Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[CH2:11]([N:13]([CH2:27][CH3:28])[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][C:18]2[CH:22]=[C:23]([NH2:26])[CH:24]=[CH:25][C:17]1=2)[CH3:12]>CCO>[CH2:27]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][C:18]2[CH:22]=[C:23]([NH:26][C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])[CH:24]=[CH:25][C:17]1=2)[CH3:28]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(CC)CCN1CCSc2cc(N)ccc21
Agent: I
Solvent: CCO
Product: CCN(CC)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (2.266 g, 7.94 mmol) was added to a mixture of 4-(2-(diethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (1.054 g, 3.97 mmol) in EtOH (20 mL). The mixture was stirred for 2 days at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with CH2Cl2 (50 mL). The aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (CH2Cl2 followed by 3.5% (2M NH3 in MeOH):CH2Cl2). The collected fractions were concentrated, and the sample was subjected again to flash chromatography on silica gel (2.5% MeOH:CH2Cl2). The collected fractions were concentrated to give compound 15 as a brown solid. (1.23 g, 83%). 1H NMR (CDCl3) δ 7.40-7.36 (m, 2H), 7.05 (dd, J=3.9, 4.8 Hz, 1H), 6.73 (m, 3H), 3.65-3.61 (m, 1H), 3.39 (t, J=7.2 Hz, 2H), 3.05-3.02 (m, 2H), 2.67-2.54 (m, 6H), 1.04 (t, J=7.2 Hz, 6H); ESI-MS (m/z, %): 377, 375 (MH+, 35), 278, 276 (100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13](C)=O.C(=O)=O.C([Mg]Br)=C.[N+](C1C=CC=CC=1)([O-])=O.CC#N.C(=O)=O>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[C:4]=1[CH:12]=[CH:13][NH:9]2
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: CC(C)=O
Agent: C=C[Mg]Br
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=[N+]([O-])c1ccccc1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-fluoronitrobenzene (4.4 g, 20 mmol) in dry THF (200 mL) under N2 was cooled to −65° C. (acetone/CO2). A solution of vinylmagnesium bromide (60 mL, 1 M, 60 mmol) in THF was added to the nitrobenzene solution as rapidly as possible maintaining the reaction temperature below −40° C. After addition of the Grignard reagent, the cooling bath was switched to a −40° C. bath (CH3CN/CO2), and the mixture was stirred at −40° C. for 30 min. The reaction mixture was quenched with sat. NH4Cl solution (500 mL) and extracted with ether (2×200 mL), then dried (brine, Na2SO4) and concentrated in vacuo. The resulting material was purified by SiO2 flash column chromatography (5:95) EtOAc/Hexanes to give 4-fluoro-7-bromoindole, as a light brown oil (2.03 g, 9.5 mmol, 54%). 1H NMR (CDCl3) δ 6.72 (m, 2H), 7.24 (m, 2H), 8.4 (br s, 1H). MS m/e 215 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]2[N:16]([C:20]3[CH:25]=[C:24]([S:26][C:27]([CH3:35])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:28])[C:23]([O:36][CH3:37])=[CH:22][C:21]=3[Cl:38])[C:17](=[O:19])[NH:18][C:13]2=[C:12]([O:39][CH3:40])[CH:11]=1)(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:38][C:21]1[CH:22]=[C:23]([O:36][CH3:37])[C:24]([S:26][C:27]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])=[CH:25][C:20]=1[N:16]1[C:14]2=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]([O:39][CH3:40])=[C:13]2[NH:18][C:17]1=[O:19]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO[Si](C)(C)C(C)(C)C)nc32)cc1SC(C)(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO)nc32)cc1SC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxy)methyl-3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylthio)phenyl]-7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (24 mg) in tetrahydrofuran (2 mL) was added tetra(n-butyl)ammonium fluoride hydrate (31 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (10 mg).
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:37]([Si:40]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[O:41][C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[C:49]2[C:52](O)=[O:53])=[CH:44][CH:43]=1)([CH3:39])[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][N:16]([C:52]([C:49]2[C:50]3[C:45](=[CH:44][CH:43]=[C:42]([O:41][Si:40]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:37]([CH3:38])[CH3:39])[CH:51]=3)[CH:46]=[CH:47][CH:48]=2)=[O:53])[CH2:15]1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Reactant: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCNC1)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)c2cccc3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-{2-[1-(4-Cyano-3-fluorobenzyl)-1H-imidazol-5-yl]ethyl}-N-(pyrrolidin-3-yl)carbamic acid triisopropylsilyl ester, as described above in Step H, (242 mg, 0.471 mmol), 7-(triisopropylsilyloxy)-1-naphthlenecarboxylic acid, as described in Example 54, Step C, (162 mg, 0.471 mmol), PYBOP (245 mg, 0.471 mmol), and triethylamine (0.085 mL, 0.612 mmol) were combined in CH2Cl2 (4 mL). The reaction mixture was stirred at ambient temperature for 4 hours, then poured into 10% aqueous citric acid and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: C1([C@H]([N:9]([C@@H:21]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:23]=3[CH2:22]2)[CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C)C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:37]([O:36][C:34]([CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:24]2[CH2:25][CH2:26][CH2:27][C@@H:21]([NH:9][CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][C:23]=2[CH:31]=1)=[O:35])[CH3:38]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](N(C[C@@H](O)COc1ccccc1)[C@H](C)c1ccccc1)CCC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](NC[C@@H](O)COc1ccccc1)CCC2
Yield: 85.8 %

Procedure:
A mixture of (2R)-1-[N-((R)-1-phenylethyl)-((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (2.0 g) and 10% palladium on activated carbon (50% wet, 0.70 g) in ethanol (24 ml) and tetrahydrofuran (12 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours, and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel to afford (2R)-1-[((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (1.37 g).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:19][OH:20]>>[OH:20][NH:19][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])=[O:4]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)CCc1ccccc1
Product: CN(CCc1ccccc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-[methyl(phenethyl)amino]sulfonyl-acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][CH:12]([F:28])[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25])[NH:19][CH2:18][CH2:17][CH2:16]2.[C:29]1([O:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:28][CH:12]([F:11])[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:22]=1[CH:23]([O:24][CH3:25])[O:26][CH3:27])[N:19]([C:36]([O:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:37])[CH2:18][CH2:17][CH2:16]2
Reactant: COC(OC)c1nc2c(cc1C(F)F)CCCN2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C(F)F)CCCN2C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of LHMDS in THF (1.6M, 6.64 ml, 10.63 mmol) was added drop wise to a solution of 6-(difluoromethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 101, 1.7 g, 6.25 mmol) and diphenylcarbonate (1.41 g, 6.57 mmol) in THF (20 ml) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C., then for 18 h at room temperature, partitioned between saturated aqueous NH4Cl and DCM, extracted DCM (2×), dried over Na2SO4 and evaporated. The residue was preabsorbed onto isolate and purified by normal phase chromatography using a 40 g RediSep® silica column, eluting with a gradient from heptane to 50% EtOAc in heptane. Product containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 7) tR 1.19 min; ESI-MS 379.4 [M+H]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([C:11]2([C:14]3[C:23]([F:24])=[C:22]([F:25])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:26])[C:15]=3[F:27])[CH2:13][CH2:12]2)=[O:10])C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:9]([C:11]1([C:14]2[C:15]([F:27])=[C:16]([F:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([F:25])[C:23]=2[F:24])[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: COC(=O)c1c(F)c(F)c(C2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1c(F)c(F)c(C2(C(=O)O)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
In 60 ml of anisole was dissolved 22.5 g of methyl 4-(1-diphenylmethoxycarbonylcyclopropyl)-2,3,5,6tetrafluorobenzoate. To the resulting solution was added 80 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. n-Hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 12.7 g (yield: 88.8%) of methyl 4-(1-carboxycyclopropyl)-2,3,5,6tetrafluorobenzoate.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[NH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:3].[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N:5]=[C:1]=[O:2])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C=Nc1cccnc1
Temperature: 0 °C

Procedure:
A 1.93 solution of phosgene in toluene (20%) (584 mL) was diluted with dry CH2Cl2 (1 L) and the mixture was stirred at 0° C., under nitrogen atmosphere. A solution of 3-aminopyridine (21.1 grams) and dry pyridine (19 mL) dissolved in dry CH2Cl2 (600 mL) was added dropwise to the stirred solution at 0° C. over a period of 5.5 hours. The mixture was stirred at 0°-25° C. for an additional 48 hours. A stream of nitrogen was passed through the solution to remove most of the phosgene and the solution was then evaporated until almost all of the solvent was removed to give the title compound which was then taken up in dry pyridine (850 mL) to give a stock solution of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(3-benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:20]([CH2:35][C:36]([OH:38])=[O:37])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:34])([F:33])[F:32])(=[O:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:20]([CH2:35][C:36]([OH:38])=[O:37])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:33])([F:34])[F:32])(=[O:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F

Procedure:
To a solution of compound 31k (2.8 g, 5 mmol) in DCM (100 mL) was added TFA (20 mL). After the reaction was over, the solvents were removed by reduced pressure to give a white solid. The product was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[N:4]/[NH:5][C:6](=O)[CH2:7][C@H:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][C@H:23]([O:25][CH2:26][CH3:27])[CH3:24])=[CH:16][CH:15]=2)[C@@H:11]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)[CH2:10][N:9]1S(C1C=CC(C)=CC=1)(=O)=O.CN.C(O)(=O)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH2:26]([O:25][C@H:23]([CH3:24])[CH2:22][O:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@H:8]([CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][N:5]=3)[NH:9][CH2:10][C@@H:11]2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)N/N=C/N(C)C)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](Cc3nncn3C)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 100 °C

Procedure:
Into a solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) -piperidin-2-yl]-acetic acid [1-dimethylamino-meth-(E)-ylidene]- hydrazide in 2 ml of acetonitrile is condensed ca. 1 ml of gaseous methylamine, at RT. Acetic acid (2 mL) is carefully added, then the reaction system is sealed, and heated at 100° C. for 4 h. The reaction mixture is cooled to RT, poured into saturated aqueous NaHCO3, and extracted with EtOAc (3×). The combined organic extracts are dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (SiO2 60 F), to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:22]([NH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1)=[O:23])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c(N)cccc2nn1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc2nn1

Procedure:
Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 377 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]1[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:27]5[CH:26]=[C:25]([CH3:24])[NH:29][N:28]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(C)[nH]n4)nc3cc21

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (111 mg, 0.89 mmol). The title compound was obtained as light brown powder (72 mg, 21%).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH:11]1([C@@:17]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:20])[CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCOCC>CN(C=O)C>[CH:21]1([C@:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:27][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:18](=[O:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)[C@](O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: 85 °C
Yield: 68.7 %

Procedure:
To a solution of 12 ml (95 mmoles) of trimethylsilyl chloride and 11.6 g (172 mmoles) of imidazole in 100 ml of DMF was added 20 g (86 mmoles) of (R)-1-cyclohexyl-1-hydroxy-1-phenyl-2-propanone. This mixture was heated to 85° C. overnight. The next day, the mixture was cooled and poured onto a mixture of 100 ml of petroleum ether and 100 ml of ether. This was extracted with water. The organic layer was separated, dried, and the solvent removed. The residue was chromatographed on silica gel with hexane as the eluent to give 18.0 g of clear oil. IR 2950, 1730 cm-1NMR (CDCl3) δ7.4(m, 5H), 2.3(t, 1H), 2.1(s, 3H), 1.9-1.0(m, 10H), 0.3(s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl.CN1CCOCC1.[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:40](=[O:41])[C@H:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:31][C:29]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][N:23]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
L-phenylalanine methyl ester hydrochloride (0.8 g, 3.69 mmol) was dissolved with 20 ml of THF, then the hydrochloric acid was neutralized with NMM (0.49 ml, 4.43 mmol), cooled with an ice bath for later use. N-Pyrazineformyl-L-phenylalanine (1.0 g, 3.69 mmol) of Preparation example 3 was added to another reaction flask, dissolved with 20 ml of THF, and cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (0.76 g, 3.69 mmol), HOBt (0.60 g, 4.42 mmol) were added at 0° C. and reacted for 40 min at 0° C., then the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble DCU was removed by filtration, to the filtrate was added 80 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.52 g of white solid was obtained with a yield of 95.6%, m.p.: 111˜113° C. 1H-NMR (CDCl3, 300 MHz): δ 3.04 (—CH2, m, 2H), 3.18 (—CH2, d, 2H), 3.69 (—CH3, s, 3H), 4.82 (—CH, m, 2H), 6.36 (—CONH, d, 1H), 6.92˜7.30 (-Ph, m, 10H), 8.26 (—CONH, d, 1H), 8.54 (-Pyz, d, 1H), 8.76 (-Pyz, d, 1H), 9.33 (-Pyz, s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(OCCCCCCl)cc1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC
Yield: 69.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound and 5-(3,4-dimethoxyphenoxy)pentyl chloride (1.3 g) were reacted and treated in the same manner as in Example 168 to give 1.46 g of 4-amino-5-chloro-N-((1-(5-(3,4-dimethoxyphenoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]([C:11]2[C:12](=[O:31])[NH:13][C:14]3[C:19]([C:20]=2[NH:21]CC2C=CC(OC)=CC=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=CC=1>C(O)(C(F)(F)F)=O>[NH2:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:31])[C:11]=1[C:9]([NH2:8])=[O:10]
Reactant: COc1ccc(CNc2c(C(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)c(=O)[nH]c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(N)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 249.5 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Example 74a) (2.0 g, 3.55 mmol) was dissolved in TFA (15 mL) and the solution was stirred at room temperature for 6 hours. The TFA was removed under vacuum, and the resultant solid was stirred in water overnight, then collected by filtration to give 1.8 grams of crude final product. 1H NMR (400 MHz, DMSO-d6) δ7.18 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 8.09 (d, J=7.6 Hz, 2H), 9.83 (d, J=4.8 Hz, 1H), 10.85 (bs, 1H), 11.12 (s, 1H). MS 204 (MH+).