Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.[Ag-]=O>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CO
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC(=O)COCc1ccccc1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of methyl glycolate (2 g, 22.2 mmol) in anhydrous diethyl ether (100 mL), at room temperature, under a nitrogen atmosphere, was added silver(I)oxide (10.3 g, 44.4 mmol). The suspension was stirred for 15 minutes and benzyl bromide (4.5 g, 26.3 mmol) was added. The mixture was stirred at the same temperature for 24 h and the insoluble materials were removed by filtration through a short pad of celite. The filtrate was concentrated under reduced pressure and the crude product chromatographed over a column of silica gel, eluting with 20% diethyl ether-petroleum ether to give 70, as a colorless liquid in 70% yield (2.8 g).
Reaction SMILES: [F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8](S(C)(=O)=O)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>CC(O)C.CCOC(C)=O>[F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8]([NH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(S(C)(=O)=O)ncc2C(F)(F)C1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred suspension of 204 (349 mg, 1 mmol) in IPA (3 mL) at RT under nitrogen was added sequentially via syringe neat DIPEA (174 μL, 1 mmol) and neat tetrahydro-2H-pyran-4-amine (101 mg, 1 mmol). The mixture was heated to 90° C. and became homogeneous. Heating was continued for 60 min them cooled to RT, diluted to 30 mL with EtOAc and was washed sequentially with 10% citric acid solution (2×30 mL) and satd. aq. NaHCO3 (2×30 mL). The organic phase was isolated, dried (MgSO4), filtered and concentrated to a clear oil. The oil was triturated with hexane/EtOAc (4/1) with sonication to produce a precipitate that was filtered and rinsed with hexane/EtOAc (4/1). The mother liquor was recovered and re-precipitated. Both precipitated batches were combined to afford 215 mg (58%) of tert-butyl 5,5-difluoro-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (206) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.Br[C:24]1C=CC([N+]([O-])=O)=CC=1C(OC)=O.COC1C=CC(C)=CC=1B(O)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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([CH3:24])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(C)ccc1OC
Yield: 98 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.80 g, 6.92 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2-methoxy-5-methylphenylboronic acid (1.58 g, 9.51 mmol) to afford 2.03 g (98%) of methyl 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate as a white solid. Data for methyl(2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.69 (d, J=2.5, 1H), 8.36 (dd, J=8.4, 2.5, 1H), 7.51 (d, J=8.5, 1H), 7.20 (m, 1H), 7.07 (d, J=2.1, 1H), 6.81 (d, J=8.4, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:8]([S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH2:22])(=[O:20])=[O:21])(=[O:10])=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccccc1
Yield: 7.8 %

Procedure:
2-[[(E)-2-Phenylethenyl]sulfonylamino]benzenesulfonamide (0.052 g, 0.15 mmol) was dissolved in MeOH (5 mL) followed by the addition of 10% Pd/C (30 mg). The solution was subjected to hydrogen overnight at 40° C. After filtration, the crude product was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (4 mg, 8%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[C:13](=O)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:2][O:3][N:4]=[C:13]([C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=1[CH3:5])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(=O)c1c(C)cccc1C
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1c(C)cccc1C
Reaction time: 32 h

Procedure:
At room temperature (about 25° C.), 83.5 ml (0.15 mol) of a 15% strength solution of O-methylhydroxylamine hydrochloride in methanol were added dropwise to a mixture of 19.2 g (0.1 mol) of methyl 2,6-dimethylphenylglyoxylate and 100 ml of methanol. At the boiling point of the solvent, the resulting reaction mixture was stirred under reflux for 16 hours and then admixed with a further 24 ml of the 15% strength solution of O-methylhydroxylamine hydrochloride in methanol. After a further 32 h at the boiling point of the solvent, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate. The organic phase was washed with water, dried and freed of the solvent under reduced pressure. The resulting residue (20 g) was purified by distillation. This gave 12 g of the title compound which can be subjected to the isomerization according to Example 3 without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26](S(C)(=O)=O)=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1.CN.C[CH2:36][N:37](C(C)C)C(C)C>C(O)(C)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26]([NH:37][CH3:36])=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3-c3cnc(S(C)(=O)=O)nc3)CC2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CC(C)O
Product: CNc1ncc(-c2ccccc2N2CCN(C(=O)Cn3nc(C)cc3C)CC2)cn1
Reaction time: 0.25 h
Yield: 42 %

Procedure:
The above sulfone (40 mg, 0.088 mmol) is added to a 0.5-2 mL Biotage microwave tube followed by methylamine (2M in THF, 0.22 mL, 0.44 mmol), Hunig's base (0.045 mL, 0.264 mmol) and isopropanol (1 mL). The reaction is carried out in a microwave oven at 175° C. for 15 min. After cooling, the mixture is filtered and purified via prep-HPLC. Removal of the solvent gives the title compound as colorless foam (15 mg).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1.C1(C=O)CC1>CN(C=O)C.O>[CH:17]1([CH:21]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C1CCOC1
Agent: O=CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 13.0 ml (64.85 mmol) of ethyl diethylphosphonoacetate were added dropwise to a suspension of 2.59 g (64.85 mmol) of sodium hydride (60% in mineral oil) in 110 ml of abs. THF. After 30 min, the mixture was warmed to RT and, after cooling again to 0° C., 5.3 ml (71.34 mmol) of cyclopropanecarboxaldehyde were added dropwise. After the end of the addition, the reaction mixture was warmed to RT and diluted with 35 ml of DMF. The mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the crude product was purified by filtration through silica gel (mobile phase cyclohexane/ethyl acetate 10:1→6:1). This gave 8.53 g of the target product (93.8% of theory).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.O>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
Benzoyl chloride (0.92 ml, 7.93 mmol) was added dropwise to a stirred solution of 2-amino-5-nitropyrimidine (1.00 g, 7.14 mmol) in pyridine (20 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, poured into water (200 ml) and allowed to stand for 16 hours. The solid was collected by suction filtration, washed with water (3×20 ml) and dried in vacuo. An oil residue on the surface of the aqueous phase was dissolved in dichloromethane (50 ml) and then purified by flash chromatography on silica gel, eluting with 1–3% methanol in dichloromethane. The two materials were identical and yielded 2-(N-benzoyl)amino-5-nitropyrimidine (826 mg, 47% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][CH:28]=[C:29]2[CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.CC(=O)CC.O>[C:35]([NH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH:31]=[C:22]([O:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=1)[CH:23]=[CH:24]2)(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)NCCc1cccc2ccc(OCCBr)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1

Procedure:
In a 100 ml round-bottomed flask, 0.003 mol of methyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate and 0.003 mol of the compound obtained in Step A are dissolved in a mixture of 3 ml of dimethyl sulphoxide and 20 ml of butanone. 0.009 mol of potassium carbonate and one potassium iodide crystal are added and then the mixture is heated at reflux for 12 hours. The reaction mixture is then cooled and poured into 100 ml of water. The precipitate that forms is suctioned off and recrystallised to yield the title product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[O:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15]([O:17]C)=O)=[CH:4][C:3]=1[CH3:21].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:38](=[O:39])[C:37]([C:32]3[NH:31][C:30]4[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=4[S:34](=[O:36])(=[O:35])[N:33]=3)=[C:15]([OH:17])[C@H:9]3[C@@H:8]2[C@H:13]2[O:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH3:21]
Reactant: COC(=O)[C@H]1[C@@H](NCc2ccc(F)c(C)c2)[C@@H]2CC[C@H]1O2
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@H]3[C@@H]2[C@@H]2CC[C@H]3O2)ccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl (1R,2S,3R,4S)-3-[(4-fluoro-3-methylbenzyl)amino]-7-oxabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 0.34 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 114 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (4 mL) under a nitrogen atmosphere, N-methylmorpholine (0.075 mL, 0.68 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) were added sequentially. The mixture was stirred at 25° C. for 2.5 h, poured into 1.0 M aqueous hydrochloric acid solution, and then was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate which was used in the next step without further purification.
Reaction SMILES: C1(N2C(S[CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:32][CH3:33])[C:20](CCC)=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=NN=N2)C=CC=CC=1.BrC[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:13]([N:14]1[C:24](=[O:25])[C:23]2[C:18](=[C:19]([O:32][CH2:33][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:20]=[CH:21][C:22]=2[O:26][CH2:27][CH3:28])[S:15]1(=[O:16])=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (part B of Example 50, 0.5 g), t-butyl bromoacetate (0.3 g, 0.25 mL), potassium carbonate (0.30 g) and methyl ethyl ketone (about 10 mL) was heated at 70°-80° C. for about one hour, let cool and poured into ice-water (400 mL). The mixture was stirred overnight and the solid was collected affording 2-benzyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 0.58 g, 86% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)ccn1
Temperature: 80 °C
Yield: 44.3 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (2.465 g, 4.72 mmol), 2-methylpyridine-4-boronic acid (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K2CO3 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/H2O (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80° C. overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted with EtOAc (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75% EtOAc in hexanes to yield 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44%) as a solid. MS ESI calc'd. for C31H24ClN4 [M+1]+487, found 487.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:5]2[NH:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=[C:4]2[N:3]=1.[H-].[Na+].CS(O[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28])(=O)=O.O>CN(C)C=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:12]2[C:5]3=[N:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=[C:4]3[N:3]=[C:2]2[CH3:1])=[C:22]([Cl:28])[CH:23]=1.[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:3]2[C:4]3[C:5](=[N:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=3)[N:12]=[C:2]2[CH3:1])=[C:22]([Cl:28])[CH:23]=1
Reactant: Cc1nc2ccc(C#N)[nH]c-2n1
Reactant: CS(=O)(=O)OCc1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(C#N)nc2n1Cc1ccc(Br)cc1Cl
Product: Cc1nc2nc(C#N)ccc2n1Cc1ccc(Br)cc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methylimidazo[4,5-b]pyridine-5-carbonitrile (200 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (70% in mineral oil, 55 mg) under ice-cooling, and the mixture was stirred for 30 min. To this reaction mixture was added 4-bromo-2-chlorobenzyl methanesulfonate (450 mg), and the mixture was stirred for 2 hr at room temperature. The reaction mixture was poured into water and the product was extracted three times with ethyl acetate. The organic layers were combined and washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography (dichloromethane/ethyl acetate=5/1) to give two isomers, 3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Rf 0.4, 233 mg) and 1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (Rf 0.1, 163 mg) as a white powder and a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Cl:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Cl:10])=[CH:4][C:3]=1[NH:11][C:12]([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[Cl:14])=[O:13]
Reactant: O=C=Nc1cc(Cl)c(F)c(Cl)c1F
Reactant: NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(F)c(Cl)c1F
Reaction time: 5 h

Procedure:
A mixture of 9.0 gm (0.040 mol) of 2,4-difluoro-3,5-dichlorophenyl isocyanate, 6.5 gm (0.042 mol) of 2-chlorobenzamide, and 100 ml of xylene was boiled for five hours under reflux. It was then allowed to cool, and the product which precipitated was removed by suction filtration and dried.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44]>>[CH3:44]/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:46])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccccn1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 441 mg (0.92 mmol) of Intermediate 45 (as the TFA salt) and 150 mg (0.92 mmol) of Intermediate 35 to yield 240 mg of Example 34: TLC (DCM/MeOH, 4/1): Rf=0.46; 1H NMR (DMSO-d6, 400 MHz) δ11.49 (d, 1H, J=9.2), 8.52 (d, 1H, J=4.8), 7.90 (m, 4H), 7.47 (m, 4H), 7.11 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 6.13 (s, 1H), 4.12 (m, 3H), 3.16 (m, 2H), 2.87 (t, 2H, J=6.4), 2.77 (dd, 1H, J=13.6, 9.2), 2.34 (s, 3H), 1.71 (s, 3H); low resolution MS (ES−)m/e 510.1 (M-H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH2:18]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:32][C:25]1([C:2]2[C:3]([CH2:11][OH:12])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:24]1=[O:33]
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Reactant: OCc1cc2c(cc1Br)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 17.1 %

Procedure:
To a solution of (6-bromo-1,3-benzodioxol-5-yl)methanol (Mann, J., et al, J. Chem. Soc. Perkin Trans. 1 (1984):2081-8) (1.27 g, 5.50 mmol) in THF (45.0 mL) was added n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) dropwise at −75° C. The reaction mixture was stirred at −75° C. for 45 min followed by the addition of a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in THF (20.0 mL) at −75° C. The resulting mixture was stirred at ambient temperature for 12 hrs and quenched with ammonium chloride solution (5.00 mL). More ethyl acetate and water were added and separated. The organic layer was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 50% EtOAc:Hexanes to yield the title compound (0.29 g, 25%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H), 6.81(s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56 (m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 147.4, 147.2, 142.8, 133.5, 132.2, 131.1, 130.1, 125.3, 123.8, 111.4, 109.2, 108.1, 101.5, 79.5, 64.7, 40.4, 29.0, 26.8, 22.3, 13.9; MS (ES+) m/z 352.1 (M−17).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].C(N(CC)CC)C.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].[OH2:25]>>[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:23][CH2:3][CH:2]=[CH2:1])=[O:25])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: C=CCO
Reactant: O
Reactant: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 11.5 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of allyl alcohol (48.3 g, 56.5 ml, 831 mmol, Eq: 10) and triethylamine (12.6 g, 17.4 ml, 125 mmol, Eq: 1.5) at 0° C. was added 2-(3-nitrophenyl)acetyl chloride (intermediate B2a) (16.59 g, 83.1 mmol, Eq: 1.00) and the mixture was stirred at 0 to 23° C. for 2 h. Poured into water, extracted with ethyl acetate, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a light brown oil, which was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the title compounds as a yellow liquid (14.89 g, 81%).