Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=1)[C:18](O)=[O:19])=[N:9][NH:8][C:7]2=[O:23].[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:18]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]3)=[O:19])[CH:21]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Reactant: COC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)ccc2F)CC1
Reaction time: 1 h
Yield: 38.8 %

Procedure:
5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (103) (0.2 g, 0.60 mmol), 4-methoxypiperidine (0.069 g, 0.60 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.251 g, 0.78 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.136 mL, 0.78 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.100 g, 38.7%); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.49 (1H, m), 1.83-1.64 (2H, m), 1.94-1.89 (1H, m), 3.17-3.05 (1H, m), 3.35 (3H, s), 3.48-3.44 (2H, m), 3.61-3.48 (1H, m), 4.03-3.93 (1H, m), 4.65 (2H, s), 7.00 (1H, t), 7.17-7.14 (2H, m), 7.66 (1H, t), 7.80 (1H, dd), 8.49 (1H, dd) NH missing; m/z (LC-MS, ESI+), RT=1.89 (M+H 430).
Reaction SMILES: CS[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.ClCl.[C:15](Cl)([Cl:18])([Cl:17])[Cl:16]>>[Cl:16][C:15]([Cl:18])([Cl:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSc1cccc2ccccc12
Agent: ClCl
Product: ClC(Cl)(Cl)c1cccc2ccccc12

Procedure:
100 g of 1-naphthyl methyl sulphide are dissolved in 250 ml of carbon tetrachloride. Chlorine is introduced into the solution at 75° to 80° C., until the solution is saturated. The solvent and the resulting sulphur chloride are then distilled off. 30 g of 1-trichloromethylnaphthalene of boiling point 124° to 128° C./0.3 mm are obtained, after fractional distillation, from the reaction product which remains as a residue.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C)C=O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH:15]([CH3:17])[CH3:16])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: CC(C)I
Reactant: COC1=CN=C(CO)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(CO)cc1OC(C)C
Reaction time: 0.12 h
Yield: 32229.2 %

Procedure:
To a stirred suspension of 2-hydroxymethyl-5-methoxy-4-pyridone (1.00 g, 6.45 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in mineral oil; 0.26 g, 6.5 mmol). The fizzy mixture was stirred for 5-10 minutes before adding, dropwise, 2-iodopropane (0.65 mL, 6.5 mmol). The reaction was stirred at room temperature overnight and then at reflux for 4 hours. At this time, additional sodium hydride (0.07 g, 1.8 mmol) and 2-iodopropane (0.16 mL, 1.6 mmol) were added and the mixture was heated at reflux for another 4 hours. The reaction was then concentrated and partitioned between methylene chloride and aqueous sodium carbonate solution. The resulting biphasic mixture was filtered through Celite to remove a small amount undissolved solid. The organic layer of the filtrate was dried (sodium sulfate) and concentrated to afford a dark brown oil. This material was purified by flash chromatography over silica (methylene chloride/methanol) to afford 410 g (32%) of product as a crystalline light brown solid: 1H NMR (CDCl3) δ 7.92 (s, 1H), 6.61 (s, 1H), 4.54 (sept, J=6.2 Hz, 1H), 4.53 (s, 2H), 3.79 (s, 3H), 1.29 (d, J=6.0 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1C=CC(C(C)C)=C[CH:7]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[CH:2]([C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1)([CH3:7])[CH3:1]
Reactant: c1ccc2ccccc2c1
Reactant: Cc1ccc(C(C)C)cc1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out similarly as in Example 11, but using p-cymene to transalkylate naphthalene. Yield of isopropylnaphthalene obtained was 21%, with 90% β- and 10% α-isopropylnaphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.ClS([N:35]=[C:36]=[O:37])(=O)=O.Cl>C(Cl)Cl>[C:25]1([C:22]2[CH:23]=[CH:24][N:10]3[C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:36]([NH2:35])=[O:37])[CH:7]=[N:6][CH:5]=2)=[N:9]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.254 mmol) (prepared as in Example 3) was dissolved in CH2Cl2 (10 mL) and chlorosulfonyl isocyanate (0.0330 mL, 0.381 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Concentrated hydrochloric acid was added until the reaction mixture forms a clear solution. The aqueous mixture was extracted with CH2Cl2 (30 mL) and the organic layer was separated. The aqueous layer was adjusted to pH 11 using saturated solution of sodium hydroxide. The aqueous solution was extracted with CH2Cl2 (20×3 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-62 as described in general methods) to obtain 1-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)urea (30.0 mg, 27.0%). LCMS Condition B-14: retention time 1.831 min, [M+1]=437.2. HPLC Condition B-30: retention time 5.48 min, Purity 95.9%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.91 (d, J=4.8 Hz, 2H), 6.05 (br s, 2H), 6.81 (d, J=2.4 Hz, 1H), 7.27 (t, J=4.8 Hz, 2H), 7.46-7.61 (m, 7H), 7.76 (dt, J=1.6 Hz, J=7.6 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 8.38-8.39 (m, 1H), 8.66-8.68 (m, 1H), 8.88 (s, 1H), 8.96 (d, J=1.6 Hz, 1H).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:13][CH:12]=1>CO.[Pd]>[ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C#CCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(CCCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Reaction time: 0.33 h

Procedure:
N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine hydrochloride (125 mg) is dissolved in MeOH (12 ml) in an argon atmosphere and then 27 mg Pd/C catalyst is added. H2 is bubbled into the reaction mixture for 1 minute and stirred under H2 for 20 minutes. The mixture is purged with argon and filtered through celite and washed with MeOH and THF. Several drops of HCl/EtOH are added until acidic and the mixture concentrated to dryness to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methyl-phenyl)propoxy] ethanamine hydrochloride as a white solid. (m.p. 138°-139° C.).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1.[Br:20][Si](C)(C)C>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)Nc1ccccc1-c1ccc(CO)cc1
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A solution of 4-hydroxymethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl (239 mg, 0.93 mmol) in methylene chloride (4 mL) was treated with bromotrimethylsilane (3.0 mL, 22.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with additional methylene chloride and washed with saturated aqueous sodium chloride. After drying over magnesium sulfate, the filtered organic layer was evaporated under vacuum The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride/methanol (100:3) to give 190 mg of the product.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (17 mg, 0.049 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (7 mg). MS 364.3 (M+H); UV 210.2, 275.0, 323.7 nm; t 0.458 min.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[Se:8][C:7]=1[C:15]([O:17]CC)=[O:16])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:3]
Reactant: CCOC(=O)c1[se]c(C(C)(C)C)cc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1cc(C(C)(C)C)[se]c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carboxylate (400 mg, 1.2 mmol) prepared as described in Example 4 step c) in methanol (10 mL) was added a solution of sodium hydroxide (240 mg, 6.04 mmol) in water (5 mL) and stirred at room temperature (rt) for 16 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and the precipitated solid was filtered, washed with water and dried. The product was recrystallized from hexane-chloroform to give the product as a pale brown color solid (160 mg, 45%), mp 120-122° C. IR (neat) νmax 2960, 2927, 1713, 1248, 1180, 1110, 1069, 1010, 844, 767 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.23 (1H, s, —COOH), 7.38 (1H, s, H-4), 3.63 (3H, s, —NCH3), 3.23 (3H, s, —NCH3), 1.39 (9H, s, 3×—CH3); 13C NMR (100 MHz, CDCl3): δ 171.7, 164.1, 153.7, 123.2, 115.6, 44.2, 37.2, 36.9, 32.4; LC-MS (positive ion mode): m/z 324, 326 (M+Na)+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3].[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:26][C:13]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]=[C:10]2[C:9]=1[C:8](=[O:23])[N:7]([CH3:24])[C:6](=[O:25])[N:5]2[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Temperature: 25 °C
Yield: 120.9 %

Procedure:
1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.88 g, 5.5 mmol) and hexachloroethane (6.5 g, 26.5 mmol) are dissolved in anhydrous THF (3 mL), and then 1.0 M LiHMDS in THF (11 mL, 11 mmol) is added dropwise over 2 hours. The reaction mixture is stirred at room temperature for an hour, and then quenched with saturated ammonium chloride aqueous solution. The mixture is poured into cold water (100 mL), and then extracted with ethyl acetate three times. The combined organic phase is dried with anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 2.5 g of crude product as light brown solids, which is used in the next step without further purification. MS (ESI) m/z 376.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)([CH3:45])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)([CH3:45])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)(C)N3CCOCC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Yield: 29.1 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.363 g, 0.522 mmol) in TFA (3 mL) was treated with trifluoromethanesulfonic acid (0.232 mL, 2.61 mmol). The reaction was sealed and heated at 80° C. for 30 min, cooled, and poured onto ice. The mixture was basified with 10 N NaOH and the reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (10-55% MeCN/H2O with 0.1% TFA). Product-containing fractions were treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.069 g, 0.152 mmol, 29.1% yield). m/z (ESI, +ve ion) 455 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (s, 1H); 8.90 (d, J=2.5 Hz, 1H); 8.48 (d, J=2.5 Hz, 1H); 8.33-8.44 (m, 2H); 7.88 (br. s., 1H); 7.73 (br. s., 1H); 3.93 (s, 3H); 3.57 (br. s., 4H); 2.44 (s, 3H); 2.36-2.43 (m, 4H); 1.35 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]([C:28]1[C:29](=[O:35])[NH:30][C:31](=[O:34])[NH:32][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:26][C:28]5[C:29](=[O:35])[NH:30][C:31](=[O:34])[NH:32][CH:33]=5)[CH2:23][CH2:24]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5c[nH]c(=O)[nH]c5=O)CC4)ccnc3[nH]2)cc1
Reaction time: 18 h
Yield: 36 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-piperazin-1-yl-3H-imidazo[4,5-b]pyridine (7) (50 mg, 0.15 mmol) and 5-formyluracil (21 mg, 0.15 mmol) were dissolved in NMP (4 ml) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The reaction mixture was allowed to stir for 18 h under nitrogen. It was judged complete by MS, and purified by HPLC Method E to yield the title product 9 (25 mg (36%), 0.054 mmol). 1H NMR (DMSO-d6): δ 11.45 (s, 1H), 11.30 (d, J=3 Hz, 1H), 9.85(bs, 1H), 8.11 (d, J=8.3 Hz, 3H), 7.74 (d, J=6.1 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 6.78 (s, 1H), 4.05 (s, 2H), 3.20-3.65 (m, 8H), 1.33 (s, 9H). (ESI-POS): [M+H]+=460; MS(ESI-NEG):[M−H]−=458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:22][C@H:23]([C:35]2[NH:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:39]=2)[CH2:24][C:25](OCC2C=CC=CC=2)=[O:26])=[CH:13]1>C1COCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][N:22]2[C@H:23]([C:35]3[NH:36][CH:37]=[C:38]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:39]=3)[CH2:24][C:25](=[O:26])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:10]2=[O:11])=[CH:13]1
Reactant: O=C(C[C@H](NCc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)OCc1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)C[C@@H](c3nc(-c4ccccc4)c[nH]3)N(Cc3c[nH]c4ccccc34)C2=O)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
4-methoxyphenylisocyanate (40 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (80 mg, yield 74
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ccno2)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(-c2ccno2)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 5-(4-bromomethyl-phenyl)-isoxazole analogous to Example 1 to afford 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-(4-isoxazol-5-yl-benzyl)-benzenesulfonamide: MS: m/e=496.0 (MH+), 513.2 (MNH4+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 58.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (100 mg, 0.19 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (Intermediate 65D) (69 mg, 0.20 mmol) using sodium carbonate (61 mg, 0.57 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.009 mmol) in DME/water (5/0.5 mL). This afforded 72 mg (58.5% yield) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CO.C[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OCC(CO)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1000 ml round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were added 132.2 g (1.0 mol) of 2,2-dimethyl-1,3-dioxolane-4-methanol, 202.5 g (1.05 mol) of a 28% methanol solution of sodium methoxide, and 500 ml of toluene. With introduction of nitrogen thereinto, toluene was refluxed under reduced pressure for 1 hour to remove the methanol by evaporation. With maintaining the solution at 80° C., 126.6 g (1.0 mol) of benzyl chloride was added dropwise over a period of 2 hours using a dropping funnel, followed by another 2 hours of reaction. After completion of the reaction, the temperature was lowered to 60° C. and 10 g of KYOWAAD 600 was added, followed by 1 hour of stirring. After filtration of the reaction liquid, the solvent was removed and the residue was purified by distillation (b.p. 93-95° C./266 Pa) to obtain 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane.