Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19]1([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc2c(n1)CCN(C(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.9 %

Procedure:
To a solution of the product of step (c) (1.78 g, 0.1 mol) and triethylamine (2.21 ml, 0.016 mol) in CH2Cl2 (20 ml) was added diphenylchloromethane (2.13 ml, 0.012 mol). The reaction mixture was stirred at room temperature for 20 h and evaporated under reduced pressure. The residue was dissolved in DMA (20 ml) and heated to 100° C. for 18 h and once cooled, the solution was diluted with CH2Cl2 and washed sequentially with saturated aqueous sodium bicarbonate solution, H2O and saturated brine then dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as a solid (1.0 g, 30%), Rf 0.7 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 335 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH:8]([CH3:11])[CH2:9][OH:10])[N:3]=1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:15].[K+].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH:8]([CH3:11])[C:9]([OH:15])=[O:10])[N:3]=1
Reactant: CC(CO)n1cc(Br)c(Br)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: CC(C(=O)O)n1cc(Br)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3,4-dibromo-β-methylpyrazole-1-ethanol (2.8 g., 0.01 mole) prepared in Example 38, above, in sodium hydroxide (0.3 g., 0.0075 mole) and water (3.0 ml.), a solution of potassium permanganate (3.4 g., 0.0215 mole) in water (30 ml.) was added over a period of 20 minutes. A further 30 ml. of water was added and the reaction mixture was stirred at about 25° C. for 4 hours, followed by acidification with 6N sulfuric acid and addition of sodium bisulfite until all the precipitated manganese dioxide went into solution. The aqueous solution was extracted with three 50-ml. portions of ether and the combined ether extracts were washed with water and dried over anhydrous sodium sulfate. Evaporation of the ether under reduced pressure followed by chromatography on silica gel using the solvent system benzene, 85:chloroform, 5:glacial acetic acid, 10 (by volume) gave a solid which on recrystallization from acetone-hexane gave 3,4-dibromo-α-methylpyrazole-1-acetic acid having a melting point at 124.5° to 126.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20](S(C)=O)[N:19]=[C:18]([CH3:25])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:27]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:17]=[C:18]([CH3:25])[N:19]=[C:20]([NH2:27])[CH:21]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nccnc2-c2cc(S(C)=O)nc(C)n2)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2cc(N)nc(C)n2)cn1
Temperature: 100 °C
Yield: 83 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)pyrazin-2-amine (11.40 mg, 0.032 mmol) (crude product from the last step) and ammonium hydroxide, 28.0-30.0% (0.5 mL, 12.84 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 6-(3-(6-methoxypyridin-3-ylamino)pyrazin-2-yl)-2-methylpyrimidin-4-amine (8.2 mg, 0.027 mmol, 83% yield). 1H NMR (300 MHz, CDCl3) δ 12.46 (s, 1H); 8.42 (s, 1H); 8.15 (s, 1H); 8.10 (dd, J=8.77, 2.48 Hz, 1H); 7.98 (d, J=1.32 Hz, 1H); 7.47 (s, 1H); 6.78 (d, J=8.62 Hz, 1H); 4.95 (s, 2H); 3.95 (s, 3H); 2.64 (s, 3H). m/z (ESI, +ve ion) 310.1 (M+H)+.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].FC(F)(F)S([O-])(=O)=O.[F:40][C:41]1([F:54])[CH2:44][N:43]([S:45](N2C=C[N+](C)=C2)(=[O:47])=[O:46])[CH2:42]1>CC#N>[F:40][C:41]1([F:54])[CH2:44][N:43]([S:45]([NH:31][C:26]23[CH2:29][CH2:30][C:23]([C:20]4[N:19]5[C:14]6[CH:13]=[CH:12][N:11]([S:1]([C:4]7[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=7)(=[O:3])=[O:2])[C:15]=6[N:16]=[CH:17][C:18]5=[N:22][N:21]=4)([CH2:28][CH2:27]2)[CH2:24][CH2:25]3)(=[O:47])=[O:46])[CH2:42]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: C[n+]1ccn(S(=O)(=O)N2CC(F)(F)C2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)N6CC(F)(F)C6)(CC4)CC5)n23)cc1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
To a solution of 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine (0.20 g, 0.46 mmol, Example #9, Step F) in MeCN (5 mL) was added 1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (0.19 g, 0.50 mmol). The reaction mixture was heated to about 70° C. for about 24 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (10 mL). The layers were separated and the organic layer was washed with water (10 mL) and brine (2×10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give 3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide (0.119 g, 38%): LC/MS (Table 1, Method a) Rt=2.32 min; MS m/z 592 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[C:31]([CH3:32])=[C:30]([O:12][C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[N:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Fluoro-4-methanesulfonyl-phenol (4) (1.33 g, 7.01 mmol) and 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3) (2.00 g, 6.39 mmol) were dissolved in DMSO (10 mL). To the resulting solution, potassium iodide (0.21 g, 1.27 mmol) and potassium carbonate (0.97 g, 7.01 mmol) were added. The resulting mixture was heated to 130° C. and stirred overnight. The crude was cooled to room temperature, poured into ice water (150 mL) and stirred for 2 h. The precipitate was filtered, washed twice with water (2×10 mL) and dried at 60° C. in a vacuum oven (2.74 g, 91%). The desired product was recrystallized from isopropanol (10 mL) to afford 2.39 g of the title compound (80%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C(#N)C.C(N(CC)CC)C>[CH3:12][C:4]1[N:3]=[C:2]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=2)[N:7]=[C:6]([NH2:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 94.1 %

Procedure:
A mixture of 2-chloro-6-methyl-5-nitropyrimidin-4-ylamine (300 mg, 1.591 mmol), 4-trifluoromethylbenzylamine (369 mg, 2.107 mmol) in acetonitrile (3 ml) and triethylamine (0.5 ml) were flashed with argon, sealed in the Emrys process vial and heated at 120° C. for 2 min under microwave irradiation. The obtained suspension was quenched with 10% aqueous sodium carbonate (2 ml) and organic volatiles were evaporated under reduced pressure. Methanol (5 ml) and water (100 ml) were added to the residue. The product was separated by filtration, washed with water and dried in vacuo to give 490 mg of yellow solid. Yield 94%. LC-MS (m/z) 328.1 (MH+); tR=2.58. 1H NMR (500 MHz, DMSO-d6): ca. 3:1 mixture of two rotamers, 2.54 (s, 3H), 4.57 (d, 1.5H), 4.63 (d, 0.5H), 7.52 (t, 2H), 7.68 (d, 2H), 7.81 (s, 0.5H, NH2), 8.0 (s, 1.5H, NH2), 8.17 (t, 0.25H, NH), 8.48 (t, 0.75H, NH).
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1>>[Br:1][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCCC(CCO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CCBr)C1

Procedure:
Prepared similarly to Intermediate 10 from phenylmethyl 3-(2-hydroxyethyl)-1-piperidinecarboxylate (for example, as prepared for Intermediate 15).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[C:17]1([CH3:31])[CH:22]=[CH:21][C:20]([N:23]2[C:27](B(O)O)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[C:10]1([N:7]2[C:6]3[CH:16]=[C:2]([C:27]4[N:23]([C:20]5[CH:21]=[CH:22][C:17]([CH3:31])=[CH:18][CH:19]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white foam (36 mg, 28%), MS (ISP) m/z=351.3 [(M+H)+], was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (96.2 mg, 476 μmol).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:25][CH:22]2[CH2:24][CH2:23]2)[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: NC1CC1
Reactant: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Product: CC(C)c1cc(C=Cc2ccccc2OCC(O)CNC2CC2)on1

Procedure:
7 g (0.025 mole) of 3-isopropyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3 g (0.05 mole) of cyclopropylamine are reacted by the method described in Example 5. 3.0 g (30% of theory) of colorless crystals are obtained as the fumurate. Melting point 148°-152° C.
Reaction SMILES: [C:1]([OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].O>CC(C)=O>[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]([O:13][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([OH:21])=[O:20]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCC(CC=CCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
To a mixture of ricinoleic acid (1600 g), triethylamine (1100 mL) in acetone (6 L) at 0-5° C., was added 4-nitro benzoyl chloride (1200 g). It was stirred at room temperature for 16 hours. After the reaction was completed then the total reaction mass was poured onto cold water (12 L) and extracted with ethyl acetate (6 liter) and combined total organic layers and washed with 15% NaHCO3 solution (IL) and 15% NaCl solution (1.0 L) followed by water washing (1.0 L), then dry the organic layer with sodium sulphate and distilled up the solvent under reduced pressure completely till thick oily mass is obtained. Resulting crude was purified by column chromatography by using hexane: ethyl acetate (9:1) to yield pure 4-nitro-benzoic acid 11-carboxy-1-hexyl-undec-3-enyl ester product as light yellow thick syrup (750 g). The resulting compound was characterized by 1H NMR (DMSO-d6) δ 0.85 (t, 3H, CH3), 1.12-1.6 (m, 22H, 11×CH2), 1.91 (m, 2H, CH2), 2.2-2.32 (m, 4H, 2×CH2), 3.5 (m, 1H, CH) 5.52 (m, 1H, CH), 5.65 (m, 1H, CH), 8.25-8.35 (m, 4H, Ar).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=[C:28](N1C=CN=C1)[N:29]1C=CN=C1.CN>ClCCl.O>[CH3:28][NH:29][C:22]([C:21]1[CH:20]=[CH:19][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:26][CH:25]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Methylamine (64 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D24). MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:27]=[CH:26][C:18]([CH:19]=[CH:20][C:21](OCC)=[O:22])=[CH:17][CH:16]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C=Cc1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/CO)cc1

Procedure:
Ethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]cinnamate was reduced with diisobutylaluminum hydride in the same manner as in Reference Example 22 to yield (E)-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]2-propenol, which was then recrystallized from ethyl acetate-hexane to yield colorless needles having a melting point of 102°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[CH:31][C:24]=12.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([C:32]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:30]=[CH:31][C:24]=34)=[O:20])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)ccc21
Reactant: Nc1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3cnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Yield: 73.8 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)thiochromane-7-carboxylic acid (500 mg), 4-amino-1-triphenylmethylpyrazolo[3,4-b]pyridine (670 mg) synthesized according to a known method and 2-chloro-1-methylpyridinium iodide (496 mg), the objective (S)-4-(tert-butoxycarbonylamino)-N-(1-triphenylmethylpyrazolo[3,4-b]pyridin-4-yl)thiochromane-7-carboxamide (796 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:24]([CH3:26])[CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)=O>ClCCCl.C(O)(=O)C>[CH3:25][CH:24]([CH3:26])[C@@H:16]([NH:15][CH2:27][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)N3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one (84 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (128 mg, 85%). [M+H] calc'd for C24H34N4O5, 459; found, 459.6.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:33]5[C:32](=[O:41])[N:31]([C:28]6[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=6)[C:36]([CH3:37])=[CH:35][CH:34]=5)=[O:39])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
To a solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.324 mmol) and 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (96.1 mg, 0.389 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (147.8 mg, 0.389 mmol) and N,N-diisopropylethylamine (111.6 μL, 0.648 mmol), and the mixture was stirred at room temperature for 20 hr. Tetrahydrofuran, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with tetrahydrofuran and collected by filtration to give the title compound (154 mg, 88%) as a white solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCC2)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.83 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) were added to a solution of 4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Example 33-(1); 2.6 g, 6.9 mmol) in dichloromethane (26 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (1.8 g, 51%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:7]=1.[CH2:30]([O:32][P:33]([O:37]CC)[O:34][CH2:35][CH3:36])[CH3:31]>>[CH:19]1([NH:18][C:11]2[CH:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][P:33](=[O:37])([O:34][CH2:35][CH3:36])[O:32][CH2:30][CH3:31])=[CH:7][N:8]3[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:13][C:12]=2[F:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOP(OCC)OCC
Reactant: CCC(CC)n1cc(CCCCBr)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Product: CCOP(=O)(CCCCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)OCC
Temperature: 160 °C
Reaction time: 4 h

Procedure:
To 557 mg of 3-(4-bromobutyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one was added 5 ml of triethylphosphite, followed by stirring at 160° C. for 4 hours. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by a column chromatography to obtain 240 mg of diethyl {4-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]butyl}phosphonate.