Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][CH:5]1[O:6][N+]([O-])=O)=[N+:2]=[N-:3].[C:27]([O-])(=[O:29])[CH3:28].[Na+]>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][CH:5]1[O:6][C:27](=[O:29])[CH3:28])=[N+:2]=[N-:3]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC[C@H]1OC(O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of nitrate ester 68 (17.5 g, 46.5 mmol) in 500 mL of glacial acetic acid is added sodium acetate (7.63 g, 93.0 mmol). The solution is stirred at 100° C. for 3 h and then allowed to cool to room temperature. The reaction mixture is diluted with 1000 mL of ice water and extracted with CH2Cl2 (2×200 mL) The organic layers are combined and washed with ice water (2×400 mL), saturated NaHCO3 (400 mL), saturated NaCl (400 mL), dried over Na2SO4, filtered and concentrated. The crude product is crystallized from hexane/EtOAc to give 7.2 g of 2-azido-2-deoxy-1,3,4,6-tetra-O-acetyl-α,β-D-galactopyranose 69 (mixed anomers). The mother liquors from the crystallization are concentrated and purified by flash chromatography (25% EtOAc/hexane) to give an additional 7.0 g of the product (14.2 g, 81.7% in total) as a mixture of anomers: Rf 0.3 (30% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz, mixture of anomers) δ 6.26 (d, J=3.6 Hz, 1 H, H-1α), 5.50 (d, J=8.6 Hz, 1 H, H-1β), 5.42 (d, J=3.0 Hz, 1 H, H-4α), 5.32 (d, J=3.0 Hz, 1 H, H-4β), 5.25 (dd, J=11.2, 3.0 Hz, 1 H, H-3α), 4.85 (dd, J=10.6, 3.3 Hz, 1 H, H-3β), 4.23 (t, J=6.6 Hz, 1 H, H-5α), 3.95-4.10 (m, 5 H, H-6α, H-5β, H-6β), 3.88 (dd, J=11.2, 3.6 Hz, 1 H, H-2α), 3.78 (dd, J=10.9, 8.6 Hz, 1 H, H-2β), 1.90-2.20 (6s, 24 H, OAc).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50])([CH3:46])[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:50][C:49]4[CH:51]=[CH:52][CH:53]=[C:47]([CH:44]([CH3:46])[CH3:45])[CH:48]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: CC(C)c1cccc(N)c1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2cccc(C(C)C)c2)c1)C3
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.25 mmol, 100 mg) and N, N-diisopropylethylamine (0.75 mmol, 0.131 mL) in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.325 mmol, 0.193 mL). After 5 min at rt, 3-isopropylaniline (0.375 mmol, 0.053 mL) and catalytic DMAP was added and the reactions continued for 2 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.025 mL 3-isopropylaniline was added and the reaction continued for 19 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3/EtOAc and then recrystallized from EtOAc/hexane to give the title compound as a white solid (20 mg, 17%).
Reaction SMILES: O.[OH-].[Li+:3].[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]([C:17]([O:19]CC)=[O:18])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=1)[CH3:5].C(=O)=O>O.O1CCOCC1>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]([C:17]([O-:19])=[O:18])=[C:11]([C:13]([CH3:15])([OH:16])[CH3:14])[N:12]=1)[CH3:5].[Li+:3]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOCc1nc(C(C)(C)O)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
A solution of 51.5 mg of lithium hydroxide monohydrate in 8 ml of water was added to a solution of 600 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 86(a)] in 19.5 ml of dioxane, whilst ice-cooling, and the mixture was stirred at 5°-10° C. for 16 hours. At the end of this time, a small piece of dry ice was added, and the reaction solution was concentrated by evaporation under reduced pressure down to approximately 8 ml. The concentrate was then mixed with ethyl acetate and sodium chloride and stirred. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give lithium 2-ethoxymethyl-4-(1-hydroxyl-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as an amorphous powder. The whole of this product was dissolved in 6 ml of N,N-dimethylacetamide, and 113 mg of potassium carbonate were added to the resulting solution, after which a solution of 240 mg of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity grade: 74%) in 2 ml of N,N-dimethylacetamide was added dropwise to the mixture. The mixture was then stirred at 50° C. for 1 hour, after which it was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 548 mg of the title compound as crystals, melting at 129°-130.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[N:20]([O-])=O.[Na+].[Sn]>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [Sn]
Product: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(Quinolin-2-ylmethoxy)-phenylamine (1.73 g) in 30 mL of concentrated HCl at 0° C. was added sodium nitrite (531 mg). After 3 h, tin chlrodie (3.95 g) was dissolved in 20 mL of concentrated HCl and added slowly dropwise and the reaction mixture stirred at ambient temperature for 18 h. The reaction mixture was filtered and the solid dried to provide the title compound as the HCL salt (3.94 g). MS: (M+H m/z=266.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2]>CO.[Rh]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Yield: 0 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (described in Example 1a) (0.5 g; 1.5 mole) was hydrogenated at atmospheric pressure using rhodium on charcoal as catalyst (5%, 50 mg) in methanol (20 ml). The crude product was purified by chromatography using heptane:ethyl acetate (5:1) as eluent to give 50 mg (yield 10%) of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34](Cl)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1.CCO>CC(N(C)C)=O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([N:1]7[CH2:6][CH2:5][O:4][CH2:3][CH2:2]7)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: C1COCCN1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(N4CCOCC4)ccc3Cl)cc1-2
Reaction time: 36 h

Procedure:
The title compound was synthesized from 0.27 g of morpholine and the title compound of Example 216 (0.522 g) by the same procedure used for Example 207 except that EtOH was replaced by 0.5 ml of DMA. The reaction was carried out at 80° C. for 36 hours. The title compound, isolated by preparative HPLC, is a white solid (0.30 g, 52%), m.p. 260–262° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDCl3) δ 2.96 (m, 2H), 3.15 (m, 2H)), 3.48 (m, 4H), 3.86 (m, 4H), 5.41 (s, 1H), 6.74–6.86 (m, 2H), 6.90–7.04 (m, 2H), 7.16 (d, 1H, J=1 Hz), 7.28–7.35 (m, 2H), 7.54–7.22 (m, 2H), 9.32 (s, 1H). ESI mass spectrum for C29H26ClN6O5+: 573 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[N:22]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:20][N:21]1[C:25]([C:2]2[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[S:5][C:6]=2[CH2:7][CH2:8][CH3:9])=[CH:24][CH:23]=[N:22]1
Reactant: CCCc1sc(C(=O)OC)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of methyl 4-bromo-5-propyl-2-thiophenecarboxylate (1.0 g, 3.80 mmol), potassium carbonate (2.63 g, 19.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.949 g, 4.56 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.097 g, 0.19 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated and purified by column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (1.07 g, 3.76 mmol, 99% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.C(O[C:24]([CH3:33])([CH3:32])[CH:25]([OH:31])[C:26]([O:28]CC)=O)C.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:26](=[O:28])[C:25](=[C:24]([CH3:32])[CH3:33])[O:31][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(O)C(C)(C)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 205 °C
Yield: 46.1 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (10.0 g, 33.1 mmol), ethyl 3-ethoxy-2-hydroxy-3-methylbutanoate (9.44 g, 49.7 mmol), ferric chloride hexahydrate (90.2 mg, 0.03 mmol) and tributylamine (309.5 mg, 1.7 mmol) were introduced into a two-necked eggplant type flask (200 cc) equipped with a Dean Stark and a Dimroth condenser and heated at 205° C. (oil bath) for 10 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, toluene (60 mL) was added, and the reaction solution was washed with water (100 mL). The organic layer was concentrated under reduced pressure, and ethanol (35 mL) acidified with hydrochloric acid was added to the resulting oily substance to form a homogeneous solution. The solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with ethanol acidified with hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione as white crystals (5.40 g, yield 46.1%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([C@@:18]1([CH2:33][CH2:34]Br)[CH:22]([CH3:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>O1CCCC1>[C:11]([O:15][C:16]([C@@:18]12[CH2:33][CH2:34][C@:22]1([CH3:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[CH2:19]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCBr)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC[C@]2(C)C1=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (3.8 mL, 3.80 mmol) was added dropwise to a solution of (3S)-3-(2-bromoethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.30 g, 3.17 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −72° C. over seven minutes. The mixture was stirred at the same temperature for 30 minutes. After heating to −10° C. and stirring for 1.5 hours, a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.0 mL, 4.0 mmol) was added over two minutes, and the mixture was stirred at 0° C. for 20 hours. A 10% citric acid solution (20 mL) was added at the same temperature. The reaction solution was poured into a mixture of ethyl acetate (100 mL) and a 10% citric acid solution (10 mL). After extraction with ethyl acetate (150 mL), the organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give 0.845 g (81%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]1([NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30](=[O:31])[C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)=[CH:34][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4ccc(C(=O)Nc5ccccc5)cc4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 4-phenylaminocarbonylphenylboronic acid (37.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a yellow solid (68 mg, 100%). (HPLC (method F): 77%, RT: 4.21 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 10.41 (s, 1H), 8.65-8.56 (m, 1H), 8.30 (d, J=7.9, 2H), 8.21 (d, J=8.5, 2H), 7.85-7.76 (m, 3H), 7.70 (dd, J=3.9, 1.2, 1H), 7.38 (t, J=7.6, 2H), 7.34 (s, 2H), 7.13 (t, J=7.4, 1H), 3.92 (s, 6H), 3.79-3.70 (m, 3H); MS (m/z) 481 [M+H]+, RT: 4.2 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=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>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
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: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 9 h
Yield: 74.7 %

Procedure:
To a suspension of 2-amino-5-bromo-3-nitropyridine (2.2 g, 10.1 mmol) in dimethoxyethane (20 mL) were added 4-fluorophenylboronic acid (4.83 g, 13.1 mmol), tetrakis(triphenylphosphine)palladium (580 mg, 0.50 mmol) and 2N aqueous sodium carbonate solution (10 mL). The mixture was stirred at 80° C. for 9 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate to give a precipitate, which was collected by filtration, washed with ethyl acetate and then dried to give the title compound (1.76 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Cl:29]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[Cl:29][C:4]1[C:5]([OH:28])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)ccc3O)n2)c1C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)cc(Cl)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 2 Step B (1.50 g, 3.79 mmol) in acetonitrile (9.5 mL) was added N-chlorosuccinimide (760 mg, 5.69 mmol), and the resulting mixture was placed in a pre-heated oil bath (90° C.). After 1 h, the reaction mixture was allowed to cool to room temperature, then was diluted with DCM, and the resulting mixture was washed with brine. The organic phase was then concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 429.9 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 12.50 (s, 1H), 8.18 (s, 1H, 8.14 (t, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.46 (dd, J=9.0, 3.0 Hz, 1H), 7.25 (dd, J=9.0, 3.0 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:31][CH2:30][CH2:29]1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Cl[Mg]C1CCC1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CCC3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Cylobutylmagnesium chloride (0.5 M, 1.1 mL, 0.55 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give cyclobutyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 M HCl/dioxane and heated to 65° C. for 2 hours, concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1.[C:17]([C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](=[O:14])[O:28][C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH:22]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C(=O)Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C(=O)Oc1ccc(Cl)c(C(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To 30 ml of acetone were added 2.04 g of N-(3-chlorophenyl)-N-methylcarbamoyl chloride, 1.84 g of 3-tert-butyl-4-chlorophenol and 1.6 g of anhydrous potassium carbonate, and the mixture was refluxed with heating for 48 hours. The reaction mixture was cooled down to room temperature and thereafter was poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and was dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier and benzen as developing solvent), and further recrystallized from hexane to give 3.2 g of 3-tert-butyl-4-chlorophenyl N-(3-chlorophenyl)-N-methylcarbamate, having melting point of 65°-67° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CCOC(=NC(=O)c1ccc(C(C)(C)C)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-tert.butylbenzoyl chloride, there is obtained ethyl N-(p-tert.butylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 426 (8), 398 (6), 194 (100), 161 (36);
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0, methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et3N (6.4 g, 64 mmol) in DCM (100 mL). After the addition, the mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with water (3×30 mL), 1N HCl (20 mL) and brine (30 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo. After vacuum drying, the title compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1 (M+H+).