Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-])(C)C.N12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[O:18])[CH2:9]1)[CH2:15]2.CO.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[N:6]12[CH2:5][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([C:11](=[O:18])[CH2:9]3)[CH2:17]1)[CH2:15]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CC2CC3CC1CN(C2)C3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of trimethylsilyldiazomethane (2 N in hexanes, 9.00 mL, 18.00 mmol; Aldrich) was added a solution of 1-azaadamantan-4-one (2.268 g, 15 mmol; Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) in tetrahydrofuran (12 mL) dropwise over 20 minutes Anhydrous methanol (6 mL) was added and the mixture was allowed to warm to room temperature. After 18 hours, glacial acetic acid was added dropwise until the mixture was colorless (about 1 mL). The reaction mixture was shaken with saturated sodium carbonate (4 mL), the tetrahydrofuran layer was separated, and the aqueous portion was extracted with dichloromethane (3×12 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.72 (m, 1H), 1.78 (dddd, J=13.6, 4.0, 2.4, 2.1 Hz, 1H), 1.88 (m, 1H), 1.90 (dddd, J=14.6, 4.0, 2.4, 2.1 Hz, 1H), 2.14 (dddd, J=14.4, 6.5, 4.4, 1.9 Hz, 1H), 2.27 (m, 1H), 2.59 (t, J=5.8 Hz, 1H), 2.63-2.68 (m, 2H), 2.96 (m, 1H), 3.01 (dd, J=4.4, 2.0 Hz, 1H), 3.07 (m, 1H), 3.14 (m, 1H), 3.25 (ddd, J=14.6, 4.9, 1.2 Hz, 1H), 3.43 (dd, J=14.2, 5.1 Hz, 1H); MS (DCI/NH3) m/z 166 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([I:14])[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:22]([CH3:24])[CH3:23])=[C:7]([I:14])[CH:6]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([I:14])[C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([CH:22]([CH3:24])[CH3:23])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc(I)c2cn[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c2cn(C(C)C)nc2c1
Product: COC(=O)c1cc(I)c2cnn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %
Yield: 32 %

Procedure:
To a solution of 4-iodo-1H-indazole-6-carboxylic acid methyl ester (2.0 g, 6.62 mmol) in DMF (50 mL) was added Cs2CO3 (4.32 g, 13.24 mmol) followed by 2-iodopropane (0.5 mL, 7.94 mmol). The reaction mixture was stirred overnight at room temperature, then partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide 1.13 g (50%) of 4-iodo-1-isopropyl-1H-indazole-6-carboxylic acid methyl ester (0.73 g (32%) of the regioisomer 4-iodo-2-isopropyl-2H-indazole-6-carboxylic acid methyl ester was also recovered).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[CH3:18][CH:19]1[O:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([N:21]1[CH2:20][CH:19]([CH3:18])[O:24][CH:23]([CH3:25])[CH2:22]1)=[O:8]
Reactant: CC1CNCC(C)O1
Reactant: COc1cc2sc(C(=O)Cl)c(Cl)c2cc1OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2sc(C(=O)N3CC(C)OC(C)C3)c(Cl)c2cc1OC

Procedure:
3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonyl chloride (2.0 g) and 2,6-dimethylmorpholine (1.82 g) was suspended in tetrahydrofuran (15 ml) and triethylamine (0.96 ml) was added and stirring continued at room temperature for weekend. Water was added, pH adjusted to 3 by HCl, and the precipitate filtered.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]=[O:21])[C:18]=1[OH:25].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:18]1[C:17]([F:16])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1cccc(F)c1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3c(F)cccc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 3-fluorosalicylaldehyde (280 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](#[N:16])[CH:14]=[CH2:15]>C1C=CC=CC=1.CO>[C:13]([CH2:14][CH2:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:16]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: C=CC#N
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)C(CCC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-phenylacetate (5.00 g, 30.5 mmol) in benzene (50 mL) was added Triton-B (40% solution in methanol) (0.240 mL, 0.609 mmol) at 0° C. After stirring for 10 minutes, acrylonitrile (2.005 mL, 30.5 mmol) was added, and the reaction was allowed to warm to room temperature. The reaction was stirred for 3 hours, concentrated, loaded directly onto silica gel (GraceResolv High Resolution Flash Cartridge, 80 g) and eluted using a gradient of 5% to 40% ethyl acetate/hexanes over 40 minutes (flow rate=40 mL/minute). Concentration of product containing fractions provided the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.19 (m, 5H), 4.26-4.00 (m, 2H), 3.81-3.59 (m, 1H), 2.50-2.01 (m, 4H), 1.20 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 59.4 %

Procedure:
1-[5-(3,4-Dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.139 mmol, 39.7 mg) synthesized in Synthetic Example 1 and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) were stirred with dimethylformamide (4 mL) and two drops of concentrated hydrochloric acid at room temperature for 22 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (39.5 mg, yield 59%).
Reaction SMILES: [OH:1][CH:2](S([O-])(=O)=O)[CH2:3][CH2:4][CH:5]([N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH:8]([OH:13])S([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[N+:14]([CH:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH2:6][CH2:7][CH:8]=[O:13])([O-:16])=[O:15]
Reactant: O=[N+]([O-])C(CCC(O)S(=O)(=O)[O-])CCC(O)S(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: O=CC(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=CCCC(CCC=O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium 1,7-dihydroxy-4-nitro-heptane-1,7-disulfonate, 9, (219 g, 0.57 mol) in methylene chloride (1.6 L) was added a solution of glyoxylic acid (160 g, 1.7 mol) and sodium bicarbonate (150 g, 1.78 mol) in water (2 L). The resulting mixture was stirred at room temperature for 30 to 60 minutes until all solids were dissolved. The organic layer was split and the aqueous layer was extracted with methylene chloride twice (2×400 ml). Combined extracts were then concentrated to give a colorless oil. The product was carried to next step without further purification. Yield: 85 g, 86%. 1H NMR (400 MHz, CDCl3) δ 2.09-2.24 (m, 4H), 2.58 (m, 4H), 4.61 (m, 1H), 9.77 (s, 2H). 13C NMR δ 26.2, 39.9, 86.9, 200.0.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1.Cl>C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:6]=1
Reactant: COC(=O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Lithium hydroxide monohydrate (0.062 g, 1.49 mmol) was added into a suspension of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)thieno[2,3-d]pyrimidine-6-carboxylate (0.100 g, 0.25 mmol) in THF/water (1:1; 1.0 mL) and the reaction stirred at ambient temperature for 16 hours. The mixture was cooled in an ice-bath and 1 N hydrochloric acid added drop wise until the solution reached pH 5. The precipitate was collected, washed with water and dried over P2O5 to yield off-white solid (0.060 g, 62%).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=O)[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])/[N:7]([CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])=[S:46])/[N:7]([CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 95 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of Example 24 (300 mg, 0.571 mmol) in toluene (6 mL) at ambient temperature was added Lawesson's Reagent (231 mg, 0.571 mmol). This mixture was warmed to 95° C. and allowed to stir for 4 hours. The mixture was then cooled to ambient temperature, concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with NaHCO3 solution. The organics were combined, dried, concentrated, and the residue was purified by Analogix® Intelliflash280™ (SiO2, 0-10% (7 M ammonia in methanol) in CH2Cl2 over 25 min) to obtain the title compound in 87% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 1.47-1.63 (m, 4 H) 1.73-1.89 (m, 4 H) 2.10 (q, J=8.59 Hz, 1 H) 2.19 (s, 3 H) 2.38-2.47 (m, 1 H) 2.81-2.90 (m, 1 H) 3.59-3.67 (m, 1 H) 3.71-3.81 (m, 1 H) 3.96 (ddd, J=14.67, 9.41, 5.76 Hz, 2 H) 4.27-4.34 (m, 3 H) 7.23 (d, J=8.82 Hz, 1 H) 7.55-7.59 (m, 2 H) 7.63 (dd, J=8.82, 2.03 Hz, 1 H); MS (DCI/NH3) m/z 542 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[CH3:44][C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:44][C:45]1[N:46]=[C:47]([NH:50][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])[S:48][CH:49]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Cc1csc(N)n1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.8 %

Procedure:
A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 5 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 4-methyl-thiazol-2-ylamine (166 mg, 1.45 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (25 mL) and ethyl acetate (25 mL) and treated with a 1N aqueous hydrochloric acid solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and a saturated aqueous sodium chloride solution (1×20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (4-methyl-thiazol-2-yl)-amide (50 mg, 24%) as a yellow solid: mp 201-203° C.; (ES)+-HRMS m/e calcd for C16H16ClN3OS (M+) 333.0703, found 333.0704.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]2[CH:8]=[N:9][N:10]([CH3:13])[C:11]=2[CH:12]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[CH:8]=[N:9][N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Lithium hydroxide (156 mg, 6.51 mmol) was added to a stirred suspension of methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (730 mg, 2.71 mmol) in tetrahydrofuran (THF) (25 ml) and water (5 ml) and the reaction mixture was stirred at room temperature for 1 h. During this time the cream suspension turned to a pale brown solution. The reaction mixture was poured onto 2N HCl (100 ml) with stirring. The precipitate formed was filtered off under vacuum and dried at 50° C. in a vacuum oven for 18 h to give the title compound as a white solid (480 mg).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[S:19])[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:26]I.Cl>O.CCO>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([S:19][CH3:26])=[N:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-propyl-6-thioxo-1,3,6,7-tetrahydro-purin-2-one (120 mg, 0.36 mmol) was suspended in 3 mL of H2O and 1.5 mL of EtOH. NaOH was added as a solution in 0.4 mL of H2O, followed by MeI. The reaction mixture was stirred at rt for 1 h. It was then neutralized with 0.1 N HCl and extracted with CHCl3. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford essentially quantitative amount of the titled compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11])([O-:6])=[O:5].C(OCC)(=O)C>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CNC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dimethylamine (50% aqueous solution, 3.6 ml) was stirred in an ice bath and a solution of 3-nitrobenzoyl chloride (1.8 g) in 1,4-dioxan (4 ml) was dropwise added thereto. The resulting mixture was stirred vigorously at ambient temperature for 2.5 hours. Ethyl acetate was added and organic layer was washed with water, 1N hydrochloric acid, 1N sodium hydroxide, water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was recrystallized from benzene-n-hexane to afford N,N-dimethyl-3-nitrobenzamide (1.5 g) as a pale yellow prism.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].[C:25](N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.IC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:25])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Agent: [B]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (50 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (113 mg) and N,N-dimethyl formamide (2 ml) was shaken at room temperature for 30 minutes. To the mixture was added iodomethane (28 mg), and the mixture was further shaken for 1 hour. After the resin was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4 to 1:1:0, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to isolate 2-(3-methoxyphenyl)-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (22 mg, 41%) (As a result of this reaction, a mixture of two isomers was obtained, and the isomer having higher polarity is the desired compound.)
Reaction SMILES: [CH2:1](Br)[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[CH3:2]
Reactant: Cc1ccc(N)cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1ccc(C)c(O)c1

Procedure:
88.6 gm of ethyl bromide were added to a solution of 50 gm of 5-amino-2-methylphenol in 250 ml of ethanol; and the mixture was refluxed for four hours. After the solution had cooled, it was diluted with 1.2 liters of water and was made weakly alkaline with sodium carbonate. After repeated extraction with ether, the ether extracts were dried and concentrated. The residue was recrystallized from ethanol, and had a melting point of 128° C. to 129° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNCc1ccccc1

Procedure:
The title compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from ethyl acrylate and benzylamine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:16][C:15]1=[O:31])(=[O:13])[CH3:12].[CH2:32]([O:39][CH2:40][C:41]1[C:42]([O:51][CH3:52])=[N:43][CH:44]=[CH:45][C:46]=1[C:47](=[O:50])[CH2:48][CH3:49])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:39][CH2:40][C:41]1[C:42]([O:51][CH3:52])=[N:43][CH:44]=[CH:45][C:46]=1[C@@:47]([OH:50])([CH2:48][CH3:49])[CH2:12][C:11]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:16][C:15]1=[O:31])=[O:13])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCC(=O)c1ccnc(OC)c1COCc1ccccc1
Reactant: CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@](O)(CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1)c1ccnc(OC)c1COCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 10 ml round bottomed flask was charged with 389.4 μL lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.385 mmol, 1.1 eq) and the solution was cooled to −78° C. 108.4 mg (4R,5S)-3-acetyl-4,5-diphenyl-oxazolidin-2-one (0.385 mmol, 1.1 eq), as obtainable from Example 8, in 650 μL THF were slowly added (addition time: 5 min). During the addition, the color changed from colorless to bright yellow. After 2 h at −78° C., the solution was cooled to −95° C. and 100.0 mg 1-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-propan-1-one (0.350 mmol), as obtainable from Example 7, dissolved in 400 μL THF were slowly added (addition time: 5 min). The solution was kept for additional 30 min at −95° C. and then for 45 min at −78° C. Subsequently, the reaction was quenched by addition of 5 mL aqueous 0.5 M HCl. The mixture was extracted three times with 10 mL, in total 30 mL dichloromethane and the combined extracts were dried over 1 g sodium sulfate (30 min) and filtered. The filter cake was washed with 2 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 5 mbar), the title compound was obtained as a colorless oil (206.7 mg, 104% by weight, dr=92:8 (1H-NMR).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Li+].CC([N-]C(C)C)C.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:25]([OH:27])=[O:26])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)O)CCc2cccc(OC)c2C1
Reaction time: 1.5 h

Procedure:
A THF (1.0 mL) solution of 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (660 mg, 3.0 mmol) was added to freshly made LDA (made by addition of 2.0 mL of 2.3 M BuLi to 1.5 mL THF solution of 0.7 mL iPr2NH) at −78° C. and the mixture was allowed to stir for 1.5 hour. A CO2 balloon was then applied. The reaction mixture was quenched with aqueous NH4Cl and the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to provide the crude-8-methoxy-3,4-dihydro-1H-naphthalene-2,2-dicarboxylic acid methyl ester (470 mg).