Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccc(F)cc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-fluorocinnamyl trichloroacetimidate (112 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 20 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (33 mg).
Reaction SMILES: C(Br)C=C.[C:5]([O-:8])([O-])=O.[K+].[K+].[CH2:11]([O:14][C:15]1[CH:22]=[CH:21][C:18](C=C)=[CH:17][CH:16]=1)[CH:12]=[CH2:13]>CC(C)=O>[CH2:11]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:5]=[O:8])=[CH:17][CH:16]=1)[CH:12]=[CH2:13]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1ccc(C=C)cc1
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1

Procedure:
4-allyloxybenzaldehyde was prepared by reaction of allyl bromide on 4-hydroxybenzaldehyde in refluxing acetone in the presence of K2CO3. The distilled product was used as a precursor for 4-allyloxystyrene synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:24].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:24])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: Cn1cc(-c2cncc(Br)c2)cn1
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2cc(Br)c[n+]([O-])c2)cn1

Procedure:
A slurry of 266 mg (1.12 mmol) 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine and 1.30 g (2.23 mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 5 ml 2-propanol was stirred for 18 hours at room temperature. The reaction mixture was evaporated and the residue partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic phase was dried over sodium sulfate and evaporated yielding 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine 1-oxide as slightly yellow solid; HPLC-MS: 1.34 min, [M+H] 254/256.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:44])=[N:17][C:18]([CH3:43])=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:29][CH:28]=2)[C:20]=1[N:21]1[CH2:24][C:23]([F:26])([F:25])[CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:44])=[N:17][C:18]([CH3:43])=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:29][CH:28]=2)[C:20]=1[N:21]1[CH2:22][C:23]([F:26])([F:25])[CH2:24]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CC(F)(F)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
The 0.40 mL of 1M sodium hydroxide (14.78 mg, 0.37 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-difluoroazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (54 mg, 0.09 mmol) in ethanol (2 mL) and stirred for 18 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep to afford (S)-2-(tert-butoxy)-2-(4-(3,3-difluoroazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 46 mg (92%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.04-6.95 (m, 3H), 5.03 (s, 1H), 4.23 (t, J=6.6 Hz, 2H) 4.04 (t, J=12.8 Hz, 4H), 3.06 (t, J=6.6 Hz, 2H), 2.40 (s, 3H), 2.05 (s, 3H), 1.09 (s, 9H). UPLC (M+H)=544.05.
Reaction SMILES: [CH3:1][C@:2]([C:14]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].[C:27]12([CH2:37][C:38](Cl)=[O:39])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C1COCC1>[OH:26][CH2:25][CH:17]([NH:16][C:14](=[O:15])[C:2]([CH3:1])([NH:3][C:38](=[O:39])[CH2:37][C:27]12[CH2:36][CH:31]3[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]3)[CH2:34]1)[CH2:28]2)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C[C@@](N)(Cc1c[nH]c2ccccc12)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)CC12CC3CC(CC(C3)C1)C2)C(=O)NC(CO)Cc1ccccc1
Yield: 113 %

Procedure:
A solution of α-methyl-D-tryptophyl-L-phenylalaninol (1 g, 2.85 mmol) and 4-N,N-dimethylaminopyridine (0.35 g, 2.87 mmol ) in dry THF (50 mL ) at 0° C. was treated dropwise, with stirring, with a solution of 1-adamantylacetyl chloride (0.605 g, 2.85 mmol). A precipitate formed immediately. The reaction mixture was left until all starting materials were consumed as assayed by TLC and IR spectroscopy. The final TLC showed three spots (10% MeOH:90% CH2Cl2). The reaction mixture was washed with 1M citric acid solution and extracted into ethyl acetate. The organic phase was then washed with water and dried over MgSO4. Concentration in vacuo gave a syrup (1.7 g) which was chromatographed over silica using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.35 g, 90%) as a white solid crystallized from ethyl acetate-hexane, mp 91°-94° C. (EtOAc-hexane); IR (KBr) 3304 and 1652 cm-1 ; NMR (CDCl3) δ1.48 (9H, m), 1.59 (6H, m), 1.76 (2H, q, J 13 Hz), 1.9 (3H, m), 2.74 (2H, d, J 7Hz), 3.21 (1H, half ABq J 14.5Hz), 3.30 (1H, 6, J 6Hz), 3.40 (1H, half Abq J 14.5Hz), 3.45 (1H, m), 3.70 (1H, m), 4.16 (1H, m), 5.91 (1H, s), 6.38 (1H, d, J 8Hz), 6.92 (1H, d, J 3Hz), 7.07-7.27 (7 H, m), 7.35 (1H, d, J 8Hz), 7.56 (1H, d, J 8Hz) and 8.54 (1H, s); Anal. (C33H41N3O3.0.25 H2O), C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[N:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH:6]([OH:7])[CH3:11])=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: Cc1nc(Cl)ccc1C=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1C(C)O
Temperature: -78 °C

Procedure:
6-Chloro-2-methylnicotinaldehyde (300 mg, 1.93 mmol) was taken up in THF (9.6 ml) under argon and cooled to −78° C. Methylmagnesium bromide (1.29 ml, 3.86 mmol) was added dropwise over 5 minutes. The reaction temperature was maintained at −78° C. for 20 minutes, then was allowed to warm to 0° C. over 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction mixture was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-75% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:9]([CH:8]=[C:7]([C:5]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:2]=[CH:3][N:4]=4)[N:16]=3)[CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1
Reactant: CC(C)NN
Reactant: CN(C)/C=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Yield: 89.6 %

Procedure:
Alternatively, to a suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide (8.52 g, 23.5 mmol) in acetic acid (50 mL) was added isopropylhydrazine hydrochloride (3.37 g, 30.5 mmol) and the reaction mixture heated at 100° C. for 1 h. The reaction mixture was allowed to cool to RT and was poured onto water (500 mL) causing the product to precipitate as an off-white solid. The product was collected by filtration, washed with water (˜200 mL) and dried in vacuo at 45° C. for 16 h to yield 194 as an off-white solid (7.88 g, 86%). 1H NMR (400 MHz, d6-DMSO) 8.43 (1H, d, J=8.6 Hz), 7.97 (1H, s), 7.92 (1H, d, J=0.6 Hz), 7.36 (1H, dd, J=8.6, 2.0 Hz), 7.30 (1H, d, J=2.0 Hz), 5.86 (1H, sept, J=6.6 Hz), 4.56-4.52 (4H, m), 1.48 (6H, d, J=6.6 Hz). LCMS: RT=4.69 min, M+H+=374/376. 1H NMR showed product to contain ˜5% 8-iodo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[O:20])=[CH:13]1)[N:8]=[C:7]([C:33]([O:35]CC)=[O:34])[C:6](=[O:38])[NH:5]2.[OH-].[K+]>C(O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][N:12]([C:11]3[CH:10]=[C:9]4[C:4]([NH:5][C:6](=[O:38])[C:7]([C:33]([OH:35])=[O:34])=[N:8]4)=[CH:3][C:2]=3[Cl:1])[CH:13]=2)=[O:20])=[CH:27][CH:26]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1ccc(NC(=O)NCc2ccn(-c3cc4nc(C(=O)OCC)c(=O)[nH]c4cc3Cl)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCc1ccn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)c1)Nc1ccc(C(=O)O)cc1

Procedure:
To a solution of the compound (25.4 mg, 47.2 μmol) of Example 6 in ethanol (2 ml) was added 1 mol/L aqueous solution of potassium hydroxide (189 μl, 189 μmol), and the mixture was refluxed for 1.5 hours. After cooling, solvent was distilled off. The residue was dissolved into a small quantity of water, which was brought to pH2 using 4 mol/L hydrochloric acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Al+3].[CH3:6][CH:7]([CH3:9])[O-].[CH3:10][CH:11]([CH3:13])[O-].[C:14]1([CH3:20])[CH:19]=[CH:18]C=C[CH:15]=1>>[CH3:6][C:7]1([CH3:9])[C:13]2[CH2:11][CH2:10][CH2:4][CH:2]([OH:3])[C:1]=2[C:14]([CH3:15])([CH3:20])[CH:19]1[CH3:18]
Reactant: CC(C)[O-]
Reactant: Cc1ccccc1
Agent: [Al+3]
Product: CC1C(C)(C)C2=C(C(O)CCC2)C1(C)C
Reaction time: 8 h

Procedure:
Into a 2-liter reaction vessel are placed 831 ml of toluene and 226.9 grams (1.11 moles) of aluminum isopropoxide. The mixture is heated to reflux and while refluxing, over a one hour period, tetrahydro pentamethylindane epoxide having the structure: ##STR63## is added to the reaction mass. The reaction mass is continued to be refluxed for a period of twelve hours while being monitored by GLC analysis. An additional 0.5 moles of aluminum isopropoxide is added (101.5 grams) at the end of the twelve hour period and the refluxing is continued for an additional eight hours. At the end of the twenty hour period, an additional 50.7 grams of aluminum triisopropylate is added and the reaction mass is continued to be refluxed for an additional twenty two hours (total reflux time 42 hours).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:16][N:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 36.9 %

Procedure:
[1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-acetic acid tert-butyl ester (280 mg, 0.866 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (245 mg, 0.953 mmol), Et3N (486 uL, 3.46 mmol) and BOP (402 mg. 0.909 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid tert-butyl ester as a solid (170 mg). ES-MS calcd for C26H27F3N4O5 (m/e) 532.52, obsd 533.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]3[CH:36]=[C:35]([NH:37][CH3:38])[N:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:15])[N:37]([C:35]1[CH:36]=[C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:29][CH:28]=2)[N:32]=[CH:33][N:34]=1)[CH3:38]
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
The title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl-isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5 h at reflux. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0/561.9 [MH]+; tR=3.54 min (purity: 100%, gradient J); TLC: Rf=0.28 (DCM/MeOH+1% NH3aq, 95:5). Analysis: C26H31N7O3Cl2, calc. C, 55.72%; H, 5.57%; N, 17.49%; O, 8.56%; Cl, 12.65%. Found C, 55.96%; H, 5.84%; N, 17.17%; O, 8.46%; Cl, 12.57%. The title compound was characterized by XRPD, thermal and other methods as described below.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](Cl)(C)C>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1F
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1F
Yield: 72.5 %

Procedure:
2,5-Difluoro-3-nitrobenzoic acid (2.00 g, 9.847 mmol) was dissolved in MeOH (60 mL). TMSCl (6.220 mL, 49.24 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to about 20 mL, and the crystals produced were filtered and dried under high vacuum providing methyl 2,5-difluoro-3-nitrobenzoate (1.55 g, 72.4%) as a crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[C:31]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:32]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(-c5ccccc5)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (product from Example 69, step B) and biphenyl-3-boronic acid. MS (ESI): mass calcd. for C24H16N4O3, 408.1; m/z found, 409.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (s, 1H), 12.92 (s, 1H), 9.00 (s, 1H), 8.44 (s, 1H), 8.32-8.25 (m, 2H), 8.01 (s, 1H), 7.83-7.77 (m, 4H), 7.72 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.53-7.48 (m, 2H), 7.43-7.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)=[O:10].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][CH2:34]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:34][CH2:33][O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Cc1ccccc1Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: ICCOC1CCCCO1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)C(CCOC1CCCCO1)c1ccccc1Cl

Procedure:
2-(2-Chlorophenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-one is prepared by PTC reaction according to the method described in the example 4d using 2-(2-chlorophenyl)-1-[4-(2-piperidinylethoxy)phenyl]ethanone (1.5 g, 4.2 mmol) and 2-tetrahydropyranyloxy-1-iodoethane (1.3 g, 5.1 mmol) as the starting materials. The product (1.6 g) is used for the following reaction step without further purification.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:11]=1[O:24]C)(C)[C:4]([O:6]CC)=[O:5])#N.I.[OH-].[K+].CO>C(O)(=O)C>[OH:24][C:11]1[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2C)c1OC
Agent: I
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1Sc1cccc(C(C)C(=O)O)c1O
Yield: 47.5 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]propionate (10 g) and hydriodic acid (58%, 12 ml) in acetic acid (24 ml) was refluxed under heating for 24 hours. After concentration, the residue was dissolved in aqueous sodium hydrogen sulfite and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the residue was added acetic anhydride (10 ml), and the mixture was refluxed under heating for 10 minutes and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with benzene to give oily crude 3-methyl-7-(o-tolylthio)-2,3-dihydrobenzofuran- 2-one (5.4 g). To this product (5.4 g) were added potassium hydroxide (1.5 g) and methanol (50 ml), and the mixture was refluxed under heating for an hour and concentrated under reduced pressure. The residue was crystallized with a mixture of benzene and n-hexane to give 2-[2-hydroxy-3-(o-tolylthio)phenyl]propionic acid (3.85 g), mp. 123°-125° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([O:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:49]([O:48][C@@H:45]1[CH2:44][CH2:43][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:47][CH2:46]1)[CH3:50]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCO[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166A). 1H NMR (DMSO-d6, 400 MHz): δ=1.15-1.22 (m, 9H), 1.44-1.56 (m, 4H), 1.69-1.82 (m, 2H), 1.95 (d, J=11.62 Hz, 2H), 2.53-2.63 (m, 1H), 3.07 (s, 3H), 3.22-3.30 (m, 2H), 3.45 (q, J=6.99 Hz, 2H), 3.60 (br. s., 1H), 3.75 (s, 3H), 3.94-4.04 (m, 4H), 4.49 (s, 2H), 6.91 (d, J=7.58 Hz, 1H), 7.06 (s, 1H), 7.18 (br. s., 1H), 7.49 (br. s., 1H), 8.22-8.48 (m, 2H), 9.00 (br. s., 1H), 10.56 (s, 1H). MS (ES+): m/z 706.30 [MH+] (TOF, polar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1>O1CCCC1.C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
Into a 1-L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-iodobenzene (25.0 g, 88.4 mmol) in tetrahydrofuran/diethyl ether (400/200 mL). The solution was cooled to −78° C. then n-BuLi (2.5 M, 37.1 mL, 92.8 mmol) was added drop-wise over 10 min. To the resulting mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (16.6 g, 97.0 mmol) in THF (100 mL) drop-wise at −78° C. The resulting mixture was stirred for 1.5 h at −78° C., then carefully quenched with water (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20-1:5) as the eluent followed by re-crystallized from ethyl acetate:PE in the ratio of 1:100 to yield 8.0 g (28%) of the title compound as a white solid.