.1 g.), melting point 250°-252° C.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)/[C:5](=[O:14])[NH:6]2.CCN(C(C)C)C(C)C.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>C1COCC1.CCO>[N:34]([C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)/[C:5](=[O:14])[NH:6]2)=[N+:35]=[N-:36]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])c(F)c2/C1=C/c1ccc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 25 °C
Yield: 78.6 %

Procedure:
(Z)-1,3-Dihydro-4-fluoro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (400 mg, 1.46 mmol) (from Example 10) was suspended in THF/EtOH (20 mL/10 mL). Hunig's base (diisopropylethyl amine, 3.8 mL, 22 mmol)(Aldrich) and trimethylsilyl azide (1.87 mL, 14.65 mmol)(Aldrich) were successively added at r.t. The mixture was refluxed for 12 h. The homogeneous reaction mixture was cooled to r.t. and quenched with 1N HCl. The precipitate was collected by suction filtration, washed with water and dried in a vacuum oven to yield (Z)-4-azido-1,3-dihydro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red solid (Yield 340 mg, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([CH:26]([F:28])[F:27])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:28][CH:26]([F:27])[C:21]1[CH:20]=[C:19]([C:8]2([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:7]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[C:23]([CH3:25])[N:22]=1
Reactant: Cc1cc(C2(c3ccnc(Cl)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Temperature: 140 °C
Yield: 13.6 %

Procedure:
1-(2-Chloropyridin-4-yl)-1-(2-(difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (400 mg, 0.99 mmol), pyrimidin-5-ylboronic acid (135 mg, 1.09 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (82 mg, 0.10 mmol) were mixed in THF (3 mL). Aqueous sodium carbonate (2M) (1.490 mL, 2.98 mmol) was added and the mixture was heated in a microwave reactor for 40 min at 140° C. The mixture was filtered through a pad of Celite®, eluated with DCM (15 mL) and concentrated in vacuo. Purification by preparative HPLC afforded 60 mg (14%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (s, 2 H) 9.25 (s, 1 H) 8.69 (d, 1 H) 7.68 (s, 1 H) 7.50-7.58 (m, 1 H) 7.39 (d, 1 H) 7.35 (s, 1 H) 7.25 (dd, 1 H) 7.22 (s, 1 H) 7.19 (d, 1 H) 6.75-6.42 (t, 1 H) 2.56 (s, 3 H); MS (ES+) m/z 447 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]([NH2:31])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)[CH:19]=[CH:20][CH:21]=1>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([NH:31][C:23]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)=[C:26]3[N:27]=[CH:28][CH:29]=[CH:30][N:25]3[N:24]=2)=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: Nc1nn2cccnc2c1-c1cccc(F)c1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Product: COc1cc(CC(=O)Nc2nn3cccnc3c2-c2cccc(F)c2)cc(OC)c1

Procedure:
3,5-Dimethoxyphenylacetic acid and the product from Example 128A were processed as using the method analogous to that described in example 104 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.40-10.51 (bs, 1H), 9.11 (dd, J=7.0, 1.8 Hz, 1H), 8.65 (dd, J=4.1, 1.7 Hz, 1H), 7.59 (ddd, J=11.2, 2.6, 1.6 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.26-7.34 (m, 1H), 7.16 (dd, J=7.0, 4.1 Hz, 1H), 7.02-7.09 (m, 1H), 6.46-6.54 (m, 2H), 6.38-6.43 (m, 1H), 3.67-3.77 (bs, 6H), 3.59-3.62 (bs, 2H); MS (ESI) m/z 407 (M+H)+. Anal. calculated for C22H19FN4O3: C, 65.02; H, 4.71; N, 13.79. Found C, 64.80; H, 4.54; N, 13.77.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:4][O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[C:8]([C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CCl
Reaction time: 1 h

Procedure:
To a chilled (5° C.) mixture of 6.5 g of (4-amino-5-methylisoxazol-3-yl)phenylmethanone, 65 ml of 2N sodium carbonate, 163 ml of a saturated solution of sodium bicarbonate, and 150 ml of dichloromethane was added, dropwise, 5.1 ml of chloroacetyl chloride. The resulting mixture was stirred for one hour, diluted with dichloromethane and water, and separated. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil (20% ethyl acetate/hexane as the eluent) afforded 7.15 g of N-(3-benzoyl-5-methylisoxazol-4-yl)chloroacetamide, m.p. 86°-88° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=O.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>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4cnn(C)c4)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 82.3 %

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.160 mg, 0.412 mmol) in 0.861 ml ACN/0.400 mL water. To this suspension was added potassium acetate (182 mg, 0.00185 mol) and 1-methylpyrazole boronic acid pinacol ester (107 mg, 515 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water×1, saline×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 454 (55% theoretical yield). MS: (ESI+)=390.2
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>CS(C)=O.C(#N)C>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[F:29])=[N:6][C:5]=2[N:19]=1
Reactant: Fc1ccccc1CBr
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Reaction time: 1 h
Yield: 62.3 %

Procedure:
The product from step (a) (20 mg, 67 μmol) was suspended in dimethyl sulphoxide (450 μL) and Hunig's base (13 μL, 74 μmol) was added. 2-Fluorobenzyl bromide (8.0 μL, 67 μmol) was quickly added to the stirred solution. The reaction was stirred for 60 minutes to give a homogeneous solution The crude solution was diluted to 1 mL with acetonitrile and chromatographed on a reverse phase column using a gradient (40–70% acetonitrile) to give the title compound as a white solid (17 mg, 61% yield).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)C>[N:25]([C@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Into a solution of trans-2-diphenylmethylpyran-4-yl methanesulfonate 4a (0.33 g, 0.95 mmol) in dry DMF (40 ml) was added sodium azide (0.18 g, 2.85 mmol). The mixture was heated to 100° C. and stirred for 4 hr. The mixture was diluted with ethyl ether, washed with 2M aqueous NaHCO3 and brine, and then dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (Hexane/Ethyl Acetate 9:1) afforded compound 5a (0.23 g, 82.7% yield) as a liquid.