Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Linoleic acid (2.80 g, 10.5 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.55 g, 1.2 eq.) and DIEA (5.21 mL, 3.00 eq). After work-up and column purification the pure amide 102g was isolated as pale yellow gummy liquid (Yield, 6.10 g, 78%). 1H NMR (DMSO-d6, 400 MHz) δ=7.71-7.67 (m, 1H), 7.33-7.25 (m, 4H), 7.23-7.13 (m, 5H), 6.87-6.80 (m, 4H), 5.35-5.24 (m, 4H), 4.97 (d, J=3.90 Hz, 1H), 4.88 (d, J=3.90 Hz, 1H), 4.39-4.05 (m, 2H), 3.72 (s, 6H), 3.58-3.41 (m, 1H), 3.32-3.12 (m, 2H), 3.01-2.93 (m, 3H), 2.72-2.67 (m, 2H), 2.20-1.80 (m, 9H), 1.46-1.08 (m, 23H), 0.83 (t, J=6.34 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=176.63, 170.97, 170.86, 162.22, 158.09, 157.97, 145.07, 144.73, 135.87, 135.73, 135.48, 135.43, 129.60, 129.57, 129.55, 127.81, 127.71, 127.57, 127.55, 126.69, 126.53, 113.15, 113.07, 113.06, 85.79, 85.12, 68.61, 67.47, 63.36, 55.07, 55.01, 54.96, 54.93, 38.60, 38.56, 38.29, 38.18, 38.02, 36.30, 36.16, 36.01, 35.71, 34.17, 32.55, 30.70, 29.06, 29.02, 27.73, 27.70, 27.53, 26.08, 26.04, 24.49, 24.10.
Reaction SMILES: [OH:1][C:2]1[C:13]2[C:12](=[O:14])[O:11][CH2:10][C:9]3[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:19][CH3:20])[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[OH:1][C:2]1[C:13]2[C:12](=[O:14])[O:11][CH2:10][C:9]3[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:19][CH3:20])[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:22]([OH:27])[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(O)c1C(=O)OC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C)cc2c1Oc1ccc(C(O)CC(C)C)c(O)c1C(=O)OC2
Reaction time: 14 h

Procedure:
2.2 g (5.9 mmol) of the compound from Example 109 are dissolved in 40 ml of tetrahydrofuran, and 7 ml of glacial acetic acid and 0.96 g (15 mmol) of sodium cyanoborohydride are added. After 14 h at room temperature, the mixture is concentrated in vacuo, the residue is taken up in dichloromethane, and the solution is washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate and concentrated in vacuo. Purification is carried out by column chromatography on silica gel using dichloromethane/methanol 150/1 as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([Cl:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: O=C=NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 65.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-chloro-3-(trifluoromethyl)benzo yl isocyanate (Intermediate-100, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.1 Hz, 2H), 7.36 (d, J=9.3 Hz, 1H), 7.43 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.10-8.18 (m, 2H), 8.27 (s, 1H), 12.82 (s, 1H); MS (m/z): 487.29 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][CH:24]([CH2:28]C)[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 87.6 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 1.50 g (7.45 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide and 1.82 g (8.95 mmol) of racemic 2-(tert-butoxycarbonylamino)butanoic acid (purchased from ABCR, cat. no. AB154485). After recristallysation of the crude product in diethylether, 2.43 g (84% yield) of the title compound were obtained.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:35])[CH:6]([O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][CH2:30][CH2:29]2)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.CO.Cl>O>[CH2:31]1[C:32]2[C:28](=[CH:27][C:26]([O:25][CH:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:9][CH:8]=3)[C:5]([OH:35])=[O:4])=[CH:34][CH:33]=2)[CH2:29][CH2:30]1
Reactant: COC(=O)C(Oc1ccc2c(c1)CCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(Oc1ccc2c(c1)CCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 100.2 %

Procedure:
A mixture of 5 g of potassium hydroxide, 7.0 g of methyl(5-indanyloxy){p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate, 5 ml of methanol and 50 ml of water is refluxed for 4 hours. The mixture is acidified with concentrated HCl, chilled and the aqueous layer decanted from the gum which separated. The gum is washed with water, dissolved in chloroform and the solution dried (MgSO4). The solvent is removed under reduced pressure to give 6.8 g of gum. The gum is crystallized from petroleum ether containing a small amount of ether to give 5.4 g of off-white crystals. Recrystallization from chloroform-hexane gives white crystals, mp 104°-108° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:21][NH:22][CH3:23])[CH:18]([CH3:20])[CH3:19]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:22]([CH3:23])[O:21][CH2:17][CH:18]([CH3:20])[CH3:19])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNOCC(C)C
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC(C)C)n1
Yield: 82 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-isobutyl-N-methyl-hydroxylamine hydrochloride as described in Example 13, affording LXXXII in 82% yield. ESI-MS (m/z) 297 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][B:44]1[O:48]C(C)(C)C(C)(C)[O:45]1>CC#N>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:43][B:44]([OH:48])[OH:45])=[CH:33][CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC1(C)OB(CBr)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCB(O)O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 65 °C
Yield: 81 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (85.0 mg, 0.172 mmol), potassium carbonate (0.119 g, 0.859 mmol), and 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.152 g, 0.688 mmol) in MeCN (3 mL) in a sealed tube was heated to 65° C. with stirring. After 2 hours the mixture was cooled to RT, filtered to remove solids, and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/water to give the title compound (77 mg, 81%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.15 (s, 1H) 8.03 (s, 2H) 7.97 (dd, J=8.8, 5.4 Hz, 2H) 7.53 (d, J=9.0 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.90 (d, J=9.1 Hz, 2H) 3.58 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.24-2.38 (m, 1H) 0.76-1.10 (m, 3H) 0.47 (br. s., 1H). LCMS (m/z, ES+)=553 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].Cl.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.N>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:5]=[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:7][N:6]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1cccc(F)c1F
Agent: Cl
Agent: N
Product: Fc1cccc(-c2noc(-c3cccnc3)n2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.61 (m, 1H), 7.67-7.85 (m, 2H), 7.91-8.04 (m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.92 (dd, J=4.8, 1.6 Hz, 1H), 9.36 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
A mixture of (4-tert-butoxycarbonylaminopiperidin-1-yl)acetic acid (0.50 g; 1.94 mmol), phenylamine (0.18 mL; 1.94 mmol), the coupling reagent TBTU (0.62 g; 1.94 mmol) and DIPEA (0.35 mL; 2.0 mmol) in DMF (5 mL) is stirred at r.t. over night. The solvent is evaporated and the residue is purified by silica gel column chromatography (DCM:MeOH=40:1) to give tert-butyl N-[1-(2-anilino-2-oxo-ethyl)-4-piperidyl]carbamate.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27]([NH:29][C@@:30]([CH2:42][CH3:43])([CH2:33][O:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][OH:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCOCC>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C@:30]([CH2:42][CH3:43])([CH2:33][O:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][OH:32])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCCCCC(=O)OC[C@@](CC)(CO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(=O)OC[C@](CC)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
Molecular sieve 4A (117 g) and pyridinium dichromate (117 g, 311 mmol) were added to a solution of (2R)-2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanol (66.7 g, 210 mmol) obtained in Reference example 2 (2a) in methylene chloride (700 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture and the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-5:1) to obtain the title compound (45.9 g, yield: 69%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:16]([C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]>C(O)C>[C:16]([C:18](=[CH:24][NH:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(C#N)=CNNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
4-Trifluoromethyl-2-nitrophenylhydrazine (13.5 g) and ethyl 2-cyano-3-ethoxyacrylate (10.3 g) were heated under reflux in ethanol (300 ml) for 24 hours. The solvent was removed under reduced pressure and the resulting residue triturated with dichloromethane/hexane to give ethyl 2-cyano-3-(2-nitro-4-trifluoromethylphenylhydrazino)acrylate, m.p. 163°-164°.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=O)[CH3:5].Cl.[Cl:9][C:10]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][NH2:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:9][C:10]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5]
Reactant: NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(=O)CC(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(CC(C)C)=NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 0.10 g of 4-methyl-2-pentanone and 5 ml of pyridine as added 0.40 g of O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.42 g (yield, 95.4%) of 4-methyl-2-pentanone O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-pentyl)oxime, nD24.5 1.5230.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:18][C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)=[CH:23][CH:24]=4)[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Fc1cccc(Oc2ccc3c(c2)OCO3)n1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: c1cc(Oc2ccc(-n3ccnc3)cc2)nc(Oc2ccc3c(c2)OCO3)c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To DMSO (5 mL) was added 2-(1,3-benzodioxol-5-yloxy)-6-fluoropyridine (1.3 g, 5.3 mmol), 1-(4-hydroxyphenyl)imidazole (0.92 mL, 5.8 mmol), and cesium carbonate (1.82 g, 5.6 mmol). After heating at 90° C. for 18 hour, the reaction was partitioned with water and ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuo. The residue was chromatographed on silica with ethyl acetate/hexane to get 1.1 g of 2-(1,3-benzodioxol-5-yloxy)-6-[4-(1H-imidazol-1-yl)phenoxy]pyridine; NMR (CDCl3) δ 7.8 (s, 1H), 7.7 (t, 1H), 7.35 (d, 2H), 7.2 (m, 3H), 6.75 (d, 1H), 6.6 (m, 3H), 6.55 (m, 2H), 5.9 (s, 2H) ppm.
Reaction SMILES: O[CH2:2]/[C:3](/[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[C:4](/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)\[C:5]([NH:7][CH3:8])=[O:6].P(Br)(Br)Br.C([O-])(O)=O.[Na+]>CCOCC.C(Cl)Cl>[CH3:8][N:7]1[CH2:2][C:3]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:13][CH:14]=2)[C:5]1=[O:6]
Reactant: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)-but-2-enamide (430 mg, 1.01 mmol) in Ether: DCM (20 mL; 1:1) was added PBr3 (0.114 mL, 1.21 mol) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then diluted with DCM and basified with NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (350 mg, 85%) as a solid. 1H NMR (500 MHz, CD3OD): δ 8.81 (d, J=7.8 Hz, 2 H), 8.24-8.19 (m, 2 H), 8.11-7.94 (m, 3 H), 7.85-7.80 (m, 1 H), 7.59 (d, J=7.2 Hz, 2 H), 7.44 (s, 2 H), 7.21 (d, J=7.2 Hz, 2 H), 5.61 (s, 2 H), 3.38 (s, 2 H), 3.09 (s, 3 H). MS: M+H: m/z=408.2. HPLC: 89%, (Condition-B).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:36][N:37]([CH2:38][CH2:39][CH3:40])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CCCNCC1CC1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCOC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml, 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.N(C(OCC)=O)=NC(OCC)=O.[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56](O)[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
PPh3 (412 mg), phthalimide (252 mg), and diethyl azodicarboxylate (40% in toluene solution) (0.712 ml) were added to a THF (5 ml) solution containing benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidin-1-carboxylate (500 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 15:7). Colorless oily matter of benzyl 3-((tert-butoxycarbonyl)amino)-4-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (205 mg) was thus obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:29])[CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccs4)C3)cc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cccs4)C3)cc21

Procedure:
A mixture of 200 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid, 0.3 ml of 37% formalin and 0.35 ml of 90% formic acid was refluxed for 2 hours, then evaporated. A 10 ml portion of water was added and the mixture neutralized with 1N sodium hydroxide. The solid was collected, washed with water, methanol, ether and dried, giving 170 mg of the desired product, mp 238°-240° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([OH:13])[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:45][N:46]1[C:50]2[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=3[O:57][C:58]3([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[C:49]=2[CH:48]=[N:47]1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:61]2[CH2:62][CH2:63][C:58]3([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[C:50]=4[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=4[O:57]3)[CH2:59][CH2:60]2)=[O:10])=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.6 %

Procedure:
In a vial were added 4-ethoxy-2-hydroxybenzoic acid (0.40 mmol) followed by HATU (170 mg, 0.44 mmol), DMF (0.7 mL), and triethylamine (220 μL, 1.6 mmol). The mixture was stirred for 10 minutes before 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (100 mg, 0.40 mmol) was added. The reaction mixture was allowed to stir at 25° C. for 12 hours before it was filtered and purified by HPLC (1-99%) MeOH:H2O to yield (4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (53 mg, 32%). ESI-MS m/z calc. 419.5, found 420.4 (M+1)+. Retention time: 2.96 minutes (4 min run).