Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH:22]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 61 %

Procedure:
Following general procedure D, (6-bromo-4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino) quinoline-3-yl)(cyclopropyl)methanone (50 mg, 0.11 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.17 mmol) to afford the desired product (36 mg, 63%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.68 (s, 1H), 7.40 (s, 1H), 4.62 (m, 1H), 3.68 (d, J=12.8 Hz, 2H), 3.41 (m, 1H), 3.25 (m, 2H), 2.94 (s, 3H), 2.37 (m, 3H), 1.22 (m, 3H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=10.57 min.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1>C(O)C>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OCCCc1cccc(O)c1
Reactant: CCCCCCCCCCCBr
Solvent: CCO
Product: CCCCCCCCCCCOc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A 15N aqueous sodium hydroxide solution (2 ml) and a solution (10 ml) of 8.0 g of undecyl bromide in ethanol was added to a solution (30 ml) of 4.56 g of 3-(3-hydroxyphenyl)propanol in ethanol and the mixture was stirred at 70° C. for 12 hours. The solvent was distilled away and the residue was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20-1:3) to give 7.37 g of 3-(3-undecyloxyphenyl)propanol as a colorless, oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.CO>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][N:15]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc2c1ccn2-c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
4-Aminoindole (5.8 g, 44 mmol) and sodium hydride (80% dispersion in mineral oil, 1.3 g, 44 mmol) were stirred together in N,N-dimethylformamide (60 ml), with ice-bath cooling for 5 minutes, and then 2,3-dichloro-5-trifluoromethylpyridine (5,8 g, 44 mmol) was added slowly. The mixture was stirred at room temperature for 18 hours, and then a small quantity of methanol was added. The mixture was partitioned between diethyl ether and water. The ethereal solution was dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to give 4-amino-1-(3'-chloro-5'-trifluoromethylpyridin-2-yl)indole (6.5 g) as a dark solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>>[CH2:27]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]2=[N:3][C:2]=3[NH2:1])=[CH:19][CH:18]=1)[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCC(C)C)cc3)cc12

Procedure:
2-(4-(Isopentyloxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using 1-bromo-3-methylbutane. 1H NMR (Acetone-d6): δ 8.72 (s, 1H), 8.69 (s, 1H), 8.26 (d, 1H), 7.43 (s, 1H), 7.12-7.18 (m, 3H), 6.84 (d, 2H), 6.50 (br, 2H), 3.98 (t, 2H), 3.21 (t, 2H), 3.06 (t, 2H), 2.46 (s, 3H), 1.78-1.87 (m, 1H), 1.61-1.67 (dd, 2H), 0.96 (s, 3H), 0.95 (3H). LRMS [M+H]=400.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Yield: 19.5 %

Procedure:
An amount of 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 mL of carbon tetrachloride, following which 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added and the mixture was refluxed under heating for 19 hours. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 143 mg of 2-bromo-5-bromomethylpyridine (yield, 20%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11].C(N(CC)CC)C.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[OH:11][C:5]1[CH:6]=[C:7]([NH:10][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(NC(=O)N2CCOCC2)cc1O
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A solution of 4-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6 mmol) and triethylamine (0.8 mL, 6 mmol) in CHCl3 (25 mL) was treated with morpholine-4-carbonyl chloride (4.2 mL, 48 mmol) and stirred at reflux for 72 h. After cooling to room temperature, the solution was washed with 5% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated to an orange solid. The crude solid was triturated with CHCl3 (10 mL) to afford the product as an off-white solid (0.25 g, 15%).
Reaction SMILES: [O:1]=[C:2]1[CH:9]=[C:8]2[C:4]([C:10]([O:12][CH3:13])=[O:11])([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[CH2:14](O)C>[Pd]>[O:1]=[C:2]1[CH2:3][C:4]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9]1
Reactant: CCO
Reactant: COC(=O)C12CCCC1=CC(=O)C2
Agent: [Pd]
Product: CCOC(=O)C12CCCC1CC(=O)C2
Yield: 81 %

Procedure:
Methyl 5-oxo-1,2,3,3a,4,5-hexahydropentalene-3a-carboxylate (2.5 g, 12.8 mmol) in ethanol (25 mL) was purged with nitrogen for about 10 minutes with stirring. Palladium on carbon (0.043 g, 20 mol %) was added and the reaction vessel was purged with nitrogen for about 10 minutes. The flow of nitrogen was stopped and the flask was flushed with hydrogen. The reaction mixture was stirred overnight under an atmosphere of hydrogen. The flask was flushed with nitrogen for about 20 minutes. The reaction mixture was passed through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 25% ethyl acetate/heptane) to afford ethyl 2-oxooctahydropentalene-3a-carboxylate (2.04 g, 10.4 mmol, 81%).
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.[CH3:21]I.[Cl-].[NH4+]>N.O.C(O)C>[CH3:21][O:2][N:3]=[C:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: CI
Reactant: O=c1[nH]c2c(n3ccnc13)C(=NO)c1ccccc1-2
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CON=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
0.1 g of sodium is dissolved in 3 ml of liquid ammonia at -33° C., followed by portionwise addition of 0.3 g of 10-hydroxyimino-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one. After stirring for 30 minutes, 0.3 g of methyl iodide is added dropwise and the stirring is continued for 4 hours at the same temperature and then for 16 hours while allowing the temperature to return gradually to 20° C. The solid obtained is suspended in a solution of 0.25 g of ammonium chloride in 20 ml of distilled water and, after stirring for 15 minutes, it is filtered and washed with distilled water. The solid obtained is suspended in 50 ml of boiling ethanol, filtered at 20° C., washed twice with 10 ml in total of ethyl ether and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.2 g of 10-methoxyimino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained as a 95/5 mixture of the E and Z forms, subliming at 310° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 4.22 (s, 3H: =NOCH3); 7.37 and 7.50 (2 broad t, J=8 Hz, 1H each: --H 7 and --H 8); 7.57 and 8.01 (2s, 1H each: --H of the imidazole); 7.76 and 8.00 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); from 12.50 to 13.00 (broad mult., 1H: --CONH--)).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:22][C:21]([CH2:23][CH2:24][CH3:25])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:22][C:21]([CH2:23][CH2:24][CH3:25])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1
Reactant: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2s1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3cc(O)ccc3c2s1
Temperature: 65 °C
Yield: 54.2 %

Procedure:
To 7-benzyloxy-2-propylthiazolo[4,5-c]quinolin-4-amine (prepared as described in Example 1, 1.59 g, 4.55 mmol) was added a 30 wt. % solution of hydrogen bromide in acetic acid (25 mL). The resulting solution was heated at 65° C. for 1 h, then cooled in an ice bath. Aqueous NaOH (50% w/w solution) was added slowly until the pH=7 and a light yellow solid formed. The solid was isolated by filtration, dried, and purified by HPFC (silica gel eluting sequentially with 0-10% of a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH (CMA) in chloroform, then 10-35% CMA in chloroform). The appropriate fractions were concentrated to a light yellow solid that was crystallized from toluene containing a small amount of methanol. The light yellow solid was isolated by filtration, washed with cold toluene, and dried at 60° C. in a vacuum oven to provide the acetic acid salt of 7-hydroxy-2-propylthiazolo[4,5-c]quinolin-4-amine (0.64 g, 54%), mp 236-239° C. 1H NMR (300 MHz, d6-DMSO) δ 9.72 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.78 (dd, J=8.7, 2.2 Hz, 1H), 6.70 (s, 2H), 3.12 (t, J=7.8 Hz, 2H), 1.83 (sextet, J=7.2 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 168.4, 158.1, 152.2, 146.6, 139.6, 135.6, 125.7, 113.3, 112.2, 108.9, 35.0, 22.8, 13.4; Anal. calcd for C13H13N3OS.0.22C2H4O2: C, 59.23; H, 5.13; N, 15.42. Found: C, 59.42; H, 5.00; N, 15.41.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]([NH2:15])=[NH:14]>C(O)C>[NH:14]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1)[C:13]([NH2:15])=[NH:12]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: N=C(N)N
Solvent: CCO
Product: N=C(N)Nc1ncnc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 10 g of 4,6-dichloro-5-nitropyrimidine in ethanol is reacted at reflux for three days with a slight excess of guanidine to give 4-guanidino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.C(OC)(C)(C)C>[Pd].C(O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[CH:7]=1
Reactant: COC(C=O)OC
Reactant: COc1ccc(N)cc1OCCN(C)C
Agent: [Pd]
Solvent: CCO
Solvent: COC(C)(C)C
Product: COc1ccc(NCC(OC)OC)cc1OCCN(C)C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28]Br)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 55 °C
Yield: 94.5 %

Procedure:
To a solution of 5-[3-(benzyloxy)phenyl]-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129 mg, 0.29 mmol) in DMF (1.5 mL) was added pyrrolidine (26 μL, 0.31 mmol), triethylamine (120 μl, 0.86 mmol), and sodium iodide (0.4 mg, 0.003 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 121 mg (96%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.87 (s, 1 H), 7.46-7.41 (m, 2 H), 7.41-7.28 (m, 4 H), 7.08-7.04 (m, 1 H), 7.02-6.97 (m, 2 H), 6.55 (s, 1 H), 5.14 (s, 2H), 2.87 (t, 2 H), 2.42-2.33 (m, 6 H), 1.76-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.56-1.46 (m, 2 H); ES-MS m/z 442.2 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[CH2:4][C@@H:3]1[OH:10].C(N(CC)CC)C.O1CCOCC1.O=C1CCC(=O)N1[C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:32]>C(OCC)(=O)C.O>[OH:10][C@H:3]1[CH2:4][C:5]([CH3:9])([CH3:8])[O:6][CH2:7][C@@H:2]1[NH:1][C:31](=[O:32])[O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)C[C@H](O)[C@@H](N)CO1
Reactant: C[Si](C)(C)CCOC(=O)N1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C[C@H](O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of (4S,5S)-5-amino-2,2-dimethyl-tetrahydro-2H-pyran-4-ol (1.1 g, 4.0 mmol) and triethylamine (1.1 mL, 8.0 mmol) in a mixed solvent of dioxane (5 mL) and water (5 mL) at room temperature was added 2-(trimethylsilyl)ethyl 2,5-dioxopyrrolidine-1-carboxylate (1.2 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 4 hours. After that, the solution was diluted with ethyl acetate and washed with brine. The organic layer was separated and concentrated. The resulting residue was purified by silica gel chromatography using petroleum ether/ethyl acetate=4/1 to 1/1 as the eluent to afford the title compound (1.0 g, 86% for 2 steps) as a yellow oil.
Reaction SMILES: Cl.[CH:2]1[C:12]2[C:11]3[CH2:13][CH2:14][CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][N:7]([CH2:17][CH:18]([OH:35])[CH2:19][N:20]3[CH2:25][CH2:24]N(C4N=CC=CC=4C(O)=O)C[CH2:21]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH:41]1CCNC[CH2:42]1)=[O:40])[CH3:37]>CC(=O)CC>[CH2:36]([O:38][C:39]([CH:41]1[CH2:42][CH2:21][N:20]([CH2:19][CH:18]([OH:35])[CH2:17][N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:12]=3[CH2:11][CH2:13][C:14]3[CH:15]=[CH:16][CH:10]=[CH:9][C:8]2=3)[CH2:25][CH2:24]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cccnc1N1CCN(CC(O)CN2C=CC3=C(CCC=C3)c3ccccc32)CC1
Agent: Cl
Solvent: CCC(C)=O
Product: CCOC(=O)C1CCN(CC(O)CN2c3ccccc3CCc3ccccc32)CC1
Yield: 15.8 %

Procedure:
A mixture of crude (10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2,3-epoxypropane (22.6 g, 90 mmol, prepared as described in Example 19) and 4-piperidinecarboxylic acid ethyl ester (14.15 g, 90 mmol) in dry 2-butanone (50 ml) was stirred and heated at reflux temperature for 24 h. The solvent was removed in vacuo and the residue was dissolved in toluene (250 ml) and water (250 ml). The pH was adjusted to 6 by addition of 1 N hydrochloric acid. The organic phase was separated, washed with water (3×100 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of toluene, ethyl acetate and triethylamine (20:20:1) as eluent to give 5.8 g (16%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-propyl)-4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl[C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[O:24][CH2:25][CH:26]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:3][C:4]=1[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)#[N:9]
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(Nc2cc(NC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.8) (100 mg, 0.418 mmol), 9H-fluoren-9-ylmethyl (2-chloro-2-oxoethyl)carbamate (264 mg, 0.835 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (3.2 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 0.29 mL, 0.50 mmol). The reaction mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was diluted with ethyl acetate and washed with sodium hydroxide (1.0 M in water). The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane (3 mL) was slowly added, and the precipitated solids were filtered and collected to afford 9H-fluoren-9-ylmethyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-2-oxoethyl]carbamate. MS ESI calc'd for C30H27N6O3 [M+H]+ 519. found 519. 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.09 (s, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.88 (d, J=7.5 Hz, 2), 7.75-7.65 (m, 3H), 7.40 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 6.65 (s, 1H), 6.61 (s, 1H), 4.29 (d, J=7.0 Hz, 2), 4.24-4.20 (m, 1H), 3.84 (d, J=6.1 Hz, 2H), 2.28 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C>[O:1]1[C:7]2[CH:6]=[CH:5][C:4]([C:8]3[C:12]4[S:13][CH:14]=[CH:15][C:11]=4[O:10][N:9]=3)=[C:3]([O:20][CH3:19])[C:2]1=2
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1c(-c2noc3ccsc23)ccc2c1O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
A mixture of 28 g of 3-(3-hydroxyphenyl)thieno[2,3-d]-isoxazole, 23 g of epibromohydrin and 30 g of milled potassium carbonate in 40 ml of dimethylformamide and 40 ml of acetonitril was stirred under nitrogen at 90°-100° C. until completion of reaction. The reaction was complete after 4 hours and allowed to cool to room temperature. Quenching with water (400 ml), extracting with 50/50 ether/ethyl acetate solution (3×400 ml), and washing with water (2×400 ml) were conducted. The organics were dried over anhydrous magnesium sulfate and the solvents were evaporated to give an oil. The oil was purified by HPLC (4:1 hexane/ethyl acetate) to yield 23.3 g of a solid with a melting point of 88°-90° C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:60]=[C:61]4[C:67]([C:68]5[CH:69]=[N:70][N:71]([CH2:73][CH2:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH:72]=5)=[CH:66][N:65](S(C5C=CC(C)=CC=5)(=O)=O)[C:62]4=[N:63][CH:64]=3)=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][N:47]1[CH2:48][CH2:49][N:50]([C:53]2[CH:54]=[CH:55][C:56]([C:59]3[CH:60]=[C:61]4[C:67]([C:68]5[CH:69]=[N:70][N:71]([CH2:73][CH2:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH:72]=5)=[CH:66][NH:65][C:62]4=[N:63][CH:64]=3)=[CH:57][CH:58]=2)[CH2:51][CH2:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1
Yield: 44.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(4-(4-methylpiperazin-1-yl)phenyl)-3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.097 mmol) was hydrolyzed by lithium hydroxide (12 mg, 0.291 mmol) in THF/methanol/water (1/1/1 ml) to afford 20 mg (45.0% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.24 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.67-7.65 (d, 2H), 7.61 (s, 1H), 7.28-7.15 (m, 6H), 4.49-4.45 (t, 2H), 4.00-3.97 (d, 2H), 3.69-3.66 (d, 2H), 3.23-3.12 (m, 6H), 3.02 (s, 3H). MS: m/z=462.9 (M+1), HPLC: 96.28% in method B.