Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:2]2=[NH:1])=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Fc1ccc(CBr)cc1
Product: N=c1n(Cc2ccc(F)cc2)c2ccccc2n1Cc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 4-fluorobenzyl bromide by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 148-150° C.). MS(ES+) m/z 351 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.07 (s, 4H), 5.75 (br s, 1H), 6.78-6.91 (m, 4H), 7.12-7.18 (m, 4H), 7.30-7.42 (m, 4H).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to room temperature overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to provide 6.5 (80%), m.p. 143–145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 63.2 %

Procedure:
10 g (60.5 mmol) of ethyl 4-aminobenzoate and 13.7 g (60.5 mmol) of 2-naphthylsulfonyl chloride were reacted by the method of procedure 4b, affording 13.6 g (64%) of the product.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C(C)(C)C)=[O:9])[C:6](=[O:7])[CH2:5][CH2:4][O:3]1.F[C:16](F)(F)C(O)=O.ClCCl>>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[C:6](=[O:7])[CH2:5][CH:4]([CH3:16])[O:3]1
Reactant: CC(C)(C)OC(=O)C1(C)OCCC1=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(=O)C(C)(C(=O)O)O1
Temperature: 25 °C
Yield: 68 %

Procedure:
2-Methyl-3-oxo-2-tetrahydrofuroic acid, t-butyl ester (100 mg, 0.5 mmol) was treated with 1/1 trifluoroacetic acid/dichloromethane at 0° C. The reaction mixture was stirred at room temperature until all starting material had disappeared by TLC. The excess trifluoroacetic acid was removed via a stream of nitrogen and the residue was coevaporated with dichloromethane and purified via a silica gel SepPak plug. This 30 provided 49 mg of the desired product (68%), homogeneous by TLC (Rf=0.1 in 4/1 hexane/ethyl acetate).
Reaction SMILES: [OH:1]O.[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][C@H:15]5[C:16]([O:22]C)=[CH:17][CH:18]=[C:19]2[C@:7]5([C:8]=34)[CH2:6][CH2:5]1>>[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][CH:15]5[C:16]([CH:17]=[CH:18][C@:19]2([OH:1])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:22]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: OO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 0.10 L round bottom flask (RBF) is charged with 18.9 g of formic acid, 9.9 g of water, and 7.8 g of 2-propanol. This mixture is stirred at 20–30° C. for 5 minutes. Into this solution is added 5.0 g of thebaine bitartrate monohydrate. This is stirred magnetically at room temperature for 10 minutes until dissolution is achieved. The color of the solution depends on the quality of the thebaine bitartrate. Good quality of thebaine bitartrate affords a pale yellowish solution. No exothermic effect is observed. The solution is cooled in an ice-bath for 20 minutes, and then into this solution 1.29 g of hydrogen peroxide is added. The resulting solution is stirred in the ice-bath for one hour. The ice-bath is removed, and an oil-bath with temperature controller is applied to the reaction flask. Heating is started and the temperature of the reaction mixture is kept at 45° C. for 3 h (completion of reaction tested by HPLC; residual thebaine <0.5 a/a %).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].C[CH:11]1[CH2:16][CH:15]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:14][CH2:13][NH:12]1>C(Cl)(Cl)Cl>[C:2]([N:12]1[CH2:11][CH2:16][CH:15]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:14][CH2:13]1)#[N:1]
Reactant: N#CBr
Reactant: CC1CC(c2nsc3ccccc23)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nsc3ccccc23)CC1
Yield: 39.1 %

Procedure:
To a stirred mixture of 5.9 g of cyanogen bromide, 8.6 g of potassium carbonate, and 80 ml of chloroform was added, dropwise, 11.0 g of 3-(2-methyl-4-piperidinyl)-1,2-benzisothiazole, in 30 ml of chloroform. The mixture was stirred under reflux for 4 hrs, cooled, filtered and the filtrate was concentrated in vacuo to a solid. The solid was triturated with hexane and recrystallized from methanol-water (twice) to yield 4.5 g (36%) of product, mp 118°-120°.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[C:10]([N:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[C@@H:19]2[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:21][C@@H:20]2[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]12
Reaction time: 8 h

Procedure:
The title compound was prepared using commercially available ethyl chloro oximidoacetate (5). N-Boc-pyrroline (1.0 g; 5.91 mmol), ethyl chloro oximidoacetate (2.55 g; 16.8 mmol) and sodium bicarbonate (1.77 g; 21.06 mmol) in ethyl acetate (15 mL) were stirred for 54 hours. An additional amount of chloro oxime (2.6 g; 17.28 mmol) and sodium bicarbonate (2.1 g; 25.00 mmol) was added and the reaction mixture stirred overnight. The addition of reagents was repeated again and the reaction mixture stirred for 36 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated. Cycloadduct 6 was isolated as a clear oil after chromatography with 20% ethyl acetate/hexanes.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][N:12]1[C:16]([NH2:17])=[C:15]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]2=[N:13]1>O>[CH3:11][N:12]1[C:16]([NH:17][CH:1]=[O:3])=[C:15]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]2=[N:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc2c(oc3ccccc32)c1N
Solvent: O
Solvent: O=CO
Product: Cn1nc2c(oc3ccccc32)c1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (200 mL) and 98% formic acid (10 mL) was heated at 50°-60° C. for 15 minutes. After cooling, 2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (5.0 g, 27 mmol, described in Example 6) was added. After stirring overnight at room temperature, the mixture was poured on a mixture of ice and water and extracted with methylene chloride. The organic extract was dried and evaporated. The residue was chromatographed through silica gel using 5% EtOH--CH2Cl2 (v/v) and the eluates were evaporated. Trituration of the resulting residue with diethyl ether gave 3.0 g of N-(2-methyl-2H-benzofuro[3,2-c]pyrazol-3-yl)formamide: mp 184°-187° C.; IR (mineral oil) 3190 and 1670 cm-1 ; UV max (MeOH) 269 nm (ε=21100), 222 (19500) and shoulder at 291 and 215; NMR (DMSO-d6) δ3.85 (3H, s), 7.5 (4H, m), 8.4 (1H, s) and 10.4 (1H, br); and Anal. Calcd for C11H9N3O2 : C, 61.39% H, 4.21% N, 19.53% and Found: C, 61.17% H, 4.27% N, 19.37%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
80 mg (0.13 mmol) N-(4-Methoxy-phenyl)-N-(tert-butyl-oxycarbonylpropyl-sulfonyl)-thieno-[2,3-b]quinoline-4-carboxamide 16 were dissolved in 1.2 mL trifluoroacetic acid and stirred for 30 minutes at room temperature. 50 mg of silica gel and 10 mL of methylene chloride were added and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (eluent: methylene chloride/diethylether 6:4+0.1% trifluoroacetic acid). Evaporation of the appropriate fractions gave 66 mg of the desired product 17.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:25][CH3:26])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[CH2:17][NH:18]C(=O)C)[N:8]=1.Cl.CO>CC#N>[NH2:18][CH2:17][C:16]1[CH:15]=[C:14]([NH:13][C:9]2[N:8]=[C:7]([C:6]3[S:5][C:4]([NH:25][CH3:26])=[N:3][C:2]=3[CH3:1])[CH:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1

Procedure:
By treatment of N-{3-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide with HCl/MeOH. Yellow solid. Mp 287-289° C. Anal. RP-HPLC: tR=10.1 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-D6) δ: 2.68 (s, 3H, CH3), 3.17 (s, 3H, CH3), 4.17 (m, 2H, CH2), 7.23 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.27 (d, 1H, J=8.0 Hz, Ph-H), 7.50 (t, 1H, J=8.0 Hz, Ph-H), 7.70 (d, 1H, J=7.5 Hz, Ph-H), 7.75 (s, 1H, Ph-H), 8.44 (d, 1H, J=6.0 Hz, pyrimidinyl-H). MS (ESI+) m/z 327.37 [M+H]+ (C16H18N6S requires 326.42).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:27]2)=[O:23]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(C(=O)OC)cc4C3)cc21
Yield: 50.1 %

Procedure:
128 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 104 mg of the target compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)NCCc1ccccc1
Temperature: 95 °C
Yield: 95.9 %

Procedure:
121.18 g of phenethylamine is dissolved in 450 ml of toluene in a 2 l three-necked flask. 102.09 g (95 ml) of acetic anhydride is added dropwise over a half hour period the temperature rises to 110° . After the addition is completed, the reaction solution temperature is maintained at approximately 95° C. The solvent is removed in vacuo and the residual oil was distilled under high vacuum (bp 160°-165° C./1mm) to afford 156.6 g of a white crystalline solid. The product exhibited NMR peaks (CDCl3, δ) at 7.35, 3.45, 2.80, and 1.90.
Reaction SMILES: [C:1]1(SC[Li])C=CC=CC=1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:22][CH2:21]1>>[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:1])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:21][CH2:22]1
Reactant: COCOc1ccccc1C1(c2ccc(O)c(OC)c2OCOC)CC1
Reactant: [Li]CSc1ccccc1
Product: COCOc1ccccc1C1(c2ccc(OC)c(OC)c2OCOC)CC1

Procedure:
When an initial charge of 3.3 moles of phenylthiomethyl lithium per mole of olefin was employed, the product was 1-(2-methoxymethoxyphenyl)-1-(4-hydroxy-3-methoxy-2-methoxymethoxyphenyl)cyclopropane, an oil obtained in 33 percent yield and identified by proton NMR spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[O:12][CH3:13]>C(O)C.C(N(CC)CC)C.[Pd]>[F:8][C:6]1[CH:7]=[CH:2][C:3]([O:12][CH3:13])=[CH:4][C:5]=1[NH2:9]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(N)c1

Procedure:
A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.FC(F)(F)C(O)=O>[CH2:24]([N:18]1[C:19](=[O:20])[C:15]2[C:16](=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[C:17]1=[O:21])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 12.8 %

Procedure:
A solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (150 mg, 0.48 mmol), phenethylalcohol (70 μl, 0.58 mmol) and triphenylphosphine (191 mg, 0.73 mmol) in anhydrous tetrahydrofuran (6 ml) was treated with diisopropyl azodicarboxylate (141 μl, 0.73 mmol) at room temperature and stirred for 6 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a brown oil. The oil was dissolved in trifluoroacetic acid (7 ml) and heated to 65° C. for 24 hours. The mixture was concentrated under reduced pressure and the product was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid which was purified by flash column chromatography (12 g SiO2, 30% ethyl acetate in hexanes). Fractions containing the product were concentrated under reduced pressure. The solid was triturated in ethyl acetate, cooled to 0° C. and filtered to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione as a white solid (18 mg, 13%). M.p.=237-239° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.51 (s, 1H), 7.23 (m, 6H), 3.85 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H); LCMS: 293 [M+H].
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared by coupling 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-3-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 201). HPLC Ret time=3.67 min. LCMS [M+H]+ 411.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([NH:20][C:21](=[O:22])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:18]([C:23](=[O:24])[C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:17]=1
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: COc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155 mmol) in THF (180 mL), at −78° C., was added dropwise 2.5 M n-butyllithium in hexanes (62 mL, 155 mmol). The solution was stirred at −78° C. for 3 h and then added to a suspension of 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in THF (280 mL) at −20° C. The mixture was allowed to gradually warm until the solution became homogenous. 1N HCl (150 mL) followed by EtOAc (250 mL) were then added and the solution allowed to warm to room temperature. The organic portion was collected and washed with H2O (250 mL), saturated NaHCO3 (2×250 mL) and H2O (250 mL). The organic portion was then dried over Na2SO4 and evaporated to dryness, in vacuo, to provide the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as an orange solid (42.7 g). To a solution of N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7 g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in H2O (100 mL). The solution was allowed to reflux for 16 h. The solution was then allowed to cool to room temperature and the resulting precipitate removed by filtration. The filtrate was concentrated in vacuo, diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic portion was then dried over Na2SO4, concentrated in vacuo and then purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac (19.6 g, 47%) MS m/z=280 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[NH:15][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[N:15]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:16]=1[CH:17]=[O:18]
Reactant: Cc1nc(Br)c(C=O)[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4-Cyanobenzylbromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimidazole-5-carboxaldehyde (1.02 g, 5.39 mmol) in dimethylacetamide (15 mL). The solution was cooled to -10° C. and powdered potassium carbonate (0.745 g, 5.39 mmol) added. The reaction was stirred at -10° C. for 2 h, and a further 4 h at 20° C. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. Solvent evaporation yielded a white solid. 1H NMR (CDCl3, 400 MHz) δ 9.68 (1H, s), 7.64 (2H, d, J=7 Hz), 7.15 (2H, d, J=7 Hz) 5.59 (2H, s), 2.40 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:44])[NH:30][C:31]3[CH:36]=[CH:35][C:34](C4C=CC=CC=4)=[C:33]([CH3:43])[CH:32]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:44])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[C:33]([CH3:43])[CH:32]=3)=[CH:25][N:24]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4cccc(OC)c4)c(C)c3)cn2)CC1

Procedure:
5′-(3′-Methoxy-2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from F-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-methoxyphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2388.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][O:23][CH3:24])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[O:23][CH3:24])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCCc1ccc(F)cc1
Product: CON(CCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 86 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[2-(4-fluorophenyl)-ethyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (86% yield): mp 106-107° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 2.95 (2H, m, CH2), 3.72 (3H, s, OCH3), 3.87 (2H, m, NCH2), 6.38 (1H, broad s, CH), 6.99 (2H, m, aromatics), 7.20 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.39; H, 5.43; N, 4.13.