Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[NH:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:51]3[CH2:56][CH2:55][S:54][CH2:53][CH2:52]3)=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Reactant: C1CSCCN1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCSCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(3-chlorophenyl)amino]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (0.2 g) in dimethylformamide (5 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.15 g), 1-hydroxybenzotriazole (0.14 g), N-ethylmorpholine (0.34 ml) and thiomorpholine (0.13 ml). The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium bicarbonate solution followed by saturated sodium chloride solution then dried (MgSO4) and evaporated. The residue was purified by MDAP to afford the title compound as a white solid (236 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(N)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(5-Chloro-4-methoxy-2-nitrophenyl)acetamide (8.0 g, Reference Example 32(i) was added to a solution of sodium methoxide (2.0 g, 0.037 mole) in methanol (150 mL) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was added to ice water (750 mL), stirred for 15 minutes and the aqueous mixture was filtered. The precipitate was washed with water and dried at 60° C. under vacuum to give 5-chloro-4-methoxy-2-nitrophenylamine (6.52 g) as an orange solid, mp 128-129° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Temperature: 100 °C
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100° C. for 4 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 74% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.18-3.22 (t, 4H), 3.75-3.85 (t, 4H), 6.9-7.0 (m, 1H), 7.1-7.15 (d, 1H), 7.2-7.3 (m, 2H), 7.55-7.6 (m, 1H), 7.65-7.7 (d, 1H), 7.8 (s, 1H), 8.3-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H), 10.17 (s, 1H); Mass Spectrum M+H+ 469 and 471.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[CH2:10][C:9](=[O:11])[NH:8][C@H:7]2[CH2:12][CH2:13][CH2:14][CH2:15][C@H:6]2[NH:5]1.[CH2:17](I)[CH3:18]>O1CCOCC1>[CH2:17]([N:8]1[C@H:7]2[CH2:12][CH2:13][CH2:14][CH2:15][C@H:6]2[NH:5][C:4]([CH3:16])([CH3:3])[CH2:10][C:9]1=[O:11])[CH3:18]
Reactant: CC1(C)CC(=O)N[C@H]2CCCC[C@H]2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1C(=O)CC(C)(C)N[C@@H]2CCCC[C@@H]21
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
1.25 g sodium hydride (50% in oil) was dissolved in p-dioxane in a 250 ml flask, and 4.15 g cis-4,4-dimethyl-decahydro-1,5-benzodiazepin-2-one added. The mixture is stirred for about 1.5 hr. and cooled. 5.0 g ethyl iodide dissolved in 5 ml dioxane was added and the mixture stirred at 55°-60° C. overnight. It is then cooled and the solvent is removed to yield 4.67 g of an oily product. The structure of the compound obtained is confirmed by IR, NMR and mass spectrometer data.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1ccccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl
Product: N=C(Nc1ccccc1F)Nc1ncccc1OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (4.13g, 0.019 mol), N-[3-(2-chloro-6-fluoro -benzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)thiourea (3.10g, 0.0076 mol) and methanolic ammonia solution (60 ml) was stirred for 24 hours at room temperature. The mixture was filtered through celite and the filtrate evaporated to a yellow solid, which was recrystallised from ethyl acetate/pet. ether. Yield 1.51 g (51%), m.p 138°-140 ° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[O:22])([O-])=O.[OH-].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[C:5]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[O:22]
Reactant: COCCOc1cc2c(cc1[N+](=O)[O-])[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cc2c(cc1N)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a refluxing solution of compound 94 (506 mg, 1.35 mmol) in acetone (120 mL), H2O (24 mL) and aqueous 1 M NaOH (24 mL, 24.0 mmol) was portionwise added with care solid Na2S2O4 (3.89 g, 18.97 mmol). The reflux was continued for 2 h then the acetone was removed under vacuum. More H2O (50 mL) was added and the aqueous phase was extracted with CH2Cl2 (4×). The organic phase was dried (MgSO4), filtered then rotary evaporated. The crude solid was purified by flash chromatography (SiO2) using 3:7 to 1:1 EtOAc/Hexanes as eluent to give compound 95 (228 mg, 49%) as a foamy solid. 1H NMR (CDCl3) δ 0.88 (3H, s), 1.37-2.78 (14H, m), 3.41 (3H, s), 3.71 (2H, t, J=5.0 Hz), 4.09 (2H, 2.9 Hz), 6.52 (1H, s), 6.65 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)[NH2:34].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:36]1[CH:37]=[C:31]([O:30][CH3:29])[CH:32]=[C:33]([NH2:34])[CH:35]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.34 mmol) were added (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (86 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27 mg, 0.03 mmol) and 340 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 87 mg (52% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[C:3](SC)=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[C:3]([NH:19][NH2:20])=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]
Reactant: CSc1nc(=O)n(Cc2cccs2)c(C)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)c(NN)nc(=O)n1Cc1cccs1

Procedure:
A solution of 5-chloro-6-methyl-4-methylthio-1-(2-thienylmethyl)pyrimidin-2-one (987 mg) and hydrazine hydrate (98-100%) (2.5 ml) in ethanol (50 ml) was stirred and heated at reflux for one hour. The solution was evaporated to a gum which crystallised from ethanol to give pale purple crystals of the title pyrimidinone (649 mg) m.p. 184°-187° C.; λmax (EtOH) 232 nm (ε 14,720), 291.5 nm (ε 10,400).
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH3:13].[CH:16]1[CH:17]=[CH:18][C:19]2[S:24][CH:23]=[CH:22][C:20]=2[CH:21]=1>>[S:24]1[C:23]([CH2:4][C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[CH2:12][CH3:13])=[CH:22][C:20]2[CH:21]=[CH:16][CH:17]=[CH:18][C:19]1=2
Reactant: CCc1ccc(Br)cc1C(=O)N(C)OC
Reactant: c1ccc2sccc2c1
Product: CCc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
To a solution of 2-ethylbenzoic acid (10.0 g) in dichloromethane (50 ml) were added oxalyl chloride (7.0 ml) and N,N-dimethylformamide (3 drops) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give a corresponding acid chloride. The acid chloride was dissolved in methanol (60 ml) and the mixture was stirred at room temperature for 3 hours, and then, the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2-ethylbenzoate, which was used in the subsequent step without further purification. (2) The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)—water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4). (3) The above methyl 5-bromo-2-ethylbenzoate was treated in a manner similar to Reference Example 4-(1) and (2) to give N-methoxy-N-methyl-5-bromo-2-ethylbenzamide as colorless oil. APCI-Mass m/Z 272/274 (M+H). (4) The above N-methoxy-N-methyl-5-bromo-2-ethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene as oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OCC)C.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([NH:34][C:35]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:2][CH2:3]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of the compound (0.10 g) obtained in Example 33, step 1 in THF (3 mL)/diethyl ether (3 mL) was added tert-butyl isocyanate (41 μL), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether/hexane to give tert-butyl 8-{4-[(tert-butylamino)carbonyl]piperazin-1-yl}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.11 g, 85%) as a white powder.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.[CH3:11]I>C(Cl)Cl>[Br:3][C:4]1[S:5][C:6]([CH2:9][O:10][CH3:11])=[CH:7][N:8]=1
Reactant: OCc1cnc(Br)s1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1cnc(Br)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromothiazol-5-yl)methanol (WO 2009/077990, p. 92) (1.19 g, 6.11 mmol) in CH2Cl2 (4.0 mL) was treated with MeI (0.46 mL, 7.33 mmol) followed by Ag2O (2.12 g, 9.16 mmol) and the resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil: TLC: rf (7:3 hept-EA)=0.33. LC-MS-conditions 07: tR=0.66 min, [M+H]+=209.93.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH:21]([CH3:23])[C:12]2=[C:13](O)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH:21]([CH3:23])[C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2nc3ccnn3c(O)c21
Product: CC1CNCCc2nc3ccnn3c(N3CCC3)c21

Procedure:
The product was prepared using 10-hydroxy-9-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (from step c to f), in step e (route 1) azetidine was used as the amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Yield: 55 %

Procedure:
2-(3-Nitro-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1 g, 2.6 mmol) was dissolved in MeOH (100 ml) and added 10% Pd/C (100 mg) followed by ammonium formate (3eq, 500 mg). The reaction mixture was refluxed overnight. Then the reaction mixture was filtered and concentrated to give a white solid. The solid was taken up in EtOAc, filtered again, concentrated to give white solid. (500 mg, 55% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][OH:39])[O:18][CH:10]1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:42]([C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Br)=[CH:47][C:46]=1[Cl:53])=[N+:43]=[N-:44].O>CN(C=O)C>[N:42]([C:45]1[CH:52]=[CH:51][C:48]([CH2:49][O:39][CH2:38][C@H:19]2[O:18][CH:10]([S:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:47][C:46]=1[Cl:53])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Reactant: OC[C@H]1OC(Sc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(COC[C@H]2OC(Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-benzyl-1-thio-D-glucopyranoside (3) (1.09 g, 2.00 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 96 mg, 2.40 mmol), and the resulting mixture was stirred at room temperature for 15 min. The reaction mixture was cooled to 0° C. and 4-azido-3-chlorobenzyl bromide (592 mg, 2.40 mmol) was added, which was followed by stirring at room temperature for 4 hr. Water (30 ml) was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-benzyl-1-thio-D-glucopyranoside (4) (1.33 g, yield 94%) as slightly yellow crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[N:13]=1>CN(C)C=O>[C:4]1([CH2:3][S:10][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([C:22]([F:23])([F:25])[F:24])[N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)nc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 0.28 g (0.008 mol) of 60% sodium hydride (in mineral oil, then washed with hexanes) in 7 mL dry dimethylformamide under nitrogen at 0° C. was added 0.8 mL (0.0067 mol) of benzyl mercaptan while maintaining the temperature below 10° C. The suspension was warmed to room temperature and stirred another 45 minutes before cooling back to 0° C. A solution of 2.0 g (0.0067 mol) of the product from Example 2a or 2b in 5 mL dry dimethylformamide was added dropwise and stirred 30 minutes at 0° C. The reaction was poured into ice water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to afford 2.3 g (100%). 1H NMR (CDCl3) δ, 3.94 (3H, s), 4.43 (2H, s), 7.2-7.6 (6H, m), 8.38 (1H, d, J=8Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 mL) and THF (1 mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N2. After 30 min of stirring, the reaction mixture was cooled to 0° C. and 2-chloro-N,N-dimethylacetamide (11 mL, 0.14 mmol,) was added. The reaction mixture was stirred for 5 min at 0° C. and then for 10 h at room temperature. The mixture was purified by preparative HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of Pd—C (10 mg). The mixture was stirred open to the atmosphere overnight at room temperature. The reaction mixture was filtrated and purified by preparative HPLC providing 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462.0.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:21]=1)[CH3:2].C([O-])(=O)C.[NH4+:30].C(OCC)C>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH2:30])[C:8]=2[N:21]=1)[CH3:2]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CC(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc(C)cc2n1CC(C)C
Temperature: 150 °C
Reaction time: 36 h

Procedure:
A sealed glass tube containing 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.51 g) from Part E and ammonium acetate (25.1 g) was heated to 150° C. After 36 hours, TLC monitoring indicated that the reaction was complete. The resulting reaction mixture was cooled and then dissolved in ethyl acetate. The ethyl acetate solution was washed with 25% aqueous sodium hydroxide. The resulting organic layer was dried with magnesium sulfate, and concentrated under reduced pressure to an orange oil. The oil was put through a column using 95/5 ethyl acetate/methanol, providing good separation. The oil recovered from the product fraction was dissolved in isopropyl alcohol, to which 1M HCl in diethyl ether was added. A white solid formed. More diethyl ether was added, and the white solid was filtered and dried under vacuum at 80° C. for 5 hours. The resulting solid was dissolved in water (50 ml), and the pH was adjusted to 11 using sodium carbonate. An oil separated and was extracted with dichloromethane. The resulting dichloromethane solution was dried with magnesium sulfate and concentrated under reduced pressure to a clear oil. The oil was triturated with methanol, and the resulting solid was dissolved in diethyl ether. The diethyl ether solution was subjected to high vacuum at room temperature to dry the product. The resulting partially solidified product was solidified by cooling with an isopropyl alcohol/dry ice bath to provide 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 77.0-79.0° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]=[C:7]([N:19]([CH3:21])[CH3:20])[N:6]=1>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]2[N:8]=[C:7]([N:19]([CH3:21])[CH3:20])[N:6]=[C:5]([C:1]#[N:2])[N:10]=2)=[CH:13][CH:14]=1
Reactant: CN(C)c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(C#N)nc(Nc2ccc(Cl)cc2)n1
Temperature: 90 °C

Procedure:
Sodium cyanide (0.138 g) was added to a solution of the product from step (ii) (0.4 g) in N,N-dimethylformamide (20 ml) and heated at 90° C. for 16 h. The mixture was partitioned between ethyl acetate and water, a solid formed which was filtered off and purified by RPHPLC 15–85% acetonitrile in aqueous trifluoroacetic acid. Yield 0.05 g