Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 46 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (27 mg, 0.0675 mmol) and 2-aminoethanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (13 mg, 46% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.28 (br s, 1 H), 8.52 (s, 1 H), 7.51 (1 H), 7.15-7.11 (m, 2 H), 7.01-6.96 (m, 2 H), 4.27 (m, 2 H), 4.10 (s, 2 H), 3.76 (m, 2 H), 3.57 (m, 2 H), 3.49 (m, 2 H), 1.79 (m, 2 H); HRMS m/z calcd for C21H23N3O5F: 416.1622. Found: 416.1634.
Reaction SMILES: [Mg].[CH2:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH2:3][CH3:4].C1O[C:15]2([C:20](=O)[CH2:19][CH2:18][CH2:17][CH:16]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)OC1.C1C[O:32]CC1>Cl>[CH2:2]([C:5]1[CH:10]=[CH:9][C:8]([C:19]2[CH2:18][CH2:17][CH:16]([CH:22]3[CH2:27][CH2:26][C:25](=[O:32])[CH2:24][CH2:23]3)[CH2:15][CH:20]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: O=C1CCCC(C2CCCCC2)C12OCCO2
Reactant: CCCc1ccc(I)cc1
Agent: Cl
Agent: [Mg]
Product: CCCc1ccc(C2=CCC(C3CCC(=O)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Grignard reagent was prepared from 2.43 g (0.10 mol) of dried magnesium and 24.6 g (0.10 mol) of 4-propyliodobenzene in THF, and 100 ml of solution of 21.4 g (0.09 mol) of bicyclohexanedione monoethylene ketal in THF was added dropwise thereto and stirred at room temperature for 3 hours. The reaction solution was added in 300 ml of 3N hydrochloric acid, and the product thus formed was extracted with diethyl ether. After the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, the solvent was distilled off under a reduced pressure. To the residue were added 30 ml of toluene and 80 ml of formic acid, and the mixture was refluxed for 3 hours. To the reaction solution was added 100 ml of water and the product thus formed was extracted with toluene. After the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=4/1), the solvent was distilled off to give 9.5 g (32 mmol) of 1-(4-propylphenyl)-4-(4-oxocyclohexyl)-1-cyclohexene. Yield of this compound was 36%.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])O[C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:26][NH:27][NH2:28].[NH2:29][NH2:30]>O.C1(C)C=CC=CC=1>[CH3:26][N:27]([C:20](=[O:21])[CH:19]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][C:23]([NH:29][NH2:30])=[O:25])[NH2:28]
Reactant: NN
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: CNN
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC(CC(=O)NN)C(=O)N(C)N
Temperature: 25 °C

Procedure:
Into a 250 mL three-necked round-bottomed flask, equipped with a mechanical stirrer, Dean-Stark water trap, addition funnel, thermocouple to temperature controller, heating mantle, and a nitrogen blanket is charged 75 mL of toluene and 17.1 grams (0.05 mole) of octadecenyl succinic anhydride. In the addition funnel is charged 2.3 grams (0.05 mole) of methylhydrazine. The hydrazine is slowly added dropwise to the stirred reaction media at room temperature over a five minute period. The reaction media showed little exotherm. The temperature is then raised to reflux the toluene to the Dean-Stark trap. The reaction media are refluxed until water is no longer removed and the infrared analysis of a sampled product shows all the anhydride has been converted to succinhydrazide. The reaction media are now cooled to room temperature and placed on a Roto-Evaporator to remove the toluene solvent. The reaction product is now filtered through a bed of Celite filter-aid to yield 18.4 grams of a clear yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:22][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)(=[O:32])[CH3:31]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine is added to the solution which is then treated dropwise at 25° C. (internal temperature) with 0.5 ml of acetyl chloride. After subsequently stirring for 2 hours at room temperature, the reaction mixture is treated with ice-water and dilute hydrochloric acid and extracted with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Column chromatography on silica gel [eluant: ethyl acetate/n-hexane (2:3)] yields 3-acetoxy-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of white crystals, m.p. 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccccc1C=CC(=O)O
Solvent: CC#N
Product: O=C(O)C=Cc1ccccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Yield: 75.6 %

Procedure:
0.76 g (3.5 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from step a in 6 ml of acetonitrile were added to 0.41 g (2.5 mmol) of 3-(2-aminophenyl)acrylic acid and the mixture was reacted for 2 hours at 40° C. After the mixture has cooled down to room temperature, the precipitate is filtered off with suction, washed twice with acetonitrile, sucked dry and dried. 0.72 g (76%) of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[CH:22]1([C:25]#[CH:26])[CH2:24][CH2:23]1.C(NC(C)C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16]([C:26]#[C:25][CH:22]3[CH2:24][CH2:23]3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1
Reactant: C#CC1CC1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(C#CC3CC3)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A vial was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (1.00 g, 2.88 mmol), cyclopropyl acetylene (0.732 mL, 8.64 mmol), copper(i) iodide (0.110 g, 0.576 mmol), and diisopropylamine (14.40 mL). tetrakis(triphenylphosphine)palladium(0) (0.333 g, 0.288 mmol) was added, the vial was flushed with argon, and the reaction was heated to 50° C. and stirred overnight. The reaction was diluted with ethyl acetate and filtered through Celite. The solution was concentrated and purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) to afford (S)-2-amino-2′-(cyclopropylethynyl)-5H-spiro[oxazole-4,9′-xanthen]-7′-ol as a tan solid.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)O)[CH3:3].S(Cl)([Cl:32])=O.[C:34](#N)C>>[ClH:32].[Cl:1][CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)[CH:11]([NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=1[O:4][CH2:2][CH3:3])[CH3:34]
Reactant: CCOc1ccccc1OCCNCC(O)c1ccc(OC)c(S(N)(=O)=O)c1
Reactant: CC#N
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCOc1ccccc1OCCNC(C)C(Cl)c1ccc(OC)c(S(N)(=O)=O)c1
Reaction time: 48 h

Procedure:
In 1,000 ml of acetonitrile was suspended 17 g of 5-{2-[2-(2-ethoxyphenoxy)ethylamino]-1-hydroxyethyl}-2-methoxybenzenesulfonamide hydrochloride and while stirring the suspension, 9 g of thionyl chloride was added dropwise to the suspension at room temperature, whereby the product was dissolved and then began to be crystallize gradually. After stirring the mixture for two days, the crystals formed were recovered by filtration, washed with chloroform and dried to provide 15 g of 5-{1-chloro-2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH:25]([F:27])[F:26])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH:25]([F:26])[F:27])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1-c1cc(Cl)ccc1OC(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 80 °C
Yield: 53.4 %

Procedure:
To a solution of 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62 g, 148 mmol) in ethanol (600 mL) was added water (200 mL), ammonium chloride (32 g, 590 mmol) and iron powder (41 g, 740 mmol). The mixture was heated at 80° C. for 2 hours then allowed to cool to room temperature. The residual solid was removed by filtration through Celite®. The filtrate was evaporated under reduced pressure, diluted with water and extracted twice with DCM. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated to afford a dark oil. The oil was purified by flash chromatography on silica eluting with 0-25% EtOAc in DCM. Appropriate fractions were collected and the solvent removed in-vacuo to afford 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine as a brown oil (30.8 g, 54%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 7.56 (d, 1H), 7.44 (dd, 1H), 7.34 (s, 1H), 7.30-7.25 (m, 1H), 6.37 (t, 1H), 5.29 (s, 2H), 3.56 (t, 2H), 0.88 (dd, 2H), 0.00 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C@@H:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].Cl>O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH:16]1([CH2:15][C@@H:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2[nH]c([C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 70 °C
Yield: 86.5 %

Procedure:
A mixture of 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 55, 610 mg, 1.43 mmol) in tetrahydrofuran (8 mL) and 10% aqueous sodium hydroxide solution (3 mL) was heated at 70° C. for 10 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (510 mg, 86.6%, 93% ee) as a light yellow solid which was further separated by Agilent high performance liquid chromatography (chiral column: Daicel OJ-H, 250 mm×20 mm i. d., 5 μm-particle size, temperature: 25° C., flow rate of 15 mL/min, 30% ethanol/hexanes as mobile phase and UV detection: 214 and 254 nm) to afford two pure enantiomers. The first peak, 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (220 mg) was isolated as a light yellow solid: LC/MS m/e calcd for C22H24N2O4S [M+H]+ 413.51, observed 412.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.73 (br. s., 1H), 8.47 (d, J=1.5 Hz, 1H), 8.03 (br. s., 1H), 7.83-7.87 (m, J=8.3 Hz, 2H), 7.53-7.58 (m, J=8.3 Hz, 2H), 6.48 (s, 1H), 4.28 (t, J=7.8 Hz, 1H), 3.04 (s, 3H), 2.20-2.28 (m, 1H), 2.04-2.12 (m, 1H), 1.55-1.82 (m, 5H), 1.38-1.51 (m, 2H), 1.05-1.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1>CN1CCCC1=O.C(OCC)(=O)C>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:20]1
Reactant: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 1-(4-chloro-2-nitrophenyl)ethanone (WO 9322287) (700 mg, 3.5 mmol) and cis-2,6-dimethylpiperazine (1.2 g, 10.5 mmol) in 1-methyl-2-pyrrolidinone (12 ml) was heated at 160° C. in a microwave reactor for 40 min. The reaction mixture was cooled, diluted with ethyl acetate and washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting 1:1 mixture of the title compound (D5) MS (ES+) m/e [M+H]+278 and 1-[4-chloro-2-(cis-3,5-dimethyl-1-piperazinyl)phenyl]ethanone MS (ES+) m/e [M+H]+267/269 was used crude in the next reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)CC)C>ClCCl>[C:4]([CH2:3][NH:2][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:23]2[CH2:22][C:21]([C:16]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=3)([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=2)=[CH:27][C:28]=1[CH3:35])(=[O:5])[NH2:6]
Reactant: NCC(N)=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(N)=O
Yield: 87.1 %

Procedure:
In a solution of 0.37 g of glycine amide hydrochloride and 0.71 g of pyridine in 20 ml of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl chloride synthesized in Step 3 of Synthetic Example 29 in 10 ml of dichloromethane was added dropwise with stirring under ice cooling, after the completion of the addition, stirred at room temperature for 3 hours, then 3.00 g of triethyl amine was added in the reaction mixture, and continued to stir at the same temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water were added in the residue, and the organic phase was collected, and the aqueous phase was further extracted with ethyl acetate (50 ml×2). The organic phases together were dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.24 g of the aimed product as white crystal.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:31]([C:35]([OH:37])=[O:36])([F:34])([F:33])[F:32]>C1(C)C=CC=CC=1>[F:32][C:31]([F:34])([F:33])[C:35]([OH:37])=[O:36].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:30])=[O:5])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)CC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)CC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-leucine t-butyl ester (184 mg, 0.57 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-leucine trifluoroacetate (183 mg, 0.37 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([C:43]3[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=3)=[N:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([C:43]3[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=3)=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1cnn(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](NC(=O)Nc1cc2[nH]nc(-c3cnn(C)c3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
To the solution of (S)-1-(2-methoxy-1-phenylethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (63.4 mg, 0.100 mmol) and trifluoroacetic acid (0.383 ml, 5.00 mmol) in Dichloromethane (2.0 ml) was added triethylsilane (17.45 mg, 0.150 mmol). The resulting mixture was allowed to stir at rt for 18 h. LC-MS showed the completion of the reaction. After concentration the residue was purified by reverse phase HPLC to provide desired product (17.3 mg, 0.028 mmol, 27.9% yield). MS ESI Calc'd for C20H21N7O2 [M+H]+ 392, found 392
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:48]1([C:53]2[CH:54]=[C:55]([CH:59]=[C:60]([C:62]3[NH:66][N:65]=[N:64][N:63]=3)[CH:61]=2)[C:56](O)=[O:57])[CH2:52][CH2:51][CH2:50][CH2:49]1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:15][CH2:16][N:17]([C:56]([C:55]4[CH:59]=[C:60]([C:62]5[NH:63][N:64]=[N:65][N:66]=5)[CH:61]=[C:53]([N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)[CH:54]=4)=[O:57])[CH2:18][CH2:19]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1
Reactant: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: O=C(O)c1cc(-c2nnn[nH]2)cc(N2CCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(-c4nnn[nH]4)cc(N4CCCC4)c3)CC1)O2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-[(1-Methyl-1H-pyrazol-5-yl)amino]spiro[chroman-2,4′-piperidin]-4-one hydrochloride (46 mg), 1-hydroxybenzotriazole monohydrate (17 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg), triethylamine (34 μL) and water (660 μL) were added in that order to a DMF (2 mL) solution of 3-(pyrrolidin-1-yl)-5-(tetrazol-5-yl)benzoic acid (27 mg), and stirred at 90° C. for 2 hours and 30 minutes. Water was added to the reaction liquid, and the formed precipitate was taken out through filtration, once dried, then washed with hexane/ethyl acetate=3/2, and taken out through filtration. After dried, the title compound was obtained as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 7.92 (1.0H, s), 7.32 (1.0H, d, J=2.0 Hz), 7.21 (2.0H, s), 7.18-7.13 (2.0H, m), 6.99 (1.0H, d, J=9.2 Hz), 6.67 (1.0H, s), 5.89 (1.0H, s), 4.30-4.22 (1.0H, m), 3.61 (3.0H, s), 3.65-3.20 (3.0H, m), 2.81 (2.0H, s), 2.05-1.85 (9.0H, m), 1.85-1.70 (3.0H, m). MS [M+H]+=554.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C(O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(P([N:32]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CCO[C:38](C)=[O:39]>C1(C)C=CC=CC=1.CCCCCC>[C:12]1([CH:8]2[C:2]3([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[O:1][C:38](=[O:39])[NH:32]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C(c1ccccc1)C1(O)CCCCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1NC(c2ccccc2)C2(CCCCC2)O1
Temperature: 120 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 100 mL round bottom flask charged with 2-(1-hydroxycyclohexyl)-2-phenylacetic acid (6.5 g, 28.14 mmole, 1 eq.) in toluene (100 mL) were added TEA (2.5 eq) and diphenyl phosphoryl azide (2 eq). The resulting mixture was then stirred at 120° C. for 12 hours. Reaction progress was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was then cooled and toluene was removed under reduced pressure to afford the product. The product thus obtained was purified by column chromatography using silica gel and eluting with 10% EtOAc in hexane to afford 4-phenyl-1-oxa-3-azaspiro[4.5]decan-2-one (2 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (s, 1H), 7.26-7.41 (m, 5H), 4.54 (s, 1H), 1.93-1.97 (m, 1H), 1.48-1.78 (m, 4H), 1.12-1.33 (m, 5H). m/z (ESI) 232.1 (M+H)+.