Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:53][CH2:54][C:55]1[N:56]=[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]2[CH:63]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:53][CH2:54][C:55]4[N:56]=[C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][N:58]5[CH:63]=4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1cn2ccccc2n1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn2ccccc2n1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.8 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (70 mg, 0.13 mmol) in CH2Cl2 (1 mL) were added N,N-diisopropylethylamine (85 μL, 0.49 mmol), 2-aminomethylimidazo[1,2-a]pyridine dihydrochloride (36 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34 mg, 0. 18 mmol), and 1-hydroxybenzotriazole (24 mg, 0.18 mmol). The suspension was allowed to stir at r.t. for 17 hr, and the solvent was removed under reduced pressure. The resulting solid was suspended in DMF (1 mL) and stirred for an additional 4 hr before being concentrated under reduced pressure, dissolved in CH2Cl2, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→20% MeOH in CH2Cl2) to afford the title compound as a yellow solid (22 mg, 35% yield). LC/MS (ESI) retention time: 1.53 min, m/z 683 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.13-1.21 (m, 1 H) 1.29-1.45 (m, 4 H) 1.57-1.67 (m, 1 H) 1.69-1.79 (m,2 H) 1.84-1.95 (m, 1 H) 1.96-2.12 (m, 3 H) 2.30-2.31 (m, 4 H) 2.57-2.75 (m, 2 H) 2.80-2.81 (m, 1 H) 3.60 (s, 4 H) 4.36 (s, 1 H) 4.80 (s, 2 H) 5.06 (s, 1 H) 6.74 (t, J=6.42 Hz, 1 H) 6.79 (s, 1 H) 7.07-7.18 (m, 1 H) 7.32-7.37 (m, 2 H) 7.39-7.46 (m, 2 H) 7.47-7.56 (m, 3 H) 7.60 (s, 1 H) 7.84 (d, J=8.56 Hz, 1 H) 7.99-8.10 (m, 2 H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.ON1C2N=CC=CC=2N=N1.[NH2:29][CH2:30][C:31]1[C:32](=[O:42])[NH:33][C:34]([CH3:41])=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38].CN1CCOCC1.C(Cl)CCl>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:29][CH2:30][C:31]3[C:32](=[O:42])[NH:33][C:34]([CH3:41])=[CH:35][C:36]=3[C:37]([F:38])([F:39])[F:40])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C(F)(F)F)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 19 from 6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.12 g, 0.489 mmol), 1-hydroxy-7-azabenzotriazole (0.100 g, 0.734 mmol), 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone (0.154 g, 0.636 mmol, DMSO (3.0 mL), N-methylmorpholine (0.215 mL, 1.957 mmol), and EDC (0.141 g, 0.734 mmol) The crude solid was purified by silica gel chromatography (eluent: gradient 5-100% of 10% 2M NH3 (in MeOH/DCM) and DCM) and the collected product dried in vacuum oven for 5 h. The final product was collected as 0.112 g (50%). LCMS E-S (M+H)=434.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.12 (m, 4 H), 1.47 (d, J=6.82 Hz, 6 H), 2.20-2.33 (m, 4 H), 4.34-4.54 (m, 2 H), 5.12 (quin, J=6.63 Hz, 1 H), 6.33 (s, 1 H), 7.39 (s, 1 H), 8.18 (s, 1 H), 8.70 (t, J=4.04 Hz, 1 H), 12.43 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:15]=1[CH3:43]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.78 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(6-(morpholinomethyl)pyridin-3-yl)phenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. Reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.1 g, 65.78%). LCMS: 559.35 (M+1)+; HPLC: 95.60% (@ 254 nm) (R1; 3.906; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.96 (s, 1H), 8.67 (m, 1H), 8.22 (d, 2H, J=8 Hz), 8.17 (t, 1H), 7.61 (d, 1H, J=8 Hz), 7.48 (s, 1H), 7.32 (s, 1H), 5.87 (s, 1H), 4.52 (s, 2H), 4.29 (d, 2H, J=4.4 Hz), 3.84 (bs, 4H), 3.26 (bs, 6H), 3.16 (t, 1H), 2.89-2.91 (m, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12](Cl)[N:11]=1>C1COCC1.C(#N)C>[NH2:9][C:10]1[N:15]=[C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:13]=[C:12]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:11]=1
Reactant: OCC(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 62 °C
Yield: 95.5 %

Procedure:
To a solution of trifluoroethanol (9.0 mL, 125 mmol) in anhydrous THF (100 mL) at 0° C. in a 3-neck round bottom flask under an atmosphere of dry N2 was added NaH (4.8 g, 120 mmol, 60% dispersion in mineral oil) over ca. 1 min. After gas evolution ceased and the solution became clear (ca. 20 min), 2-amino-4,6-dichloropyrimdine (8.2 g, 50 mmol) was added. The flask was fitted with a reflux condenser and heated to 62° C. overnight (ca. 15 h). An NMR of a quenched aliquot from the reaction mixture demonstrated the reaction was complete. After the reaction mixture was cooled to ambient temperature it was quenched by addition of 1 N HCl and diluted with EtOAc. The separated organic layer was washed with brine, sat. aq. NaHCO3 and then brine. After drying over MgSO4, filtering and concentrating, the oil thus obtained was dissolved in acetonitrile and washed with hexanes (2×, to remove mineral oil) and concentrated to afford the desired amine as an orange oil (13.9 g, 96% yield): Kugelrohr distillation (high vacuum, 90° C. bath temperature, ice bath for receiving flask) afforded the product as a white solid: m.p. 34-35° C.; 1H NMR (CDCl3) δ 5.69 (s, 1H), 4.95 (br s, 2H), 4.69 (q, 4H, J=8.1 Hz); GCMS (EI, 70 eV) m/z 291 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[CH2:7]([O:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:7]([O:25][C:26](=[O:29])[CH2:27][CH2:28][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCN(O)CC
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCON(CC)CC

Procedure:
The procedure of Example I is repeated using 4.46 g of N,N-diethylhydroxylamine, 16.03 g of n-octadecylacrylate and 0.56 g of potassium-tert-butoxide in 100 ml of tetrahydrofuran, to afford the title compound as a colorless liquid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a mixture of benzaldehyde (0.061 mL, 0.6 mmol) and N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.278 g, 0.60 mmol) in CH2Cl2 (10 mL) was added NaB(OAc)3H (0.128 g, 0.60 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.5) to give 0.21 g of the title compound. MS (EI) calcd: (M+H)+=503.3; found: 503.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Fc1ncccc1-c1nc2cc(Br)ccn2n1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 70.4 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.1 g, 3.75 mmol) and tert-butyl carbamate (528 mg, 4.5 mmol) as starting materials. The reaction affords [2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (870 mg, 70.4%), as light yellow solid. MS: m/z=330.1 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)c1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70-11.81 (m, 1H), 8.40-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.75-7.78 (m, 1H), 7.51-7.53 (m, 2H), 7.43-7.46 (m, 2H), 7.07-7.22 (m, 3H), 3.77 (s, 2H), 2.94-3.07 (m, 1H), 1.27 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 434 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cncs2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.022 g, 26%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.61-2.67 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.63-3.69 (m, 4H), 3.87 (s, 2H, NCH2), 7.48 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.82 (s, 1H, thiazole H-4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.05 (s, 1H, thiazole H-2), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.10 min—554/556 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 554.1342, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[C:27](C)([CH3:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH2:4]([O:5][C:6](/[CH:8]=[C:9]1/[C:27]([CH3:28])([CH3:32])[CH2:26][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:29]/1)=[O:7])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CCN(C(=O)OC(C)(C)C)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a suspension of NaH (0.212 g, 5.29 mmol) in THF (2 mL) was added a solution of triethyl 2-phosphonopropionate (1.05 mL, 5.29 mmol) in THF (2 mL) at 0° C. After the mixture was stirred for 1 h at rt, a solution of tert-butyl-3,3-dimethyl-4-oxopiperidine-1-carboxylate (J. Org. Chem., 2001, 66, 2487) (0.600 g, 2.64 mmol) in THF was then added and stirred for 10 h. The resulting mixture was quenched with water and the product portion was extracted with Et2O. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography (gradient: 5% EtOAc/hexane to 40% EtOAc/hexane) to afford the titled compound (784 mg, 100%); 1H NMR (CDCl3) δ 5.73 (s, 1H), 4.15 (q, J=6.8 Hz, 2H), 3.52-3.42 (m, 2H), 3.25-3.18 (m, 2H), 3.05 (t, J=5.6 Hz, 2H), 1.47 (s, 9H), 1.29 (t, J=6.8 Hz, 3H), 1.12 (s, 6H)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([O:14][CH3:15])[C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])(=[O:12])=[O:11]
Reactant: CONS(=O)(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in DMF (3.0 ml), 2-chloro-N-methoxybenzenesulfonamide (0.48 g (2.17 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2,4-dinitrochlorobenzene (0.41 g (2.02 mmol)) was added. The resulting mixture was then stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to give 0.49 g (62%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1[OH:34].[O-]O.C1(C(C)C)C=CC=CC=1>N1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:34])=[N:15][CH:16]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: c1ccncc1
Solvent: CC(C)c1ccccc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 22 °C

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) and (1R,2S)-(+)-1-amino-2-indanol (22.8 mg, 0.151 mmol) are solubilised in anhydrous pyridine (0.65 mL); titanium isopropoxide (IV) (22 μL, 0.076 mmol) is added under stirring at 22° C., followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([NH2:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:14]=1
Reactant: NC(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(O)cc1
Yield: 99.1 %

Procedure:
A suspension of 6.0 g (18.5 mmol) of N-(4-benzyloxy-phenyl)-malonamide in 150 ml methanol is treated with 0.8 g of palladium 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure overnight. The reaction mixture is then brought to reflux and filtered hot. Cooling of the filtrate yields 3.56 g (99%) of the title compound as a colorless solid. MS: m/e=285.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.C([Li])CCC.[C:21](=[O:23])=[O:22].C1COCC1>CCOCC.CCCCCC.O>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:5][CH:6]=[CH:7][C:8]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: COc1ccccc1N1CCN(C)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(=O)O)cccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(2-Methoxyphenyl)-4-methylpiperazine (10.0 g) was added in ether (20 ml) dropwise to a solution of n-butyllithium in hexane (1.6M; 36 ml) and N,N-tetramethylethylenediamine (5.6 g) under nitrogen at room temperature. The resulting suspension was stirred for 6 h and was added slowly to a mixture of solid carbon dioxide (50 g) and THF (50 ml). The mixture was allowed to warm to room temperature and was treated with water (150 ml). The aqueous solution was washed with and the filtrate was evaporated to give the title compound as a ether (2×200 ml), acidified with hydrochloric acid (2N) and evaporated. The solid was treated with methanol (150 ml), filtered white solid (15.0 g)
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[N+:8]([O-])([OH:10])=[O:9]>C(OC(=O)C)(=O)C>[N+:8]([C:6]1[CH:7]=[C:3]([C:1]#[N:2])[S:4][CH:5]=1)([O-:10])=[O:9]
Reactant: N#Cc1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc([N+](=O)[O-])cs1

Procedure:
To a solution of 2-cyanothiophene (10.9 g; 0.1 mol) in 25 ml of acetic anhydride (t=10° C.) are added 9 ml of fuming nitric acid (d=1.49 g/ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)[CH3:8])=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:8])=[O:6]
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To a cooled solution (−70° C.) of 3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (2 g, 5.64 mmol) in DCM (20 mL), BBr3 (1.7 mL, 18 mmol) was added drop-wise over a 20 minute period. The reaction temperature was allowed to increase to room temperature over 12 hrs until completion of the reaction. After concentration in vacuo the mixture was partitioned between DCM and water. 1N NaOH was added to increase pH to ˜5. The organic layer was separated and washed with brine and dried over Na2SO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (4/1 with gradient up to 3/2) yielded 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (1.78 g, 93%). MS [M+H]+: 341.9; tR=2.56 min. (method 1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.C([Sn](CCCC)=O)CCC.C[Si]([N:28]=[N+:29]=[N-:30])(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[NH:30][N:29]=[N:28][N:13]=2)[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cn1ncc2c(C#N)cc(Br)cc21
Agent: CCCC[Sn](=O)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1ncc2c(-c3nnn[nH]3)cc(Br)cc21
Temperature: 110 °C
Reaction time: 28 h
Yield: 99.4 %

Procedure:
6-Bromo-1-methyl-1H-indazole-4-carbonitrile (514 mg, 2.177 mmol) was dissolved in toluene (20 mL) and dibutyl(oxo)stannane (108 mg, 0.435 mmol) and trimethylsilyl azide (0.573 mL, 4.35 mmol) were added over 2 mins. The mixture was then stirred at 110° C. under nitrogen for 28 h. Further trimethylsilyl azide (0.03 mL, 0.228 mmol) was added and the mixture continued stirring at 110° C. under nitrogen for 44 h. The solvent was removed in vacuo to give a white solid. 2M sodium hydroxide in methanol was added and the mixture heated to 50° C. and then filtered whilst hot to remove insoluble impurities. The filtrate was cooled and then acidified via dropwise addition of 2M hydrochloric acid. The resultant precipitate was filtered and dried in a vacuum oven to give the title compound as a white solid (604 mg).