Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:30]2=[O:46]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:30]3=[O:46])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)Cc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.30 g, 1.8 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.31 g, 1.9 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide as a white solid (550 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (98.7%); mp, 229.5-231.5° C.; 1HNMR (DMSO-d6) δ 2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH), 3.50 (s, 2H, ArCH2), 4.37 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.90 (m, 7H, Ar), 8.67 (t, J=5 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 1H NMR (DMSO-d6) δ 20.92, 23.40, 30.63, 41.39, 41.87, 56.53, 120.02, 123.99, 126.57, 128.13, 130.87, 131.09, 134.03, 135.21, 137.97, 145.81, 154.61, 160.38, 169.47, 169.85, 172.61. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl: C, 61.00; H, 4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H, 4.60; N, 12.27; Cl, 7.89.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]1)(=O)C.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1>[C:19]1([C:18]([N:8]2[C:7](=[O:11])[CH:6]=[N:5][NH:4][C:9]2=[O:10])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)n1ncc(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)cn[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of 2-acetyl-1,2,4-triazine-3,5(2H,4H)-dione (1.05 g, 6.77 mmol) in 1,4-dioxane (11 ml) and pyridine (1.64 ml, 20.31 mmol) was treated dropwise at 5° C. with benzoyl chloride (0.90 ml, 7.78 mmol), then the mixture was stirred at room temperature overnight. The day after, 0.1 eq of benzoyl chloride was added and the mixture was stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the filtered was evaporated under vacuum. The residue was dissolved in ethanol (23 ml) and then hydrochloride acid 37% (0.74 ml, 24.19 mmol) was added and the reaction was refluxed for 15 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM (from 0 to 4%) to afford the title compound as a white solid (0.35 g, 23.47%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1Br.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cc(Br)c(C)s1
Product: COC(=O)c1cc(Nc2ccccc2)c(C)s1
Yield: 15.7 %

Procedure:
A stirred suspension of 400 mg (1.7 mmol) methyl 5-methyl-4-bromo-thiophene-2-carboxylate and 192 μL (2.1 mmol, 1.25 eq) of aniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 66 mg of the title compound (16%) as a brown glass. 1H-NMR (DMSO-d6, 400 MHz) δ7.70 (s, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 6.72 (m, 3H), 3.79 (s, 3H), 2.31 (s, 3H). Mass spectrum (MALDI, gentisic acid matrix, m/z): Calcd. for C13H13NO2S, 248.1 (M+H), found 247.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:23]([O+](CC)CC)[CH3:24].C(Cl)Cl.CO>C(Cl)Cl>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](=[NH:14])[O:13][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOC(=N)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under an atmosphere of argon 11.36 g of 3-benzyloxybenzamide were suspended in CH2Cl2 (200 ml) and 9.5 g triethyloxonium fluoroborate in CH2Cl2 (100 ml) were added dropwise on ice cooling. The reaction mixture was then stirred further 20 h at RT until completion of reaction according to TLC analysis (CH2Cl2/MeOH: 15/1). The solid which had formed was filtered off, washed with ether to give the desired ethyl m-benzyloxybenzimidate tetrafluoroborate as white crystals, mp 152°-154° C., which was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[N:7][CH:8]=1)=[CH2:2].BrN1C(=[O:20])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:20]1[CH2:2][CH:1]1[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(-n2cnnn2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: c1cc(-n2cnnn2)ncc1C1CO1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 5-ethenyl-2-(1H-tetrazol-1-yl)pyridine (0.664 g, 3.83 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 minutes (0.751 g, 4.22 mmol, 1.1 equiv) and stirred at 40° C. for 1 hour. After cooling to 5° C., the reaction was basified with drop wise addition of solution of sodium hydroxide (0.46 g in 5 mL of H2O, 11.50 mmol, 3 equiv) and stirred for another 1 hour. The reaction mixture was poured into H2O (10 mL) and the product was precipitated out as white solid, filtered, washed with water, dried, yielding the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.BrCCO[CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO)cc3C)cc12
Reactant: CCOP(=O)(CCCOCCBr)OCC
Product: CCOP(=O)(CCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate was prepared following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 156) and diethyl 3-(2-bromoethoxy)propylphosphonate. LRMS [M+H]=566.3.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C.C(#N)C>C(N(CC)CC)C>[N+:40](=[C:3]([C:2](=[O:1])[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])=[N-:41]
Reactant: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(OC(=O)C(=[N+]=[N-])C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
The procedure of Baumm et al, Synthetic Communication 1987, 17(14), 1709-1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) of the product of Step 2 and 0.041 g (0.171 mmol) of 4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065 ml (0.47 mmol) of triethylamine was added at 0° C. After stirring for 3 hours at room temperature the solvent was evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica gel, methylene chloride) to give 0.059 g (98% yield) of 3-methoxyphenyl 2-diazo-3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate. This was dissolved in 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 μmol) of rhodium (III) acetate was added at room temperature under nitrogen atmosphere. The resulting mixture turned deep green after 1 h of stirring at room temperature. After filtration through Celite and washing with fresh methylene chloride, the filtrate was evaporated to dryness under reduced pressure to give the title compound as an deep yellow crystals (0.049 g, 91%); 1H NMR (CDCl3) δ 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 6.58 (dd, 1H, CH aromatic, J=2.4 Hz; 8.6 Hz); 6.76 (d, 1H CH aromatic; J=2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CH aromatic, J=8.6 Hz).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[N:5]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[N:4]=1)#[N:2].C(C1C2C(=CN=CC=2)N(CC(O)=O)N=1)(=[O:30])N>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[N:5]([CH2:20][C:21]([OH:23])=[O:22])[N:4]=1)(=[O:30])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ncccn3)ccc21
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Product: NC(=O)c1nn(CC(=O)O)c2ccc(OCc3ncccn3)cc12

Procedure:
The title compound was prepared from tert-butyl 2-(3-cyano-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate in a similar manner as described in step D of Scheme A6 for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid. MS (LC-MS): 328.2 [M+H]+, 326.3 [M−H]−, tR (HPLC conditions e): 2.77 min.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12].[S-:13][C:14]#[N:15].[K+]>C(O)C>[CH3:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH2:6][S:5][CH2:4][CH2:3][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: Cc1[nH]cnc1CSCCCl
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCSC#N

Procedure:
1-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1 g) and potassium thiocyanate (0.97 g) were heated together under reflux in ethanol (50 ml) for 3 days. The mixture was evaporated to dryness and the residue was taken up in water, basified with sodium carbonate and extracted with chloroform. The chloroform extracts were dried (MgSO4) and evaporated to a residue which was recrystallised from acetonitrile to give 2-(5-methyl-4-imidazolylmethylthio)ethylthiocyanate m.p. 101°-103°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH2:4][CH2:5][OH:6].C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:29](O)=[O:30])#[N:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:3]([NH:2][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[C:26]([C:24]#[N:25])[CH:27]=2)[CH2:4][CH2:5][OH:6])=[CH:13][CH:12]=1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N[C@H](CCO)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(Br)cc2)cc1C#N
Reaction time: 0.05 h
Yield: 78.7 %

Procedure:
To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stirred at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31]>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Yield: 45 %

Procedure:
A slurry of 4-chloro-2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.52 g, 3.62 mmol) in a solution of 7 M ammonia in methanol (15 mL) was heated at 150° C. for 20 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting residue was partitioned between dichloromethane and 1 M aqueous sodium hydroxide. The aqueous layer was extracted with several portions of dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution 10% to 30% CMA/chloroform) to yield 2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (653 mg, 45%) as white powder that was dried under vacuum at 70° C., mp 240.0-242.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J=1.7 Hz, 1H), 8.64 (dd, J=3.2, 1.6 Hz, 1H), 8.16-8.20 (m, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.41-7.50 (m, 2H), 7.17 (t, J=7.0 Hz, 1H), 6.97 (s, 1H), 6.17 (s, 2H), 5.75 (s, 2H), 4.88 (s, 2H), 3.50 (q, J=7.0 Hz, 2H), 0.98 (t, J=7.0, 3H).
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1)[CH:2]=[CH2:3].CN(C)C=[O:20]>O.C(OCC)(=O)C.[Pd](Cl)Cl>[O:20]=[C:2]([CH3:3])[CH2:1][C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1
Reactant: CN(C)C=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1CC(C)=O
Reaction time: 3.5 h

Procedure:
A mixture of methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (100 mg), palladium chloride (16 mg) and cuprous chloride (44 mg) in a mixture of dimethylformamide (1 ml) and water (0.12 ml) was stirred under an oxygen atmosphere for 3.5 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and brine. The combined aqueous layer was extracted with ethyl acetate (10 ml×2) and the extract was washed with brine. The organic layers were combined, and dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (1 g) eluting with methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (89 mg as an oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([F:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:1]([CH2:4][CH2:5][C:6]2[N:7]=[C:8]([F:30])[N:9]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)=[O:3])=[CH:49][CH:48]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)Nc1ccc(Cl)cc1
Reaction time: 0.42 h

Procedure:
A solution of 4-(2-carboxyethyl)-2-fluoro-1-triphenylmethylimidazole in CH2Cl2 was treated with triethylamine. The mixture was cooled, isobutyl chloroformate added, and stirred for 25 min. 4-Chloroaniline was then added, and stirring continued for 1 hour. Extractive work-up, followed by chromatography, gave 4-[2-(4-chlorophenylcarbamoyl)ethyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 +d6DMSO: 2.4-2.75 (m, 4H); 6.25 (s, 1H); 6.9-7.65 (m, 19H); 9.9 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:23][CH:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)N
Product: CC(C)NCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In a glass lined vessel, 1-benzyloxy-4-(3-bromopropoxy)benzene (33.4 g) in 300 ml of isopropylamine was heated at 100° for 10 hours under nitrogen at 1000 psi, then the excess isopropylamine was removed in vacuo and the residue was dissolved in 300 ml of water. The solution was made alkaline with 10% sodium hydroxide and the resulting oil extracted with dichloromethane. The dichloromethane extract, dried over potassium carbonate, was concentrated and distilled to yield 22.5 g of 1-benzyloxy-4-[3-(1-methylethyl)aminopropoxy]benzene, boiling range 180°-190° (0.5 mm) (97.8% pure by gas chromatography).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:34]>C(#N)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([NH2:34])[N:19]=2)=[N:6]1
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (1.768 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(trifluoromethyl)-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 123 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, water was added, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 125 mg (18% of theory) of the target compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]3=[N:36][CH:37]=[C:38]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:39]=[C:34]3[N:33]=[C:32]2[C:46]2[C:47]([NH2:52])=[N:48][CH:49]=[CH:50][CH:51]=2)=[CH:27][CH:26]=1>CC(N(C)C)=O>[NH2:52][C:47]1[C:46]([C:32]2[N:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:30][CH:29]=3)[C:35]3=[N:36][CH:37]=[C:38]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:39]=[C:34]3[N:33]=2)=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cc(-c4cccnc4)cnc32)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: Nc1ncccc1-c1nc2cc(-c3cccnc3)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Benzoic acid (0.85 g, 7.1 mmol) and CDI (1.14 g, 7.1 mmol) were dissolved in DMA (36 ml). The reaction mixture was stirred for 1 h. 3-(3-(4-(aminomethyl)phenyl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride was dissolved in DMA (40 ml) and the solution of benzoic acid and CDI was added over 10 min at room temperature. The reaction was stirred for two hours at room temperature and quenched by addition of water. The product N-(4-(2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide precipitated and was isolated by filtration, washed with water and ether, yielding 2.9 g (5.9 mmol, 84%) of the desired product in 98% purity. 1H NMR (DMSO-d6) 400 MHz δ: 9.15 (t, J=5.6 Hz, 1H), 9.01-9.00 (m, 1H), 8.67-8.66 (m, 1H), 8.63-8.62 (m, 1H), 8.58-8.57 (m, 1H), 8.22-8.19 (m, 1H), 8.02-8.00 (m, 1H), 7.95-7.92 (m, 2H), 7.57-7.45 (m, 8H), 7.29-7.27 (m, 1H), 7.03 (s, br, 2H), 6.45-6.42 (m, 1H), 4.59-4.58 (m, 2H) MS 498.55, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH2:42]([S:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:24]2[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=[C:21]([C:8]4[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:5]=[O:6])[CH:7]=4)[CH:22]=3)[NH:26][CH:25]=2)[CH2:38][CH2:37]1)(=[O:41])=[O:40])[CH3:43]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C=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: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(C=O)c4)cc23)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H2O (6.3 mL), was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (963 mg, 2.33 mmol), and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10 min, tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The reaction was heated in the microwave 120° C. for 120 min. Compound was purified by flash chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1H-indole-7-carboxamide (58%).