Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:25]([CH:33]=O)[C:24]([CH3:35])=[N:23]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:25]3[C:24]([CH3:35])=[N:23][N:22]([CH3:21])[C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1nn(C)c(N2CCOCC2)c1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1nn(C)c(N2CCOCC2)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 35 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 1,3-Dimethyl-5-morpholin-4-yl-1H-pyrazole-4-carbaldehyde (39.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 28.80 mg (35%) of the title compound. (300 MHz, DMSO-d6) 12.67 (s, 1H), 7.93 (s, 1H), 7.68 (m, 1H), 7.18 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.31 (d, J=15 Hz, 2H), 5.28 (t, J=17 Hz, 9 Hz, 1H), 3.65 (m, 7H), 3.04 (m, 4H), 2.94 (m, 2H), 2.84 (s, 1H), 2.74 (s, 1H), 2.57 (d, J=9 Hz, 1H), 2.27 (d, J=9 Hz, 1H), 2.18 (s, 3H), 1.40 (d, J=8 Hz, 1H). MS=483 (M+H), HPLC: 1.99 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](I)[CH3:34]>>[CH2:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[CH3:34]
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Reactant: CCI
Product: CCNc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and ethyl iodide (0.07 mL) as starting materials, N-[(4-ethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g) was obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH2:21])=[CH:11][CH:10]=1.C1COCC1>N1C=CC=CC=1>[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCc1ccc(F)c2c1CCO2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCCc1ccc(F)c2c1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (0.18 ml) was added dropwise to a solution of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (256 mg) in, dry THF (10 ml) containing pyridine (0.21 ml) at 0° under nitrogen and the solution stirred overnight at room temperature. The solution was evaporated and the residue purified by column chromatography. Eluting with dichloromethane:methanol: (50:1) gave the title compound as a colouriess oil (133 mg)
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH3:25])=[CH:19][CH:18]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=1)[C:24]([CH3:25])=[C:7]2[C:8]([OH:13])=[O:1]
Reactant: [OH-]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc2c1C(=O)O
Yield: 97.8 %

Procedure:
A solution of potassium hydroxide (13.08 g, 233 mmol) in water (25.2 mL) was added slowly to a solution of 5-bromo-1H-indole-2,3-dione (9.76 g, 38.9 mmol) in ethanol (63.1 mL). 1-[4-(trifluoromethyl)phenyl]-1-propanone (8.64 g, 42.7 mmol) was added and the mixture was heated to reflux for 1 h. The reaction mixture was concentrated to remove the solvent, the residue was dissolved in water, and the mixture was washed three times with Et2O. The aqueous mixture was chilled, and concentrated HCl was added until the solution was pH 3. The solid was collected by filtration, washed with water, and dried under reduced pressure in a water bath at 100° C. The product was obtained as a light brown powder (15.6 g, 98%). This material was used without further purification. MS (m/z) 412.0 (M+H+).
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]3([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[CH2:48][C:47]1=[O:57])[CH2:35][O:36]2>>[CH2:1]([N:41]([CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:48][C:47]1=[O:57])[CH:34]1[CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[CH:40][C:31]=2[O:30][CH3:29])[O:36][CH2:35]1)[CH2:2][CH3:27]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1
Yield: 72 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 9, the expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[C:17]#[N:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[C:16]([C:17]#[N:18])[CH:19]=[CH:20][C:21]=2[F:22])[CH:9]=1
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1ccc(F)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 17.8 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-4-fluorobenzonitrile (0.29 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (60 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br.Cl.[CH:39]1([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:39]1([NH:45][C:46]([CH:48]2[CH2:49][CH2:50][N:51]([CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=3)[CH2:1][CH3:2])[CH2:52][CH2:53]2)=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: CCC(O)c1cccc([N+](=O)[O-])c1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
A solution of α-ethyl-3-nitro-benzenemethanol (0.54 g, 2.98 mmol) in DCM (10 mL) is treated with PPh3 (1.6 g, 6.1 mmol).) and CBr4 (2 g, 6.03 mmol). The yellowish solution is stirred at RT for 2 h 30. Piperidine-4-carboxylic acid cyclohexylamide hydrochloride J-1 (0.82 g) is added at once, as well as DIPEA (2 mL). The RM is stirred at RT overnight then heated to 70° C. for 1H. The RM is evaporated under reduced pressure. The residue is partitioned between DCM (25 mL) and sat. aq. NaHCO3 (25 mL). The organic layer is washed twice with sat. aq. NaHCO3, dried over MgSO4 and evaporated under reduced pressure. The crude residue is purified by flash chromatography on silica gel using a gradient of DCM/MeOH/NH4OH 95:5:1 to 90:10:1. After concentration of the product-containing fractions, the title compound (0.173 g, 16%) is obtained as a colorless solid LC-MS A: tR=0.68 min; [M+H]+=374.21.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:19].[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(Cc4ccccc4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 82 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-benzyl-piperazine as described in Steps 5 and 6, Example 24 to give the title compound as an orange solid (82% yield). LC/MS: RT 2.32 min, m/e 458 (M+H); 1H NMR (δ, ppm): 11.88 (1H, s), 11.08 (1H, s), 7.65 (1H, d), 7.55 (2H, br s), 7.45 (3H, m), 7.35 (1H, d), 7.31 (1H, d), 4.33 (2H, s), 3.36-3.40 (2H, m), 3.22 (2H, m), 2.90-2.97 (2H, m), 2.40 (2H, q), 2.33 (3H, s), 1.09 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
The crude 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (2.6 g, 11 mmol) was dissolved in N,N-dimethylformamide (15 mL) and N,N-dimethylformamide dimethylacetal (5 mL, 38 mmol) was added. The reaction was heated to 120° C. for 18 hours. The reaction was cooled to room temperature and the mixture was added directly to a 0° C. suspension of sodium periodate (12.2 g, 57.2 mmol) in water (20 mL) and N,N-dimethylformamide (5 mL). The reaction was stirred at 0° C. for 2 hours, then allowed to warm to room temperature and stir for another 6 hours. The reaction mixture was filtered, rinsing with ethyl acetate, toluene, and water. The filtrate was extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (550 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 10.47 (s, 1 H), 8.41 (s, 1 H), 7.35 (s, 1 H), 4.05 (s, 3 H).
Reaction SMILES: C([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:6]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5]1)(=O)C.C(=O)(O)[O-].[K+].C(O)(=O)C>CO.O>[CH:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:7]2[C:6]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:53])([CH3:55])[CH3:54])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:37])[CH3:36])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5][NH:4][C:8]=2[CH3:9])=[CH:16][CH:15]=1)([CH3:20])[CH3:19]
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(OC(C)C)cc2)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OC(C)C)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a suspension of 1-acetyl-4-[(4-isopropoxyphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.00 g) in methanol (10 mL) was added potassium bicarbonate (0.038 g) under stirring at room temperature. The suspension turned into a solution by heating to reflux, and the mixture was stirred for further 2 hours. After confirming the completion of the reaction, a solution of glacial acetic acid (0.022 g) in water (10 mL) was added to the mixture at 60° C. to precipitate the crystals. The suspension was cooled to room temperature, and stirred under ice-cooling for 1 hour. The crystals were collected by filtration, and the obtained crystals were washed with a mixed solution of 2-propanol and n-heptane, and dried under reduced pressure to give 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.890 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][N:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22](=[O:23])/[CH:21]=[CH:20]/[C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (1.11 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.95 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-ethoxycarbonylmethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (1.82 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 164–165° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:26])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([Cl:26])=[O:23])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-c2ccc(OCCCCCC(=O)O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCCCCC(=O)Cl)cc2)cc1

Procedure:
A solution comprising 16.3 g (52.7 mmol) of 6-(4'-cyanobiphenyl-4-oxy)caproic acid, 7.5 g (63.3 mmol) of thionyl chloride and 3 drops of dimethylformamide in 160 ml of toluene was heated at the boil for 1.5 hours. The readily volatile constituents were removed under reduced pressure at 80° C. and the residue was dried under reduced pressure at room temperature.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][OH:24].CS(O)(=O)=O>CO>[OH:24][CH2:23][CH2:22][C:21]1[CH:20]=[C:19]([CH:27]=[CH:26][CH:25]=1)[NH:18][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1cccc(CCO)c1
Reactant: COc1ccc2c(Cl)c3ccccc3nc2c1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc2c(Nc3cccc(CCO)c3)c3ccccc3nc2c1

Procedure:
A mixture of 9-chloro-3-methoxyacridine, (975 mg, 4 mmol), 3-aminophenethyl alcohol (549 mg, 4 ml) and methanesulfonic acid (0.32 ml, 5 mmol) in methanol (30 ml) is stirred under reflux for 2 hours. The mixture is concentrated in vacuo, and the residue is dissolved in methanol (10 ml). The solution is diluted with ether (150 ml). The precipitates are collected by filtration, washed with ether to give 9-[3'-(β-hydroxyethyl)anilino]-3-methoxyacridine, as the methanesulfonate (1.15 g, 65%), mp 186°-188° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reaction time: 8 h
Yield: 94 %

Procedure:
A 500 mL Par hydrogenation bottle was charged with ethyl 5-nitroindole-2-carboxylate (8) (5.0 g, 21.36 mmol), 10% Pd/C (0.3 g), methanol/THF (150 mL, 1:4 v/v), and was purged with hydrogen. The reaction mixture was shaken with 40 psi H2 overnight. The catalyst was removed by filtration and the solvent was evaporated to give 4.10 g (94% yield) of the title compound 18 as a brown solid. 1H NMR (CDCl3), 8.77 (s, 1H), 7.26 (s, 1H), 7.23 (t, 1H, J=0.8 Hz), 7.21 (d, 1H, J=0.7 Hz), 7.03 (dd, 1H, J=0.7, 1.5 Hz), 6.93 (dd, 1H, J=0.7, 1.6 Hz), 6.80 (dd, 1H, J=2.2, 8.6 Hz), 4.38 (dd, 2H, J=7.2, 14.3 Hz), 1.40 (t, 3H, J=7.2 Hz); 13C NMR (CDCl3) 162.02, 140.30, 138.14, 131.87, 128.45, 127.77, 117.12, 112.50, 107.36, 105.86, 60.87, 14.41. This product is unstable and therefor it was used immediately in next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[F-].[K+].CC#N>C(Cl)Cl.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:21]2[CH:20]=[CH:19][C:18]([Si:32]([CH3:34])([CH3:33])[CH3:35])=[C:17]([F:16])[CH:22]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
To a 5-mL microwave safe vial were added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (0.690 g, 2.344 mmol), KF (0.297 g, 5.11 mmol), and PdCl2(PPh3)2 (0.120 g, 0.170 mmol). A mixture of H2O (1 mL) and CH3CN (2 mL) was added, and the reaction vial was capped and placed in a Biotage Initiator microwave reactor for 20 min at 115° C. with external infrared (IR)-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and H2O (25 mL), and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a light pink oil (333 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=7.6 Hz, 1H), 7.55 (d, J=9.8 Hz, 1H), 7.46 (dd, J=7.6, 5.9 Hz, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.33 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −100.72, −140.12; ESIMS m/z 367 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>O>[CH3:2][O:3][C:4](=[O:11])[CH:5]([N:6]=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH2:7][CH2:8][S:9][CH3:10]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CCSC)N=Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a solution of L-methionine methyl ester hydrochloride (2 g, 10.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) in water (46 mL) was added p-chlorobenzaldehyde (1.4 g, 10.0 mmol). The resulting mixture was stirred at 40° C. for 45 minutes then 17 h at room temperature. The white cloudy solution was extracted with dichloromethane (3×50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound 2.6 g (91%) which was used in next step with out further purification.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(O)(=O)C>C(OCC)C>[CH2:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH3:39]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC(=O)OCC
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C(C)=O)C(C)=O
Reaction time: 65 h

Procedure:
To a mixture of 70 g of 2,4-pentandione and 1.72 g of trioctyl phosphine, 45 g of ethyl acrylate was added dropwise over 40 minutes, keeping the temperature at 0–5° C. by cooling. After stirring for 65 hours, 2 ml of acetic acid and 150 ml of diethyl ether were added, and the solution was extracted with an aqueous sodium carbonate solution and water. The organic layer was dried, and 4-acetyl-5-oxohexanoic acid ethyl ester was isolated by fractional distillation.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCCCO)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (2.32 mL, 30 in mmol) was added to a cooled (0° C.), stirred solution of 4-(4-hydroxybutyl)benzonitrile (from step (ii) above, 5.2 g, 29.7 mmol) and triethylamine (4.35 mL) in dichloromethane (50 mL). The resulting, mixture was stirred for 4 h before water (150 mL) was added, and the organic layer separated, dried and concentrated to give the sub-title compound. This product was used directly in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([OH:17])=[C:10]2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[OH:17][C:16]1[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=12
Reactant: CCOC(=O)Cn1nc2c(c1O)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1nc2c(c1O)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 2.73 g (8.40 mmol) of ethyl 5-t-butoxycarbonyl-3-hydroxy-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate, and under ice-cooling, 10 ml of CF3CO2H was added to the solution and the mixture was stirred at room temperature for 2 hours.