Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38](=O)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCNCC1
Reactant: CC=O
Product: CCN1CCC(F)(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-ethyl-4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione (Example 303) and acetaldehyde following General Procedure R2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[O:4].[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:8](=[O:10])[CH:7]([CH3:11])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
4-Methoxycarbonyl-2-methylbutanoic acid (3.1 g.) and L-proline tert.-butyl ester (3.78 g.) are dissolved in dichloromethane (40 ml.). The solution is chilled with stirring in an ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with chloroform to obtain 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-proline tert.-butyl ester, yield 3.5 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9](=[O:22])[N:10]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[N:10]1[CH:11]([CH3:12])[C:5]2[C:6](=[N:7][C:2]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][CH:4]=2)[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:22]
Reactant: COc1ccc(Cl)c(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)c1
Reactant: Nc1ccccc1
Product: COc1ccc(Cl)c(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)c1
Temperature: 100 °C

Procedure:
(±)-7-Chloro-3-(2-chloro-5-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g; 0.49 mmol) (from Example 12b supra) was combined with aniline (150 μL; 1.65 mmol) (Aldrich) and heated in an oil bath at 100° C. for about 70 minutes. Upon cooling, the residue was triturated with hexanes and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (Biotage, 40M; 40:60 ethyl acetate-hexanes) to give (±)-3-(2-chloro-5-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a light yellow solid. (Yield 0.15 g; 63.7%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.S(=O)(=O)(O)[OH:23]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:23])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
A mixture of 3.0 g of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005) and 150 ml of concentrated sulfuric acid was stirred at room temperature for 4 hours. The solution was then carefully poured into ice water with stirring. The white precipitate formed was collected, washed with water and then with saturated sodium bicarbonate until it was neutral. The solid was heated with one liter of isopropyl alcohol and filtered. The white solid was dried in vacuo and gave the product of the example as a colorless solid, mp 256°-258° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:20]=[N:19][CH:18]=[CH:17][C:9]=1[C:10]([OH:16])=[N:11]2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1.C(OCC)(=O)C>CC(N(C)C)=O>[F:38][C:37]([F:40])([F:39])[S:34]([O:16][C:10]1[C:9]2[CH:17]=[CH:18][N:19]=[CH:20][C:8]=2[C:7]2[C:12](=[CH:13][CH:14]=[N:15][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:36])=[O:35]
Reactant: CCCCOc1nccc2nc(O)c3ccncc3c12
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
To a mixture of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-ol (2 g, 7.43 mmol) and cesium carbonate (4.84 g, 14.85 mmol) in DMA (75 ml), N-phenyltrifluoromethanesulfonamide (5.31 g, 14.85 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 7 min. The reaction was then cooled to room temperature and added to ethyl acetate. The organic mixture was washed with aqueous sodium hydrogen carbonate (saturated), aqueous sodium carbonate (saturated), and brine. The organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.68 (s, 1H), 9.08 (d, 1H), 8.52 (d, 1H), 8.14 (d, 1H), 7.62 (d, 1H), 4.70 (t, 2H), 1.96 (m, 2H), 1.57 (m, 2H), 1.00 (t, 3H). LRMS (APCI) calc'd for (C16H15F3N3O4S) [M+H]+, 402.1; found 402.0.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[C:6]2[C:15]3[N:14]([CH:16]=1)[N:13]([CH3:17])[CH2:12][CH2:11][C:10]=3[C:9]([CH2:18]C(O)=O)=[C:8]([F:22])[CH:7]=2)([OH:3])=[O:2].C(N(CC)CC)C>C(O)C>[F:22][C:8]1[C:9]([CH3:18])=[C:10]2[C:15]3=[C:6]([C:5](=[O:23])[C:4]([C:1]([OH:3])=[O:2])=[CH:16][N:14]3[N:13]([CH3:17])[CH2:12][CH2:11]2)[CH:7]=1
Reactant: CN1CCc2c(CC(=O)O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCN3C
Yield: 75.4 %

Procedure:
100 mg of the compound (163) obtained in Example 40 and 1.4 ml of triethylamine were added to 5 ml of ethanol, and the solution was heated at reflux for 15.5 hours. After air-cooling, the solids were filtered and washed successively with ethanol and ether to obtain 65 mg of the subject compound (164).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: NC1CCCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNC2CCCCC2)c1
Yield: 59.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((cyclohexylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclohexanamine (0.057 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.035 g (58%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH:13]1[CH:8]([CH2:9][CH2:10][CH:11]([O:19][C:20](=[O:22])[CH3:21])[CH2:12]1)[N:7]=[C:6]2[C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32](=[NH:35])SC)=[O:30])=[CH:25][CH:24]=1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37].C(N(CC)CC)C>O1CCOCC1>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:32](=[N:31][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:6]3[C:5]4[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:13]4[CH:8]([CH2:9][CH2:10][CH:11]([O:19][C:20](=[O:22])[CH3:21])[CH2:12]4)[N:7]=3)=[CH:24][CH:25]=2)=[O:30])[NH2:35])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)NC(=N)SC)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Yield: 61.4 %

Procedure:
743.4 mg of acetic acid (2RS,4aRS,10bRS)-8,9-dimethoxy-6-{4-[1-(2-methyl-isothioureido)methanoyl]-phenyl}-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound A1), 384.5 mg of 1-acetylpiperzine and 0.416 ml of triethylamine are stirred in 10 ml of 1,4-dioxane at 90° C. for 5 days. After 2 days another 384.5 mg of 1-acetylpiperazine are added to the reaction mixture. The solvent is removed and the residue three times coevaporated with dichloromethane, than one time with toluene. After redissolving in 25 ml of dichloromethane the solution is extracted with water and aqueous saturated KHCO3 solution successively and the aqueous KHCO3 phase reextracted with dichloromethane. After drying the combined organic layers with sodium sulfate the solvent is removed and the residue purified by chromatography on silica to yield 530 mg of the title compound.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1>C(O)=O>[CH:1]([NH:3][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[CH3:12])=[O:2]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NC=O
Solvent: O=CO
Product: CC(NC=O)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
In the same manner as in Example 3 except that a mixture of formamide, formic acid and 4'-chloroacetophenone was heated with stirring at 160° C. for 6 hours in place of the concurrent addition of 4'-chloroacetophenone and formic acid to formamide for 3 hours and keeping the mass after the addition stirred for 3 hours, the reaction and post treatment were carried out to obtain 144.2 g of crude N-formyl-1-(4-chlorophenyl)ethylamine; the purity: 84.6%.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH2:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:18][C:2]([O:4][CH3:5])=[O:3])[CH3:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: CC(N)Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)NC(C)Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.33 ml of methyl chloroformate were added dropwise to a mixture consisting of 12.6 gm of 1-(3'-nitro-phenyl)-2-amino-propane, 9.8 gm of potassium carbonate and 100 ml of acetonitrile, whereby the temperature of the mixture rose to 45° C., and the resulting mixture was boiled for two hours. Thereafter, the reaction mixture was diluted with ice water, and the crystals precipitated thereby were collected by suction filtration, washed with water and dried, yielding 11 gm of 1-(3'-nitro-phenyl)-2-(methoxycarbonyl-amino)-propane, m.p. 104°-105° C. This compound was hydrogenated in methanol in the presence of Raney nicket at atmospheric pressure and room temperature. Thereafter, the catalyst was removed by suction filtration, the methanol was distilled out of the filtrate, and the residue, 1-(3'-amino-phenyl)-2-(methoxycarbonyl-amino)-propane, was dissolved in acetonitrile. The resulting solution was admixed with the calculated amount of maleic acid, and the precipitate formed thereby was recrystallized twice from acetonitrile, yielding 5.5 gm of the maleate of the formual ##STR27## which had a melting point of 125°-127° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:11][CH:12]=[CH:13][C:14]=3[C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[C:4]2[CH:3]=[CH:2]1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[CH2:22]([NH:24][C:25]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[CH:16][CH:17]=1)=[O:26])[CH3:23]
Reactant: CCN=C=O
Reactant: Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1
Product: CCNC(=O)Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-thienyl]aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 363.2
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:24]1[C:29]2[C:30]([O:32][C:33](=O)[C:28]=2[CH:27]=[N:26][CH:25]=1)=[O:31]>C(Cl)(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:30](=[O:31])[C:29]3[CH:24]=[CH:25][N:26]=[CH:27][C:28]=3[C:33]2=[O:32])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1OC(=O)c2cnccc21
Reactant: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CN2C(=O)c3ccncc3C2=O)cc1
Temperature: 190 °C
Yield: 88.5 %

Procedure:
A mixture of 2.5 g of product from Example 99 and 1.17 g of 3,4-pyridinecarboxylic anhydride is heated, in a sealed tube, at 190° C. for 12 minutes. The cooled crystalline product is dissolved in chloroform, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 30-40% ethyl acetate/hexane) to give 3.12 g of the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH2:8])[CH:7]=1.C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[C:32]([F:41])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH:8][C:29](=[O:28])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[C:32]([F:41])[CH:31]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)c(F)c1
Reactant: Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: O=C(Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1)c1ccc(-c2nnn[nH]2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 84, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenylamine (Example 84, intermediate a) and 3-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid methyl ester. Off-white powder (35%). MS (Turbo Spray): m/z=566.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:15])=[CH:4][CH:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2c1C(=O)CCC2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)ccc2c1C(=O)CCC2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
160 mg of 3,4-dihydro-7-hydroxy-8-(2-propenyl)-1(2H)-naphthalenone (CAS No. 122076-30-6), 140 mg of iodomethane, and 400 mg of potassium carbonate were dissolved in 15 ml of acetone. The reaction solution was then stirred at 70° C. for 1.5 hours. The mixture was filtered and then washed with acetone. The organic layer was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography, so that 140 mg of the subject compound was obtained from an ethyl acetate-hexane eluate (1:10).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)[C:9]#[C:10][CH3:11]>ClCCl>[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCNCC2)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
200 ml of trifluoroacetic acid was added to 200 ml of a dichloromethane solution containing 54.3 g of t-butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in 500 ml of ethyl acetate. 1 L of 10% aqueous sodium bicarbonate solution was gradually added. Then, 1 L of ethyl acetate and 500 ml of a 5N aqueous sodium hydroxide solution were added to the solution. The organic layer was separated. Then, the aqueous layer was extracted five times with 1 L of dichloromethane. The organic layers were combined together, washed with 500 ml of an aqueous solution of 2N sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 30.5 g of the crystalline title compound.
Reaction SMILES: [CH:1]1([N:7]([CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[C:8](=[O:22])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S([CH2:38][N+:39]#[C-:40])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:7]([CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[C:8](=[O:22])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:21][CH:40]=[N:39][CH:38]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnco2)c1)C1CCCCC1)OC
Temperature: 80 °C

Procedure:
To N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-formylphenethoxy)propanamide [Example 10, Step ii)] (600 mg) in a 10 ml microwave vial was added toluenesulfonylmethyl isocyanide (329 mg), potassium carbonate (233 mg) and methanol (2 mL). The vial was sealed and heated at 80° C. for 40 min within a microwave before cooling to room temperature. The solvents were evaporated under vacuum followed by the addition of water, which was extracted once with ethyl acetate. The organic phase was washed once with water, dried over sodium sulphate, filtered and the solvent removed to afford desired material, which was carried onto the next step directly. MS [M+H-MeOH]+=399 (MultiMode+)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH2:69])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>ClCCl.CCOC(C)=O>[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH:69][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (DCM) (50 mL), and then HBTU (0.758 g, 2.000 mmol) was added followed sequentially by {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.432 g, 2.000 mmol) and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap to give the crude product. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL), 1× with brine, dried over anhydrous Na2SO4 filtered and the solvent concentrated. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by CombiFlash on an 80 g silica column eluted with 0-10% DCM/MeOH to give the title compound as a white solid. LC-MS m/z 663.0 (M+H)+, 0.91 min (ret time); mp 123-126° C.; analytical HPLC shows 97.6% purity, (ret time 13.411 min).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([S:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[OH-].[Na+]>C1COCC1.CCO>[NH2:30][C:28](=[O:29])[CH2:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[S:25][CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 85 %

Procedure:
As described in Example 45, 245 mg (0.56 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-(methylthio)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (Example 47) was hydrolyzed with 1 mL of 5N NaOH in 5 mL of THF and 15 mL of EtOH. The crude product was washed with EtOH/ether to give 195 mg (85% yield of 4-[[3-(2-amino-2-oxoethyl)-2-(methylthio)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 187°-188° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[N:25]([C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])=[N+]=[N-].[C:41]([O:45][C:46](=O)[O:47]C(C)(C)C)([CH3:44])([CH3:43])[CH3:42]>O>[C:41]([O:45][C:46](=[O:47])[NH:25][C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])([CH3:44])([CH3:43])[CH3:42]
Reactant: C[C@H](O)[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
In nitrogen atmosphere, triphenylphosphine (5.85 g) was added to a THF solution (75 mL) of (1R,2S)-1-azido-1-(3,4,5-trifluorophenyl)propan-2-ol (5.16 g). This reaction solution was stirred at room temperature for 10 min, then water (5 mL) was added the reaction solution. This mixture was stirred at 60° C. for 3.5 hr. The reaction solution was cooled to room temperature, and then di-tert-butylcarbonate (5.35 g) was added to the reaction solution. The resulting reaction solution was stirred at room temperature for 45 min and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=9:1) to give 5.88 g of the title compound. The physical property values of this compound were as follows: