Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:12][C:13]1[C:23]2[S:22][CH2:21][CH2:20][CH2:19][N:18]([N:24]=O)[C:17]=2[CH:16]=[CH:15][CH:14]=1.[ClH:26]>CCOC(C)=O.CCOCC>[ClH:26].[CH3:12][C:13]1[C:23]2[S:22][CH2:21][CH2:20][CH2:19][N:18]([NH2:24])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2c1SCCCN2N=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c1SCCCN2N
Temperature: 23 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 1.0 M THF solution of LiAlH4 (2.3 mL, 2.3 mmol) cooled to ˜10° C. was added dropwise via cannula over 3 min (internal temperature <25° C.) a THF solution (2.3 mL) of 9-methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (crude, 470 mg, 2.3 mmol). The cooling bath was removed once the addition was finished, and the reaction was maintained at 25° C. to 32° C. for 1.5 h. H2O (0.1 mL) was added cautiously over 5 min, followed by THF (40 mL), aqueous NaOH solution (15%, 0.1 mL), and again H2O (0.3 mL). The resulting mixture was vigorously stirred at 23° C. for 1 h and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated to afford a residue which was dissolved in EtOAc (4 mL). To this solution was added a 1M HCl.Et2O solution dropwise over 1 min. The solid was isolated by concentrated in vacuo to yield 9-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-amine hydrochloride (477 mg, 80%) as a brown powder. 1H NMR (CDCl3, 300 MHz): δ7.13 (m, 2H), 6.91 (m, 1H), 4.00-3.80 (br s, 2H), 3.36 (t, 2H, J=5.7 Hz), 2.87 (t, 2H, J=5.7 Hz), 2.42 (s, 3H), 2.05 (m, 2H) ppm.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].[N:22]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH:26]=[CH:25][N:24]=[CH:23]1>>[N:22]1([CH2:27][C:28]2[N:29]=[CH:30][C:31]([C:11]3[CH:12]=[CH:13][C:8]([C@@H:7]([OH:18])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:21])[Cl:1])[CH2:19][F:20])=[CH:9][CH:10]=3)=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: Brc1ccc(Cn2ccnc2)nc1
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(Cn3ccnc3)nc2)cc1)C(Cl)Cl

Procedure:
Following the general procedure of Example 6—Step 4 and making non-critical variations but using 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)propan-2-yl)acetamide and commercially available 2-((1H-imidazol-1-yl)methyl)-5-bromopyridine the title compound is obtained (20 mg): 1H-NMR (400 MHz, DMSO-d6) 4.21-4.24 (m, 1H), 4.27-40.31 (m, 0.5H), 4.38-4.42 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.67-4.70 (m, 0.5H), 4.89 (t, J=3.6 Hz, 1H), 5.33 (s, 2H), 5.99 (d, J=4.16 Hz, 1H), 6.51 (s, 1H), 6.92 (s, 1H), 7.22 (t, J=3.84 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.28 Hz, 2H), 7.77 (s, 1H), 8.06-8.08 (d, d J=2.36 Hz, J=8.08 Hz, 1H), 8.63 (d, J=8.84 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H). LC-Ms (m/z): [M+H]=437.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[CH2:25]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:24]=[CH2:25])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: C=Cc1cccc(B(O)O)c1
Product: C=Cc1cccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)c1
Yield: 63.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-vinylphenylboronic acid (22 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-vinyl-phenyl)-thiazole-5-carboxylic acid (26 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H); 8.04 (t, 1 H); 7.85 (s, 1 H); 7.83 (dt, 1 H); 7.59 (dt, 1 H); 7.48 (t, 1 H); 7.40 (s, 1 H); 6.83 (dd, 1 H); 5.92 (dd, 1 H); 5.33 (dd, 1H); 3.86 (s, 3 H); 3.85 (s, 3 H). MS 408 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CS(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Clc1ccc(Oc2ncccc2Br)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-2-chloropyridine (10 g, 52 mmol), 4-chlorophenol (6.7 g, 52 mmol), cesium carbonate (34 g, 104 mmol) in 100 mL DMSO was heated to 90° C. with stirring overnight. The reaction mixture was dilution with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@@H:9]2[C@H:10]([NH2:15])[CH2:11][CH:12]=[CH:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Yield: 32.4 %

Procedure:
40 g of (±)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound H1) are dissolved in 400 ml of ethanol and 40 g of zinc powder are added. After heating to boiling temperature, 65 ml of glacial acetic acid are added dropwise. Afterwards, the reaction mixture is filtrated and concentrated. The residue is redissolved in diluted hydrochloric acid and extraxted with toluene. The aqueous layer is alkalized using 6 N solution of sodium hydroxide and extracted several times with toluene. The combined organic phases of the alkalic extraction are dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 11.5 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=3)[CH2:29][CH2:30]2)=[CH:17][CH:16]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(CCCN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Reaction time: 0.17 h

Procedure:
6 g 2-amino-6-chloro-3-nitropyridine, 12.6 g 1-(4-fluorophenyl)-4-(1-piperazinyl)-1-butanone dihydrochloride and 20 g potassium carbonate in 120 ml n-propanol are stirred under reflux for 21/2 hours. The mixture is then treated with 400 ml water, stirred for further 10 minutes and cooled in ice bath. The resulting precipitate is filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulphate and evaporated. The resulting 1-(4-fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanone, m.p. 128°-130°, is without further purification dissolved in 400 ml methanol. 3 g palladium on charcoal (5%) are added to the solution and the mixture is hydrogenated under normal conditions. The catalyst is filtered off and the solvent distilled off to give 1-(4-fluorophenyl)-4-[4-(2,3-diaminopyridin-6-yl)-1-piperazinyl]-1-butanone which is used without further purification.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[N:92]1([CH2:97][CH2:98][OH:99])[CH2:96][CH2:95][CH2:94][CH2:93]1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:99][CH2:98][CH2:97][N:92]2[CH2:96][CH2:95][CH2:94][CH2:93]2)=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: OCCN1CCCC1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
Compound 106A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with 2-(pyrrolidin-1-yl)ethanol and 4-(benzyloxy)phenol, respectively: DCI (+)MS: 298 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2nn[nH]n2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C1C[C@@H](c2nn[nH]n2)CN1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
(R)-3-(2H-Tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.51 mmol) was dissolved in methanol (20 mL), 4M HCl in dioxane (1.13 ml, 4.52 mmol) was then added dropwise. The solution was stirred overnight. The reaction was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford (R)-5-pyrrolidin-3-yl-2H-tetrazole (220 mg, 1.58 mmol, 63%) as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][O:16][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C.CO>[CH3:6][N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][O:16][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCc2ccoc2C1
Reaction time: 2 h

Procedure:
To 6-(t-butoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine (1.05 g), a saturated solution of hydrochloride in ethanol (30 ml) was added at room temperature. After stirring for 2 hours, the reaction mixture was concentrated. The residue thus obtained was suspended in methylene chloride (20 ml), followed by the addition of methanol (20 ml), triethylamine (1.31 ml), acetic acid (810 μl), formaldehyde (a 37% aqueous solution, 610 μl) and sodium triacetoxyborohydride (1.51 g) at room temperature. The resulting mixture was stirred for 1 hour. To the reaction mixture, a saturated aqueous solution (100 ml) of sodium bicarbonate and methylene chloride (20 ml) were added to cause separation. The water layer was extracted with methylene chloride (3×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (50 g of silica gel, methylene chloride:acetone=1:1→1:2→methylene chloride:methanol=10:1), whereby the title compound (434 mg) was obtained as a colorless transparent oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[CH:3]1.C(Cl)(=O)C(Cl)=O.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:27](=[O:42])[N:28]([C:33]4[CH:38]=[CH:37][C:36](O)=[C:35]([O:40][CH3:41])[CH:34]=4)[CH:29]=[CH:30][C:31]=3[N:32]=2)=[CH:20][CH:19]=1>C(Cl)Cl.CN(C=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:27](=[O:42])[N:28]([C:33]4[CH:38]=[CH:37][C:36]([O:8][CH2:7][C:6]5[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[C:35]([O:40][CH3:41])[CH:34]=4)[CH2:29][CH2:30][C:31]=3[N:32]=2)=[CH:20][CH:19]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cn1cncc1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCc1cncn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Treat a solution of (3-methyl-3H-imidazol-4-yl)-methanol (60.0 mg, 0.54 mmol) in CH2Cl2 with oxalyl chloride (0.15 g, 1.2 mmol) and 2 drops of DMF. Stir at room temperature for 4 h, concentrate, and dissolve in DMF (5.0 mL). Add this solution to a suspension of NaH (62.5 mg, 1.6 mmol) and 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (200.0 mg, 0.5 mmol) in DMF (5 mL). Stir at room temperature for 2 h, dilute with water, and extract with CH2Cl2 (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography, using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (100.0 mg, 40%). MS (ES+) 481.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ7.90 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=4.0 Hz), 7.41 (s, 1H), 7.07 (s, 1H), 6.97 (d, 1H, J=8.8 Hz), 6.94 (d, 1H, J=2.2 Hz), 6.81 (dd, 1H, J=8.6, 2.4 Hz), 5.04 (s, 2H), 4.07 (t, 2H, J=7.0 Hz), 3.83 (s, 3H), 3.72 (s, 3H), 3.27 (t, 2H, J=6.8 Hz).
Reaction SMILES: Cl.CN(C)[C:4](=[CH:10][CH:11]=[C:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([OH:24])C>>[OH:24][C:4](=[CH:10][CH:11]=[C:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=CC=C(C#N)c1ccccc1)N(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(C#N)c1ccccc1
Temperature: 10 °C

Procedure:
1N aqueous hydrochloric acid solution (87 cc) is added in the course of 3 minutes to a solution, maintained under reflux, of ethyl 2-dimethylamino-5-cyano-5-phenyl-2,4-pentadienoate (21.3 g) in ethanol (27 cc). The mixture is cooled to a temperature of approximately 10° C. and the precipitate obtained is filtered off, washed with ethanol (15 cc) and dried. Ethyl 2-hydroxy-5-cyano-5-phenyl-2,4-pentadienoate (12.1 g), m.p. 189° C., is thereby obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).
Reaction SMILES: [CH:1]1([N:4]([CH:43]2[CH2:45][CH2:44]2)[C:5]([C:7]2[N:40]([CH2:41][CH3:42])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/[NH:29][N:30]([CH2:38][CH3:39])C(OC(C)(C)C)=O)=[CH:21]/[C:22](=O)[CH:23]([O:26]C)OC)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:43]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:40]([CH2:41][CH3:42])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH:23]=[O:26])[N:30]([CH2:38][CH3:39])[N:29]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:44][CH2:45]1
Reactant: CCN(N/C(=C\C(=O)C(OC)OC)Nc1nc2c(cc(C(=O)N(C3CC3)C3CC3)n2CC)c2c1ncn2C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C=O
Temperature: 60 °C
Yield: 58.2 %

Procedure:
A mixture of (Z)-tert-butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (187 mg, 0.299 mmol) and TFA (25% in dichloroethane, 1.0 mL, 2.99 mmol) was heated at 60° C. for 0.5 h and LC/MS showed completion of reaction. Solvent was evaporated and the residue was partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-5% methanol/dichloromethane). N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-formyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (80 mg, 0.174 mmol, 58.0% yield) was obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C[O-]
Reactant: Cc1ccnc(Cl)c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc(C)c1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3-bromo-2-chloro-4-methylpyridine (1 g) was added to DMF (5.6 mL). Sodium methoxide (28% solution in methanol, 4.6 mL) was added to the solution, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:17]2[C:18]([C:29]([F:31])([F:32])[F:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(c1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Ethyl 4-chlorophenylcarbamate (1.2281 g) was dissolved in tetrahydrofuran (30 ml), and to the solution were added sodium hydride (246.1 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (1.3870 g). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=5:1) to give the title compound (1.7323 g, 78%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([C:77]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Cl:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Clc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 28.6 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (12.5 mg, 0.036 mmol), DMF (0.10 mL), ethanol (0.70 mL), 1M Na2S2O4 (3 eq, 0.11 mmol, 0.11 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.039 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (5 mg, 29%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.60 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2), 3.70 (s, br, 4H, piperazine N(CH2)2), 5.41 (s, br, 2H, PhCH2), 6.30 (t, J=1.9 Hz, pyrazole H-4), 7.34 (d, J=8.4 Hz, 2H, phenyl H-3 & H-5), 7.37 (dd, J=7.6, 4.6 Hz, 1H, pyridine H-5), 7.49 (s, br, 1H, pyrazole H-3 or H-5), 7.78 (d, br, J=7.5 Hz, 1H, pyridine H-4), 7.86 (d, J=2.0 Hz, 1H, pyrazole H-3 or H-5), 8.11 (d, J=8.5 Hz, 2H, phenyl H-2 & H-6), 8.12 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.47 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C(O)C.O1CCCC1>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoic acid (168 mg), ethyl 3-(methylamino)propanoate (63 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg), hydroxybenzotriazole monohydrate (74 mg) and triethylamine (67 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL). 1N Lithium hydroxide (0.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (118 mg, 60%).