Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:5]=1.[CH3:27]I.[OH-].[Na+].Cl>CN(C=O)C.CO>[Cl:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[Cl:26])[CH3:27])[CH:5]=1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)ccc2OCC(=O)O)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(c1ccc(S(C)(=O)=O)cc1Cl)c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% disp. oil, 0.11 g) was added to a solution of the product from example 31 (0.5 g) in DMF (5 ml) and stirred at RT for 10 min. Methyl iodide (1 ml) was added, stirred for 5 h then methanol (1 ml) added followed by 1M sodium hydroxide solution (3 ml). After stirring for a further 20 h the mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organics were washed with brine, dried and evaporated under reduced pressure. The residue was purified by RPHPLC, yield 0.21 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:3]=1.[ClH:22]>C(OCC)(=O)C>[ClH:1].[ClH:22].[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)ccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC1(c2cc(Cl)ccn2)CCNCC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-chloropyridin-2-yl)-4-fluoropiperidine-1-carboxylate (C4) (0.280 g, 0.890 mmol) in ethyl acetate (10 mL) was saturated with HCl(g). After 1 h, the reaction was concentrated in vacuo to provide 4-chloro-2-(4-fluoropiperidin-4-yl)pyridine dihydrochloride (C5) that gave a mass ion (ES+) of 215.2 for M+H+.
Reaction SMILES: NO.C([N:6](CC)C(C)C)(C)C.[Br:12][C:13]1[C:14]([NH:19][C:20]([NH:22]C(OCC)=O)=S)=[N:15][CH:16]=[CH:17][CH:18]=1>CO.C(O)C>[Br:12][C:13]1[C:14]2[N:15]([N:6]=[C:20]([NH2:22])[N:19]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)NC(=S)Nc1ncccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2c(Br)cccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).
Reaction SMILES: [CH2:1](C1C(O)=CC(O)=CC=1O)[CH:2]=[C:3]([CH3:5])[CH3:4].C(Cl)(=O)CCC.[C:21]([C:26]1[C:32]([OH:33])=[C:31]([C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[C:30]([OH:39])=[CH:29][C:27]=1[OH:28])(=[O:25])[CH2:22][CH2:23][CH3:24]>>[OH:39][C:30]1[C:31]([C:34](=[O:38])[CH2:35][CH2:36][CH3:37])=[C:32]([OH:33])[C:26]([C:21](=[O:25])[CH2:22][CH2:23][CH3:24])=[C:27]2[C:29]=1[CH2:1][CH2:2][C:3]([CH3:5])([CH3:4])[O:28]2
Reactant: CCCC(=O)c1c(O)cc(O)c(C(=O)CCC)c1O
Reactant: CC(C)=CCc1c(O)cc(O)cc1O
Agent: CCCC(=O)Cl
Product: CCCC(=O)c1c(O)c2c(c(C(=O)CCC)c1O)OC(C)(C)CC2

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphloroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36) after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:22][CH:23]([CH3:25])[CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[C:9]([F:21])[CH:8]=1)[CH3:2]>[Pd].C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:22][CH:23]([CH3:25])[CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:21])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)c(F)c1)OC(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)c(F)c1)OC(C)C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
0.5 g of 10% palladium on charcoal were added to a solution of 3.7 g of [rac]-3-(4-benzyloxy-3-fluoro-phenyl)-2-isopropoxy-propionic acid ethyl ester (10.26 mmol) in 30 ml of THF and the compound was stirred under an atmosphere of H2, at normal pressure and ambient temperature, until the absorption of gas stopped. After filtration of the catalyst and evaporation of the filtrate, 2.7 g of [rac]-3-(3-fluoro-4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester were obtained as colorless viscous oil (97.3% of theory).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9](=O)[CH2:10][CH3:11])[N:6]=[N:5][C:4]2=[C:13]([C:16]([NH2:18])=[O:17])[N:14]=[CH:15][N:3]12.[CH3:19][O:20][NH2:21].Cl.N1C=CC=CC=1>CCO.CCOC(C)=O.CC#N>[CH3:19][O:20][N:21]=[C:9]([CH2:10][CH3:11])[CH2:8][N:7]1[C:2](=[O:1])[N:3]2[CH:15]=[N:14][C:13]([C:16]([NH2:18])=[O:17])=[C:4]2[N:5]=[N:6]1
Reactant: CON
Reactant: CCC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCO
Product: CCC(Cn1nnc2c(C(N)=O)ncn2c1=O)=NOC
Reaction time: 16 h
Yield: 60.9 %

Procedure:
4-Oxo-3-(2-oxo-butyl)-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid amide (Compound QQ-001) (25 mg, 0.1 mmol), MeONH2.HCl (13 mg, 0.15 mmol) were dissolved in an EtOH; Pyridine solution (1:1-0.5 ml). The reaction mixture was stirred for 16 hours before being concentrated in vacuo to give a crude residue which was redissolved in EtOAc (2 ml) and MeCN (2 mL). The solution was washed with aqueous 1M HCl and then dried (MgSO4), filtered and concentrated in vacuo. The crude product was redissolved in MeCN and passed through a silica plug. The filtrate was concentrated in vacuo to give the desired product as a green solid (17 mg, 61%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.87 (1H, s), 8.86 (1H, s), 7.84 (2H, s), 7.71 (2H, s), 5.17 (2H, s), 5.04 (2H, s), 3.83 (2.85H, s), 3.73 (3H, s), 2.32 (2H, q, J=7.6 Hz), 2.19 (2H, q, J=7.2 Hz), 1.04 (3H, t, J=7.6 Hz), 0.99 (3H, t, J=7.2 Hz). m/z: 302.3 ((M+Na)+, 100), 280.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:44]1[CH:43]=[C:4]([CH:3]=[C:2]([F:1])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 16.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (105 mg, 0.1582 mmol) was hydrolyzed by lithium hydroxide (34 mg, 0.791 mmol) in THF/methanol/water (15/7.5/4 ml) to yield 13 mg of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.556-8.551 (d, 2H), 8.51-8.50 (d, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.76-7.75 (m, 2H), 7.64-7.76 (dd, 1H), 7.22-7.20 (d, 1H), 6.94-6.84 (m, 2H), 5.44 (s, 2H), 3.99 (s, 3H), 2.99 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 98.06% in method B.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([Cl:30])[CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:11][CH:10]1[C:31]([OH:33])=[O:32])=O)(C)(C)C>C(OCC)C>[Cl:30][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[CH:16][N:15]=[C:14]([CH:12]3[CH2:13][NH:9][CH:10]([C:31]([OH:33])=[O:32])[CH2:11]3)[CH:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(-c2cc(C3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)ncn2)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2cc(C3CNC(C(=O)O)C3)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
1M HCl in diethyl ether solution (2 ml) was added in one portion to a stirred solution of 4-[6-(3-chloro-4-isopropoxy-phenyl)-pyrimidin-4-yl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.02 g, 0.03 mmol) in diethyl ether (1 ml) and the mixture was stirred at room temperature overnight. After this time the reaction mixture was concentrated and the resulting residue was purified by prep HPLC to give the title compound (0.005 g, 38% yield) as a cream solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1[S:7][CH:8]=[C:9]([CH3:15])[C:10]=1[NH:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>>[CH3:5][C:6]1[S:7][CH:8]=[C:9]([CH3:15])[C:10]=1[N:11]([CH2:12][CH2:13][CH3:14])[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCCNc1c(C)csc1C
Solvent: CCN(CC)CC
Product: CCCN(C(=O)Cl)c1c(C)csc1C

Procedure:
54.5 g (0.54 mol) of phosgene, 31 g (0.18 mol) of 2,4-dimethylthiophen-3-yl-(n-propyl)amine and 18.5 g (0.18 mol) of triethylamine were reacted similarly to the process described in Intermediate 1.2. Yield 40 g. MS (m/z): 231 [M]+, 202 [M−C2H5]+, 196 [M−Cl]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCN(C)CC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.57 g, 2.2 mmol) was taken in DCM, cooled to 0° C., oxalyl chloride (0.228 mL, 2.6 mmol) was added, followed by the addition of DMAP (catalytic amount) and stirred for 1 h at RT. Solvent was evaporated under nitrogen, N-methyl piperazine (0.269 mg, 2.4 mmol) and DMAP (80 mg) in DCM was added slowly drop wise at RT (under nitrogen) and stirred at RT for 30 min. Reaction mixture was quenched with water, neutralized with 10% NaHCO3 solution and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. Crude product was purified by reverse phase chromatography to afford 100 mg of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone as TFA salt.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH2:9]Cl)=[C:7]([CH3:14])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-:29])(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH2:9][O:29][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:7]([CH3:14])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)OCc1c(C)cc(C(C)(C)C)c(O)c1C
Temperature: 0 °C

Procedure:
A mixture of 30 g. (0.13 mole) of 4-tert.-butyl 3-hydroxy-2,6-dimethylbenzyl chloride and 29.4 g. (0.13 mole) of sodium laurate in 35 ml. of dimethylformamide was heated at 94°-102° C. for a period of 7 hours. The hot melt was added to 300 g. of ice water slurry. The oil was taken up in 250 ml. of benzene, washed with water and dried over anhydrous sodium sulfate. The salt was filtered and the filtrate concentrated in vacuo to give 44 g. of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>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.[Cu]I>[C:21]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCCCC#Cc1cc(OC)ccc1C(=O)OC
Yield: 100.9 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.80 g, 2.55 mmol) with 1-heptyne (0.70 mL, 5.10 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.67 g (˜100%) of compound 110 as a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.3 Hz, 3H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.9 Hz, J2=2.7 Hz, 1H), 6.99 (d, J=2.7 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][CH:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][CH:18]=2)[CH:12]=[C:13]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cc(OCc2ccccc2)c2ccnn2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(OCc3ccccc3)c3ccnn3c2)cn1
Temperature: 90 °C

Procedure:
4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine (200 mg, 0.660 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (412 mg, 1.979 mmol), tetrakis(triphenylphosphine)palladium (0) (76 mg, 0.066 mmol), and sodium carbonate (210 mg, 1.98 mmol) were suspended in 1,4-dioxane (4 ml)/water (0.444 ml). The mixture was sparged with argon for 10 minutes, then heated to 90° C. for 2 h. After cooling to ambient temperature, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford 4-(benzyloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine contaminated with triphenylphosphine oxide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:35]=[N:36][NH:37][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nn[nH]n4)cc32)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (intermediate 54, 26 mg, 0.0534 mmol), sodium azide (17.4 mg, 0.267 mmol), and ammonium chloride (14.3 mg, 0.267 mmol) in DMF (1 mL) was heated in a microwave reactor at 130° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, and organic layer was separated, washed with aqueous NaHCO3, water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 530.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.15 (1H, s), 7.88 (1H, d), 7.65 (1H, d), 7.10-7.20 (4H, m), 6.93 (2H, d), 4.60-5.00 (2H, br s), 1.25 (9H, s).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C1(C)C=CC=CC=1>[C:33]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Yield: 88.3 %

Procedure:
To a 300-ml four-necked flask equipped with a thermometer, stirring apparatus and condenser were added 34.51 g (0.10 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 50 g of toluene and 11.13 g (0.11 mole) of triethylamine. After replacing the air in the container with nitrogen, 10.20 g (0.11 mole) of propionyl chloride was added dropwise. After completion of the dropwise addition, after-treatment was carried out in the same manner as in Comparative example 1 to obtain 35.0 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monopropionate as a white crystal. Melting point, 108°-111° C. Yield, 88.4%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[C:8](=[O:19])[NH:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:6]>S(=O)(=O)(O)O>[CH2:5]([C:7]1[C:8](=[O:19])[NH:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCC1=C(c2ccc(F)cc2)CNC1=O
Agent: O=S(=O)(O)O
Product: CCC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Nitric acid (70%, 14 mL, 0.22 mol) is added dropwise to a solution of 3-ethyl-4-(4-fluorophenyl)-1,5-dihydro -2H-pyrrol-2-one (37.6 g, 0.18 mol) in concentrated sulfuric acid (140 mL) while the temperature is maintained at 0°-5° C. The mixture is stirred for 2 hr at 0° C., and then is poured onto 2500 g of ice. The resulting precipitate is collected by filtration, and washed with water until the washes are neutral. Recrystallization of the solid from ethanol followed by drying under vacuum at 50° C. for 24 hr provides the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[CH:40]([C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:44]=1[NH2:45])([CH3:42])[CH3:41]>O.CN(C=O)C>[CH:50]([C:46]1[CH:47]=[CH:48][CH:49]=[C:43]([CH:40]([CH3:42])[CH3:41])[C:44]=1[NH:45][C:37](=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][OH:22])([CH3:52])[CH3:51]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.7 %

Procedure:
WSC (4.2 g, 22 mmols) and HOBt (3.0 g, 22 mmols) were added to a DMF (40 ml) solution of the resulting carboxylic acid 15.2 g, 20 mmols) and 2,6-diisopropylaniline (5.3 g, 30 mmols), and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the precipitate formed was taken out through filtration, and extracted with chloroform. The organic layer was washed with 1 N HCl and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was extracted with ether and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1) to obtain 1.9 g (yield: 23%) of N-(2,6-diisopropylphenyl)-15-hydroxypentadecanamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C@H:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C@H:31]2[O:43][CH3:44])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C.C1COCC1.O1CCOCC1>[CH3:44][O:43][C@H:31]1[C@@H:30]([N:28]2[CH2:29][C:26]([CH2:25][C:23]#[N:24])([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:27]2)[CH2:35][CH2:34][NH:33][CH2:32]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CO[C@@H]1CNCC[C@@H]1N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.256 g, 0.812 mmol) in acetonitrile (10 mL) were added tert-butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-methoxypiperidine-1-carboxylate (0.20 g, 0.68 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 mL, 1.02 mmol). After being stirred at room temperature for 5 minutes, the reaction mixture became a clear solution. Stirring was continued at room temperature overnight. LC-MS indicated the reaction was complete. The solution was concentrated under reduced pressure and ethyl acetate was added. The resulting solution was washed with 1 N HCl and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (20-100% EtOAc/hexanes) afforded an oily product. The product was dissolved in THF (5 mL). To it was added 4 N HCl in dioxane (5 mL). After being stirred at room temperature for 2 hours, the solution was concentrated under reduced pressure to give 0.30 g (86%) of the title compound as a solid. LCMS: 511.1 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>>[C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O

Procedure:
Methyl 4-acetamido-5-chloro-2-methoxybenzoate is stirred with aqueous sodium hydroxide until complete solution is achieved. After filtration, concentrated hydrochloric acid is added, whereupon, the product precipitates out as a white solid which is filtered off, washed and dried. 4-Acetamido-5-chloro-2-methoxybenzoic acid is crystallised from isopropanol, filtered off, washed and dried.