Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>ClCCl>[F:21][C:2]([F:1])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:30]([O:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:31])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CNCC(c2ccc(CC(F)(F)F)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.62 g (19.8 mmol, purity 90%) of the compound from Example 42A in dichloromethane (211 ml) was admixed with 9.65 ml (7.00 g, 69.2 mmol) of triethylamine and then admixed at 0° C. with 3.99 g (19.8 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 10.3 g (91% of theory, purity 81%)
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[O:27]=[S:19]1(=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[N:18]1[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: BrCCCOc1ccccc1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCCOc2ccccc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and (3-bromo-propoxy)-benzene. MS: ESI (negative): 489 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH2:37]([O:39][C:40](=[O:46])[C:41](=[N+]=[N-])[CH2:42][CH3:43])[CH3:38]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:41]([CH2:42][CH3:43])[C:40]([O:39][CH2:37][CH3:38])=[O:46])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C(CC)=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g), rhodium(II) acetate (dimer) (0.0050 g) and toluene (5 mL) was heated to 80° C. under an argon atmosphere, a solution of 2-diazobutyric acid ethyl ester (0.87 g) in toluene (5 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.35 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (93 mg, 0.27 mmol), 1-methyl-1H-pyrazol-3-ylamine (29 μL, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (79 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S [M+] 424.10, found 425 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.64 (m, 4 H, 2×CH2), 1.86 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.88 (p, J=4.1 Hz, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.3 Hz, 1 H, Ar), 7.66 (d, Jm=1.3 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.16 (s, 1 H, NH).
Reaction SMILES: C(N(CC)CC)C.P(OC)(OC)OC.[F:15][C:16]([F:22])([F:21])[S:17](Cl)(=[O:19])=[O:18].[F:23][C:24]([F:58])([F:57])[C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]2[O:34][CH:35]=[C:36]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][N:50]4[CH:54]=[CH:53][N:52]=[C:51]4[CH2:55]O)=[CH:42][CH:41]=3)[N:37]=2)=[CH:27][CH:26]=1>C1COCC1.O>[F:57][C:24]([F:23])([F:58])[C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]2[O:34][CH:35]=[C:36]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][N:50]4[CH:54]=[CH:53][N:52]=[C:51]4[CH2:55][S:17]([C:16]([F:22])([F:21])[F:15])(=[O:19])=[O:18])=[CH:42][CH:41]=3)[N:37]=2)=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: COP(OC)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (91.0 μl), trimethyl phosphite (77.0 μl) and trifluoromethanesulfonyl chloride (69.5 μl) were added to a solution of [1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]methanol (250 mg, 0.503 mmol) in THF (5 ml) at −30° C., and the mixture was stirred at the same temperature for 20 min and at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the titled compound (38 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(O)C#C)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:16][CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>[Cu](I)I.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>[C:1]([C:5]1[C:10]([N:11]([CH2:16][CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:9]([CH:27]([OH:28])[C:26]#[C:25][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc(N(CC)CC(C)C)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCN(CC(C)C)c1c(C(O)C#Cc2ccc(C(=O)O)cc2)cccc1C(C)(C)C
Yield: 107.2 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 300 mg (1 mmol) of 1-[3-tert-butyl-4-(ethylisobutylamino)phenyl]prop-2-yn-1-ol with 216 mg (0.87 mmol) of 4-iodobenzoic acid, 12 mg (0.04 mmol) of copper iodide and 15 mg (0.02 mmol) of bis(triphenylphosphine)palladium chloride. 190 mg of 4-{[tert-butyl(ethylisobutylamino)phenyl]hydroxyprop-1-ynyl}benzoic acid are obtained in the form of a beige solid (Mp=117° C., yield=53%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]12[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[CH2:52][NH:51][CH2:50][CH2:49]2>CN(C)C(=O)C.CC1CCCO1>[CH2:52]1[N:51]([C:16]([C:15]2[CH:14]=[C:13]([S:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:12])[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:50][CH2:49][N:48]2[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]12
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Reactant: C1CCN2CCNCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1)N1CCN2CCCCC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid (4.35 g, 12.6 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.27 g, 13.9 mmol) in N,N-dimethylacetamide (30 mL) and 2-methyltetrahydrofuran (90 mL) was added 1,4-diazabicyclo[4.4.0]decane (2.47 g, 17.6 mmol). The reaction was stirred at ambient temperature for 2.5 hours, and then it was diluted with 2-methyltetrahydrofuran (57 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×50 mL), and then it was concentrated. The residue was concentrated from ethanol (2×50 mL) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Ic1ccccc1
Reactant: Clc1cccc2cc[nH]c12
Product: Clc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 7-chloro-1H-indole and iodobenzene: ESMS m/e: 228.0 (M+H)+.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[BH4-].[Na+].O>CCO.CC(=O)OCC>[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1
Reactant: COCc1ccc(C=O)s1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(methoxymethyl)thiophene-2-carbaldehyde (782 mg, 5.01 mmol) in EtOH (10 mL) was treated at 0° C. with NaBH4 (379 mg, 10.0 mmol) and the resulting solution was stirred for 5 min at 0° C. and then allowed to warm to rt. Water (5 mL) and EA (5 mL) were added. The aq. layer was extracted with EA (2×15 mL) and the combined org. layers were washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.51 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]4)=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)CC1
Temperature: 105 °C
Yield: 12.1 %

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.357 mmol) and ethyl 4-aminopiperidine-1-carboxylate (129 μl, 0.714 mmol) in isopropylalcohol (2 ml) were heated at 90° C. for 24 hours. Diisopropylethylamine (125 μl, 0.714 mmol) was added and the reaction mixture was heated at 105° C. for another 24 hours. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (18 mg) as an off-white powder. NMR DMSO D6 1.20 (3H, t), 1.28-1.91 (14H, m), 2.80-2.96 (2H, m), 3.11 (3H, s), 3.50-3.58 (2H, m), 3.70-3.85 (1H, m), 3.90-3.98 (2H, m), 4.03 (2H, q), 4.60-4.70 (1H, m), 6.65 (1H, br s), 7.88 (1H, s); HPLC rt(min): 8.09; MS (ES+) 417, (ES−) 415.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])[OH:57].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][C:43]([O:57][CH3:56])=[CH:44][CH:45]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCOc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (91 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 6 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (150 mg, yield 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42].CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:12])[C:7](=[O:9])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42]
Reactant: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)NCCCCO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.3 %

Procedure:
A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester (400 mg, 1.2 mmol, 1 equiv.) in DMF (10 mL) was added to EDCI (337 mg, 1.8 mmol, 1.5 equiv.). The solution was stirred at room temperature under N2 for 40 min. 4-Amino-1-butanol (0.11 mL, 1.2 mmol, 1 equiv.) was added, followed by addition of Et3N (0.41 mL, 2.9 mmol, 2.5 equiv.) and DMAP (72 mg, 0.59 mmol, 0.5 equiv.). The mixture was stirred overnight under N2. The reaction mixture was then poured into cold water and a solid precipitated from the solution. The solid was collected by filtration and dried under vacuum to give 229 mg of 4-[(Biphenyl-4-carbonyl)-amino]-4-(4-hydroxy-butylcarbamoyl)-butyric acid methyl ester in 47% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(O)C.O>[OH:23]/[N:22]=[C:1](/[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20]2)=[O:11])=[CH:5][CH:4]=1)\[NH2:2]
Reactant: NO
Reactant: N#Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N/C(=N\O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 80 °C

Procedure:
In a 25 mL pressure tube were mixed N-(4-cyanophenyl)isoindoline-2-carboxamide (500 mg, 1.899 mmol), hydroxylamine hydrochloride (264 mg, 3.80 mmol), and triethylamine (1.323 ml, 9.50 mmol) in ethanol (6 ml)/water (0.5 ml). The reaction vessel was sealed and heated at 80° C. for four hours. The reaction mixture was diluted with water and the solid was filtered off with water washes. HPLC purification provided the title compound.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH2:22](N)C#C>>[CH2:3]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:2]#[CH:22]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: C#CCN
Product: C#CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using propargylamine instead of tert-butyl-2-amino ethyl carbamate to afford N-(prop-2-yn-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophene-2-carboxamide.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:28]([S:35][CH:36]([CH:39]([O:42][CH3:43])[O:40][CH3:41])[CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[CH2:28]([S:35][CH:36]([CH:39]([O:40][CH3:41])[O:42][CH3:43])[CH2:37][NH:38][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:4][C:3]=2[N:2]([CH3:1])[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])=[O:13])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Reaction time: 60 h
Yield: 65.3 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (600 mg), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (410 mg), diisopropylethylamine (450 mg) and N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 720 mg) at room temperature, and the mixture was stirred for 2.5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (600 mg, yield 67%) as a colorless amorphous solid.
Reaction SMILES: N=[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:13]2.[OH-:35].[Na+]>Cl>[NH2:20][C:15]1[C:14]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:4]3[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[O:35])[CH:11]=2)[N:16]=1
Reactant: [OH-]
Reactant: COc1ccccc1C(=N)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Agent: [Na+]
Product: COc1ccccc1C(=O)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 50 °C

Procedure:
A solution of 6-(2-(imino(2-methoxyphenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine (0.022 g, 0.049 mmol) in 5N aq. HCl (2 mL) was heated to 100° C. in a sealed tube for 16 h, then allowed to cool to 50° C. and heated for another 70 h at that temperature. The mixture was neutralized with 10N NaOH and filtered. The precipitate was redissolved in MeOH and purified by reverse-phase HPLC (10-90% acetonitrile/H2O, TFA modifier). A single fraction was treated with NH4OH and the acetonitrile was removed in vacuo. The resulting suspension was filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(2-methoxyphenyl)methanone. MS (ESI, pos. ion) m/z: 454 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]1([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:35]1[S:36][CH:37]=[C:33]([CH:30]3[CH2:32][CH2:31]3)[N:34]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C2CC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C3CC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(cyclopropyl)-1,3-thiazol-2-amine (36 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 40 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ0.80-0.86 (m, 2H), 1.06 (s, 9H), 1.13-1.23 (m, 2H), 1.94-2.00 (m, 1H), 3.57 (s, 2H), 6.60-6.66 (m, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.22-7.30 (m, 2H), 7.40-7.48 (m, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.08-8.16 (m, 1H), 8.52-8.60 (m, 1H), 12.99 (br s, 1H); APCI-MS (m/z) 545.18 (MH)+.