Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:23].[H-].[Na+].[CH3:26][CH2:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30].Cl.[C:35](=[O:38])(O)[O-:36].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:20][C:19]([F:22])([F:21])[C:35]([OH:36])=[O:38].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:15]([C:17]([NH2:18])=[O:36])=[CH:16][C:11]=2[N:10]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:9]1=[O:23]
Reactant: O=C([O-])O
Reactant: CCN(CC)CCCl
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(-c2ccccc2Cl)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
1-(2-Chlorophenyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (17.6 mg) was dissolved in N,N-dimethylformamide (1.5 ml), and to the solution was added sodium hydride (2.7 mg). The mixture was stirred at room temperature for 20 minutes. A solution of 2-chlorotriethylamine hydrochloride (11.7 mg) in N,N-dimethylformamide (2 ml) and triethylamine (0.011 ml) were added, and the mixture was stirred at 60-70° C. for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was dissolved in 2-methyl-2-propanol (1 ml) and heated at 50° C. To the solution was added powdered potassium hydroxide (73.1 mg), and the mixture was stirred for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted 4 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 1 to give the title compound (6.2 mg, 6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-methylpyridine (74.4 g) and ethyl 4-fluorobenzoate (134.4 g) in dry tetrahydrofuran (600 ml) was added a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.6 l) dropwise with ice cooling. The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added hexane (12.2 l) and the separated solid was collected, washed with hexane and dried. The obtained solid was dissolved in 3N-hydrochloric acid (800 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethan-1-one (148 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9 %

Procedure:
To a suspension of 1.76 g of 5-carboxyoxindol in 200 ml of methylene chloride was added 2 ml of pyridine. After completion of addition, to the suspension was added dropwise 1.4 g of thionyl chloride with stirring held at 0° to 20° C. After completion of addition, the mixture was stirred at the same temperature for 1 hour, and a solution of 1.74 g of benzylpiperazine in 10 ml of methylene chloride was added dropwise thereto. The mixture was then stirred for 4 hours at room temperature. The reaction mixture was thoroughly washed with an aqueous potassium carbonate solution, then washed with water, and dilute hydrochloric acid, dried over sodium sulfate, and the solvent was distilled off. The residue was isolated and purified by silica-gel column chromatography [silica-gel: WAKO C-200, eluent: chloroform:methanol (V/V)=20:1] followed by recrystallization from isopropyl alcohol to give 298 mg of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[S:8][S:7][C:6](=[S:9])[N:5]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O.C(O)C.C(Cl)Cl>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:8][C:4]2[N:5]=[C:6]([SH:9])[S:7][N:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1nc(=S)ss1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CSc2nsc(S)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
A solution of 2.2 grams (0.055 mole) of sodium hydroxide in 7 ml of water and 20 ml of ethanol was stirred and 4.0 grams (0.027 mole) of 5-amino-1,2,4-dithiazol-3-thione was added portionwise. After all of the 5-amino intermediate was in solution, 4.7 grams (0.027 mole) of 4-nitrophenylmethyl chloride was added dropwise. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 20 ml of water then extracted with two 25 ml portions of diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid to yield a gummy solid. The solid was extracted from the aqueous layer with two 25 ml portions of ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a gummy solid. The solid was dissolved in methylene chloride and filtered to remove a small amount of insoluble material. The filtrate was concentrated under reduced pressure to yield 2.8 grams of 3-(4-nitrophenylmethylthio)-5-mercapto-1,2,4-thiadiazole as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:15]([F:21])[CH:16]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester in MeOH (1.5 mL) was added 1 M NaOH (800 uL, 0.902 mmol). The reaction mixture was stirred at 60° C. for 4 hours and then at room temperature for 16 hours. The reaction mixture was diluted with H2O, acidified with 2 M HCl until the pH was 1-2, and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to yield 0.053 g (97%) desired product as a pale orange solid. MS ESI (+) m/z 341, 343 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 10.0 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 6.95 (t, 1H), 6.16 (d, 1H), 3.19 (s, 3H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:49]1[O:54][NH2:55]>CN(C=O)C.C(N(CC)CC)C.O>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:55][O:54][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][O:48]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1)NOC1CCCCO1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound B2) (0.300 g), HOBt.H2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC.HCl (0.508 g), O-(tetrahydro-2H-pyran-yl)hydroxylamine (0.089 g). Reaction conditions: room temperature, 1 hour; room temperature, 18 hours.
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[O:5][CH:4]=3)[CH2:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: OCc1coc2ncccc12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Clc1ccc(C2=CCN(Cc3coc4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
3-Hydroxymethylfuro[2,3-b]pyridine (101.5 mg, 0.681 mmol) was treated with thionyl chloride (2 ml) and the solution stirred at room temperature for an hour. The mixture was concentrated in vacuo, toluene added (5 ml) and evaporated to dryness. The residue was dissolved in anhydrous dimethylformamide (5 ml), potassium carbonate (0.47 g, 3.40 mmol) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (173.3 mg, 0.753 mmol) were added and the mixture stirred at room temperature, under nitrogen, overnight (19 hours). The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The extracts were washed with brine (25 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 1:1 then 2:1 ethyl acetate/hexane, to afford the title compound (118.3 mg, 54%) as a pale yellow solid. Recrystallisation from ethyl acetate/hexane gave yellow plates, m.p. 115.5°-116.5° C.; (Found: C, 70.06; H, 5.19; N, 8.52. C19H17ClN2O requires C, 70.26; H, 5.28; N, 8.62%); δH (CDCl3) 2.54 (2H, br s, tetrahydropyridinyl CH2), 2.78 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.23 (2H, m, tetrahydropyridinyl CH2), 3.78 (2H, s, ArCH2N), 6.06 (1H, t, J 3.5 Hz, tetrahydropyridinyl CH), 7.21-7.32 (5H, m, ArH), 7.68 (1H, s, 2-H), 8.12 (1H, dd, J 7.6, 1.7 Hz, 4-H), 8.34 (1H, dd, J 4.8, 1.7 Hz, 6-H); m/z (ES+) 325/327 (M+1)+.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:23][C:24]#[N:25])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:23]([C:24]#[N:25])[C:1]([O:5][CH2:6][CH3:7])=[O:8])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)OCC
Reactant: CCCOc1c(OC)cc(CC#N)cc1SC
Solvent: Cc1ccccc1
Product: CCCOc1c(OC)cc(C(C#N)C(=O)OCC)cc1SC
Yield: 92 %

Procedure:
1.4 g of sodium was dissolved in absolute EtoH with warming to 70° C., then EtOH was removed under vacuum to give a white solid residue of NaOEt. A mixture of 35 ml of diethyl carbonate, 43 ml of toluene, 13.46 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile was added slowly. The mixture was refluxed for 3 hours. EtOH was removed under vacuum. The solid was filtered and washed with toluene (3×) and ether (3×). The solid was suspended in 200 ml of H2O and acidified with 6N HCl. The solid dissolved and a brown oil formed. The oil was extracted with ether (3×), the combined ether extracts were washed with H2O (2×), saturated NaCl (2×) was finally dried over MgSO4. The ether was removed under vacuum to give 16 g (92% yield) of ethyl 3-methoxy-5-methylthio-4-propoxy-α-cyanobenzeneacetate.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[C:13](Br)=[N:14][CH:15]=[CH:16][CH:17]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.C(NC1C(Br)=NC=CC=1)C=C.CC([O:34]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:34]=[C:2]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:1]1
Reactant: C=CCN(C(=O)OC(C)(C)C)c1cccnc1Br
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=CCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl allyl(2-bromopyridin-3-yl)carbamate. To a solution of N-allyl-2-bromopyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:20][C:3]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reactant: COc1cccc(B(O)O)c1
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: [K+]
Product: COc1cccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2Cl)c1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (0.750 g, 2.01 mmol, see Example 6), 3-methoxyphenylboronic acid (0.321 g, 2.11 mmol), Pd(PPh3)4 (0.116 g, 0.100 mmol) and K2CO3 (4.20 mL, 3.02 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (8 mL). The reaction was then heated to 80° C. overnight. The reaction was then poured into water and extracted with DCM. The organic fractions were dried, filtered, and concentrated to give the crude product. The crude product was purified (1:1 to 1:2 hexane:DCM) to give 4-chloro-5-(3-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.610 g, 75.8% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:38]([O:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH2:38]([O:45][C:46]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Reaction time: 3 h

Procedure:
A solution of 1-benzyl-4-[3-(1-naphthylsulfonylmethyl)-4-nitrophenoxy]-piperidine (4.7 g, 9.1 mmol) and benzylchloroformate (6.0 mL, 42 mmol) in benzene was heated at reflux temperature, under nitrogen, for 3 hours, cooled to ambient temperatures, poured into 2.5 N sodium hydroxide and extracted with ethyl acetate. The extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 30-50% ethyl acetate in hexane to afford 4-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-piperidine-1-carboxylic acid benzyl ester as a buff foam/amber gum, 3.9 g, 76%); Mass spectrum (+EI, [M+H]+) m/z 561. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.46 (m, 1H), 8.30 (d, 1H, J=8.17 Hz), 8.07-8.10 (m, 1H), 7.94-7.99 (m, 2H), 7.61-7.68 (m, 3H), 7.27-7.37 (m, 5H), 7.09 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.72 (d, 1H, J=2.81 Hz), 5.23 (s, 2H), 5.05 (s, 2H), 4.36-4.40 (m, 1H), 3.58-3.61 (m, 2H), 3.10-3.20 (m, 2H), 1.70-1.74 (m, 2H), 1.34-1.42 ppm (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C(Cl)(Cl)(Cl)Cl>[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH2:26][Br:1])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(N)=O)cc1O[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(N)=O)ccc1CBr
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
N-Bromosuccinimide (NBS) (0.507 g, 2.85 mmol) was added to a solution of 3-t-butyldimethylsiloxy-4-methyl benzamide (Compound 7.1) in 30 mL CCl4. The mixture was irradiated with a 275 W sunlamp (Sears, #34-7105) at 60° C. Each irradiation took 10 minutes followed by 10 minutes to let the lamp cool down. It took 2 hours of irradiation over a period of 4 hours to complete the reaction. After the solvent was removed at reduced pressure, the residue was subjected to flash silica gel chromatography to yield the product as a white solid (0146 g, y=81.7%). 1H NMR (CDCl3) δ 0.318 (s,6H), 1.05 (s,9H), 4.51 (s,2H), 6.10 (b, 2H), 7.25 (d,J=7.8 Hz, 1H), 7.32 (s,1H), 7.39 (d,J=7.9 Hz, 1H); --C NMR (CDCl3 ) δ 4.08, 18.28, 25.76, 27.87, 117.99, 118.07, 119.49, 131.23, 132.54, 134.97, 168.46.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloropyridine (162 mg, 1262 μmol) and DIEA (275 μL, 1578 mmol) in DCM (6.0 mL) was added 4-nitrophenyl chloroformate (212 mg, 1052 μmol). The resulting mixture was then stirred at RT for overnight. A yellow precipitation was observed. The yellow solid was collected by filtration to give the title compound as a light yellow solid, which was used in the next step without purification requirement.
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[Br:26]CBr.[N+]([O-])(OCCC(C)C)=O>C(OCC)(=O)C>[Br:26][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: BrCBr
Agent: CC(C)CCO[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Br)nc21
Temperature: 60 °C
Yield: 98 %

Procedure:
A round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (134.4 mg, 0.397 mmol) under an atmosphere of nitrogen was treated with dibromomethane (397 μL). Isoamyl nitrate (107 μL, 0.794 mmol) was added and the reaction mixture was heated at 60° C. 3.5 h and cooled to rt. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organics were dired over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-Bromo-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (0.156 g, 0.388 mmol, 98% yield) was isolated as a brown glassy solid. The product was used immediately in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH2:20].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH3:16][O:17][C:18](=[O:25])[C@H:19]([NH:20][C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:14])[CH3:13])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(C)C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid (22.4 g) and D-leucine methyl ester hydrochloride (20.0 g) were dissolved in N,N-dimethylformamide (224 mL), and triethylamine (11.1 g) was added dropwise thereto under cooling on ice. To the mixture were sequentially added 1-hydroxybenzotriazole (14.9 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.1 g), and stirring was performed for two hours. Water (224 mL) was added to the reaction mixture, and the formed precipitates were recovered through filtration, whereby the title compound (57.8 g) was yielded as wet crystals.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)#N.Cl.[OH2:28]>ClCCl>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH:18]=[O:28])[CH:25]=1
Reactant: O
Reactant: Cc1ccnc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccnc(C=O)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
Diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) was added dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59 mmol) in dichloromethane (180 ml) at −78° C., and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was combined with concentrated hydrochloric acid (28 ml) and water (112 ml), and the water layer and the organic layer were separated. The organic layer was extracted with 2 N hydrochloric acid. The water layer was combined, neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.7 g, 37%).