Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][CH2:23][OH:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:27](=[O:28])([O:24][CH2:23][CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[NH2:29]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCO
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCOC(N)=O
Reaction time: 2 h

Procedure:
To a solution of Example 60A (110 mg, 0.298 mmol) in CH2Cl2 (2 mL) was added trichloroacetyl isocyanate (67.4 mg, 0.358 mmol) and the mixture was stirred for 2 hr. The reaction was concentrated and dissolved in methanol (0.5 mL). A solution of potassium carbonate (140 mg, 1.013 mmol) in water was added and the mixture was stirred for 24 hr. The reaction was concentrated, partitioned between ethyl acetate (3×10 mL) and water (10 mL). The organics were combined, dried, filtered, concentrated and the residue was trituated with CH2Cl2 and hexane (1:3). The solid was collected by filtration (80 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 3.79 (s, 3H) 4.29-4.38 (m, 4H) 6.55 (s, 1H) 7.10 (d, J=9.12 Hz, 1H) 7.19 (s, 1H) 7.44 (dd, J=9.12, 2.78 Hz, 1H) 7.67 (d, J=2.78 Hz, 1H); MS (DCI) m/z 412 (M+H)+. Anal calcd C18H22ClN3O4S.0.5 H2O: C, 51.36; H, 5.51; N, 9.98. Found: C, 51.23; H, 5.33; N, 9.92.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Br)(Br)([Br:14])=O.ClCCl>C(Cl)(Cl)Cl>[Br:14][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nccc(O)c1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 49.7 %

Procedure:
A mixture of 2-methyl-3-nitropyridin-4-ol (2 g, 12.98 mmol) and phosphorus oxybromide (24.93 g, 87 mmol) was melted at 140° C. in a pressure vessel over 3 hours. The reaction mixture was cooled, poured into chloroform (100 mL) and ice water (100 mL). The layers were separated and the organic layer was washed with water (2×25 mL), saturated sodium bicarbonate (2×75 mL), dried over magnesium sulfate, filtered, and concentrated to give an oil. The oil was treated with a mixture of dichloromethane and chloroform (50 mL, 3:1) to give a solid which was filtered and dried under vacuum. The filtrate was reduced in volume by 50% under vacuum, loaded on a silica column and eluted with 2% methanol in dichloromethane to give additional product which was concentrated and combined with the initial batch to give 4-bromo-2-methyl-3-nitropyridine (1.4 g, 6.45 mmol, 49.7% yield); MS [M+H] found 217.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 7.88 (dd, J=5.31, 0.51 Hz, 1H) 8.52-8.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([O:40][CH3:41])[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=1)[OH:35].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:40][CH3:41])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.4 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of guaiacol and 20 ml of dry dimethylformamide is stirred at room temperature for 23 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate, there is obtained o-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 205°-206°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(N(CC)CC)C>[Br:8][C:4]1[N:3]=[C:2]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: C#CCCCC
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cccc(Br)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2,6-Dibromopyridine (2.36 g, 10 mmole) is suspended in 32 ml degassed triethylamine in a 100 ml one-neck round bottom flask under argon. The suspension is treated successively with (bis)triphenylphosphine palladium dichloride (62 mg, 0.08 mmole) and cuprous iodide (8 mg, 0.04 mmole) and is warmed to 50° C. 1-Hexyne (0.50 ml, 4.4 mmole), in 4 ml triethylamine, is added slowly dropwise to the reaction mixture over 30 minutes at 50° C. The reaction is stirred an additional one hour at 50° C., cooled to room temperature, and the triethylamine hydrobromide is removed by filtration. The filtrate is concentrated in vacuo to a white pasty solid.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:32]4[CH2:31][CH2:30][CH:29]([C:26]5[C:25]6[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=6[O:28][N:27]=5)[CH2:34][CH2:33]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g; eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1 M in ether). The salt collected weighed 2.35 g, m.p.>270° C. dec.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20](=O)[CH3:21]>CN(C)C=O>[CH3:21][C:20]1[C:13]2[C:12](=[O:17])[CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=3)[CH2:15][C:14]=2[O:16][CH:19]=1
Reactant: O=C1CC(=O)CC(c2ccc(Br)cc2)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension was added 5-(4-bromophenyl)cyclohexane-1,3-dione (2.6 g) and then was added chloroacetone (0.92 g), and the mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([OH:16])[CH3:15]>C(OCC)(=O)C.CCCCCC>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc(I)c(C(C)O)cc1OC(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(I)c(C(C)=O)cc1OC(C)C

Procedure:
Concentration of fraction B (Rf 0.6 in 1:1 v/v ethyl acetate/hexane) afforded the starting alcohol 6 (200 mg, 19% recovery) as a pale-yellow oil that was identical, as judged by 1H NMR spectroscopic analysis, with authentic material.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(O)C>[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([N:8]1[CH2:9][CH2:10][C:11]2[NH:3][CH:4]=[N:5][C:6]=2[CH2:7]1)=[O:25]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a mixture of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.55 mmol), ethanol (10 mL) and triethylamine (1.10 mL, 7.89 mmol), 2,4-dichlorobenzyl isocyanate (0.52 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was distributed between water (20 mL) and ethyl acetate (75 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in diethylether (50 mL) and the crude product was filtered off. Recrystallization from acetone (25 mL) gave 0.30 g (37%) of the title urea as a colourless solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[N:8]([CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)=[C:9]=[O:10]>C1COCC1.[Pd]>[NH:14]1[CH2:13][CH2:12][CH:11]([N:8]2[CH:3]=[CH:4][NH:5][C:9]2=[O:10])[CH2:16][CH2:15]1
Reactant: COC(CN)OC
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1[nH]ccn1C1CCNCC1
Reaction time: 3 h

Procedure:
Aminoacetaldehyde dimethylacetal (1.2 g) was added to a solution of benzyl 4-isocyanatopiperidine-1-carboxylate (3 g) in THF (100 ml) and the mixture was stirred for 3 hours. 20% Palladium on charcoal (500 mg) was added and the mixture was hydrogenated under a hydrogen filled balloon. The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in ethanol and subjected to repeat hydrogenation with fresh palladium on charcoal catalyst (500 mg). The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in 2M HCl (50 ml) and allowed to stand for 4 hours. The reaction mixture was basified with 2M NaOH (50 ml) and evaporated to dryness using toluene (100 ml) to azeotrope final traces of solvent. The residue was triturated with methanol (100 ml) and filtered. The filtrate was evaporated to dryness to give the title compound as an off-white solid, yield 2.2 g, NMR DMSO D6 (Part spectrum some peaks obscured by DMSO): 1.3-1.8 (m, 5H) 3 (m, 2H) 3.9 (m, 1H) 6.3 (d, 1H) 6.4 (d, 1H) 9.9 (s broad, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH3:11])=[CH:5][C:4]=1[O:12][CH3:13].[H][H]>[Pd].CO>[CH2:9]([C:6]1[CH:5]=[C:4]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CC=Cc1ccc(OC)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(OC)c(OC)c1
Yield: 97.2 %

Procedure:
An atmospheric pressure hydrogenation equipment was charged with 17.8 g (0.10 M) of 1,2-dimethoxy-4-propenylbenzene, 0.9 g of palladium charcoal and 350 ml of methanol and introduced with hydrogen. The reaction was continued until the absorption of hydrogen was terminated. Palladium charcoal was filtered off from the reaction mixture. The filtrate was distilled off methanol and vacuum distilled to obtain 17.5 g (0.097 M) of 4-propylveratrole as colorless transparent liquid having a boiling point of 106°-108° C./4 mmHg.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:39])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)N1CCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 68.7 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and pyrrolidine-1-carbonyl chloride (25 mL, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(pyrrolidine-1-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (84 mg, 70%). MS (ESI) m/z 532.3 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:40])=[C:35]([CH2:37][CH2:38]O)[N:36]=2)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][C:35]2[N:36]=[C:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH:22]([CH3:23])[CH3:24])=[CH:27][CH:28]=3)[O:33][C:34]=2[CH3:40])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCO
Product: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 51 was prepared from 598 mg of N-(Boc)-L-Tyrosine methyl ester and 530 mg of Intermediate 14 to yield 540 mg (63% overall yield) of the title compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ7.77 (d, 2H, J=8.7), 7.12 (d, 2H, J=8.6), 6.9 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.5), 4.65 (hept, 1H, J=6.0), 4.13 (t, 2H, J=6.6), 3.0 (dd, 1H, J=14.4, 4.5), 2.85 (t, 2H, J=6.4), 2.76 (dd, 1H, J=14.4, 8.0), 2.31 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 425.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.C[C:26]([N:28](C)C)=O>O.ClCCl.[Zn].[C-]#N.[C-]#N.[Zn+2]>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:26]#[N:28])=[C:6]3[N:7]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 160 °C

Procedure:
400 mg 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 31), 7.0 mg zinc powder, 75.0 mg Zn(CN)2 and 39.0 mg dichloride[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct are suspended in 10 ml dimethylacetamide and the mixture is heated for 45 min under microwave irradiation to 160° C. The workup is performed by diluting the mixture with water and dichloromethane, extracting the aqueous layer twice and drying the combined organic layers over Na2SO4. The compound is isolated by evaporation of the solvent and chromatography on silica gel (dichloromethane/ethyl acetate).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([NH2:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([NH:37][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.6981 g, 2.067 mmol), 3-Amino-azepane-1-carboxylic acid tert-butyl ester (0.4752 g, 2.217 mmol), and diisopropylethylamine (0.50 mL, 2.9 mmol) in propan-2-ol (12 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in heptanes) affording 0.8869 g (83%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-azepane-1-carboxylic acid tert-butyl ester. LCMS (Method E, ESI): RT=2.07 min, m+H=516.2.
Reaction SMILES: [O:1]=[C:2]1[N:15]([CH:16]2C[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:14][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[CH:12]=[CH:13][C:5]=2[CH2:4][C@H:3]1[NH:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1)=[O:31].FC(F)(F)C(O)=O>ClCCl>[O:48]=[C:39]1[N:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:30]([NH:29][C@H:3]3[C:2](=[O:1])[N:15]([CH:16]4[CH2:17][CH2:18][NH:19][CH2:20]4)[CH2:14][C:6]4[C:7]5[CH:8]=[N:9][NH:10][C:11]=5[CH:12]=[CH:13][C:5]=4[CH2:4]3)=[O:31])[CH2:33][CH2:34]2)[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
(R)-tert-butyl 4-(8-oxo-7-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H,10H)-yl)piperidine-1-carboxylate (45 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.25 mL)was added to the mixture. Reaction stirred at room temperature for 1.5 hour. Reaction mixture was concentrated in vacuo. C18 preparatory HPLC purification afforded the title compound as yellow solid in 52% yield. High resolution MS m/e (M+H)+=543.2830.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:70])[CH2:68][OH:69]>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([O:69][CH2:68][CH2:67][OH:70])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: OCCO
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(OCCO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
To 150 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine, 187 mg of tripotassium phosphate, 84 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 46 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and the mixture was stirred at 100° C. for 13 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol as pale brown powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 52 mg of the objective compound as yellow powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1.N1C=CC=CC=1>CCOCC>[C:1]([O:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1)(=[O:3])[CH3:2]
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Oc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.08 ml, 1.05 mmole) was added dropwise to a stirred solution of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (300 mg, 1 mmole) and pyridine (0.09 ml, 1.05 mmole) in ether (10 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 1 hour and then diluted with H2O (10 ml). The organic layer was separated and washed with 1N HCl (10 ml), H2O (2×10 ml) and brine, dried over MgSO4, filtered and evaporated to provide the title compound.
Reaction SMILES: Cl[CH:2]([O:4]C)Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].CCOCC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH:2]=[O:4]
Reactant: COc1ccccc1F
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of titanium tetrachloride (182 g, 0.96 mol, 1.2 equiv.) and α,α, -dichloromethylmethyl ether (110 g, 0.96 mol) in an equal volume of methylene chloride is slowly added (30 minutes) to a solution of o-fluoroanisole (101 g, 0.80 mol) in dry methylene chloride (50 ml) at 10-20° C. The mixture is stirred at room temperature for one hour, is poured over crushed ice water and ether (1 l ) with stirring. This mixture is stirred under nitrogen until solution occurs. The organic layer is extracted with water, aqueous sodium bicarbonate, and is dried (MgSO4). The solvent is evaporated at 30° C. The residual oil is vacuum-distilled through a jacketed Vigreux column to give 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121° C. (10 mm Hg) Rf 0.6 on a silica-gel G plate with methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(CCOCCO)cc1
Yield: 88 %

Procedure:
The 2-(4-methylphenyl)ethoxyacetic acid obtained according to the preceding paragraph was reduced with lithium aluminum hydride in a manner analogous to that described in Example 1(b) to give 6.6 g (88%) of 2-[2-(4-methylphenyl)ethoxy]ethanol in the form of an oil which was homogeneous according to chromatography.