Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[ClH:6].Cl.[NH:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH2:9]>Cl>[ClH:6].[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:8]/[N:9]=[CH:2]/[C:1]([OH:5])=[O:4])[CH:11]=1
Reactant: NNc1cccnc1
Reactant: O=CC(=O)O
Agent: Cl
Product: O=C(O)/C=N/Nc1cccnc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
Glyoxylic acid (50% in water) (54.5 mL, 494 mmol) and 1 N hydrochloric acid (˜100 mL) were added to 3-hydrazinopyridine dihydrochloride (60.0 g, 330 mmol) and the reaction mixture was stirred at room temperature (about 22° C.) for 2 hours, at which point solid had started to precipitate. The reaction was stirred for 24 hours, at which point LC/MS indicated that it was complete. The mixture was transferred to a flask using acetonitrile (1 L). The mixture was azeotroped three times from acetonitrile (1 L). The resulting suspension was filtered to afford a green solid which was washed with acetonitrile and vacuum dried at 40° C. to afford the desired product (68.3 g, 98%): mp 173-174° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.55 (d, J=1.2 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.40 (dt, J=5.4, 0.9 Hz, 1H), 8.14 (ddd. J=8.7, 2.6, 1.2 Hz, 1H), 7.91 (dd, J=8.7, 5.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H); 13C NMR (101 MHz, DMSO) δ 164.29, 143.15, 133.15, 131.85, 127.97, 127.61, 126.30; ESIMS m/z 166 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:30]#[N:31])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:13](=[O:29])[NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1.[OH-].[Na+].Cl>C(O)C>[F:22][C:21]([F:23])([F:24])[C:19]1[CH:20]=[C:15]([NH:14][C:13]([C:7]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:30]#[N:31])[C:3]([OH:32])=[O:2])=[O:29])[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: COC(=O)C(C#N)=Cc1ccc(O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(=Cc1ccc(O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4 hydroxyphenyl)-2-cyanoacrylic acid methyl ester (50 mg, 0.11 mmol) was dissolved in ethanol (5 mL). 2 N sodium hydroxide (0.11 ml, 0.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate) to give the title compound (13.5 mg, 30.4%) as a light yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][CH2:51][CH2:52][O:53]C(OC(C)(C)C)=O)/[C:33]1=[O:61])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:61])[C:34]3([CH:42]([C:43]4[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=4[O:50][CH2:51][CH2:52][OH:53])[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)OCCOc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
To a toluene solution (10 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.93 mmol) was added E/Z-3-[2-(2-tert-Butoxycarbonyloxy-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 1.82 mmol). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 40 min. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid and dichloromethane was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (11 mg).
Reaction SMILES: FC(F)(F)C(O[CH2:6][N:7]([N+:9]([O-:11])=[O:10])[CH3:8])=O.[F:14][C:15]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:16][OH:17]>>[F:14][C:15]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:16][O:17][CH2:6][N:7]([N+:9]([O-:11])=[O:10])[CH3:8]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]
Product: CN(COCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]

Procedure:
reacting one mole of 2-nitro-2-azapropyl trifluoroacetate with one mole of 2-fluoro-2,2-dinitroethanol in a polar solvent at a temperature of from 0° C. to 40° C. to form 1-fluoro-1,1,5-trinitro-3-oxa-5azahexane, wherein the reaction is run under vacuum to remove trifluoroacetic acid generated by the reaction; and
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl chlorooxoacetate (72 μL, 0.77 mmol) was added in one portion to a stirred solution of ethyl cis-4-(4-aminophenoxy)cyclohexanecarboxylate (204 mg, 0.77 mmol) and pyridine (76 μL, 0.93 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 1 h. Concentration in vacuo left a residue which was taken up in EtOAc (50 mL) and an aqueous solution of hydrochloric acid (1M, 30 mL) was added. The layers were separated and the organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to leave an oil. The oil was purified by column chromatography, using a gradient of 10-70% ethyl acetate:isohexane as eluent, to give the title compound (Intermediate 108) (188 mg, 70%) as an oil; 1H NMR (CDCl3) δ 1.23-1.28 (3H, t), 1.57-1.68 (2H, m), 1.71-1.78 (2H, m), 1.92-2.04 (4H, m), 2.36-2.43 (1H, m), 3.96 (3H, s), 4.14 (2H, q), 4.43-4.45 (1H, m), 6.89-6.93 (2H, d), 7.51-7.55 (2H, d), 8.76 (1H, s); MS m/e (M−H)− 348.
Reaction SMILES: C(OC(=O)[C@H](O[C:8]1C=C(Cl)N=C(SCC2C=CC=C(F)C=2F)[N:9]=1)C)C.C([O:28][C:29](=O)[C@H:30]([O:32][C:33]1[CH:38]=[C:37]([NH:39][S:40]([N:43]2[CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])[N:36]=[C:35]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:34]=1)[CH3:31])C.CN>C(O)C>[N:43]1([S:40]([NH:39][C:37]2[N:36]=[C:35]([S:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[F:56])[N:34]=[C:33]([O:32][C@H:30]([CH3:31])[C:29]([NH:9][CH3:8])=[O:28])[CH:38]=2)(=[O:41])=[O:42])[CH2:44][CH2:45][CH2:46]1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: CN
Solvent: CCO
Product: CNC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 166 h

Procedure:
To a solution of 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 23) (100 mg) in ethanol (1.5 mL) was added 8M methylamine in ethanol. The resulting mixture was stirred in a sealed tube at ambient temperature for 166 h. The solvent was evaporated under reduced pressure. Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 60 mg MS: APCI (+ve) 474 [M+H+]
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH3:14]>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:12][CH:13]([C:15]1[CH:20]=[C:19]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1cccc(-c2cccc3nc(N)nn23)c1
Yield: 59.8 %

Procedure:
A biphasic solution of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.800 g, 3.76 mmol, 1.00 equiv), 3-(2-propyl)phenyl boronic acid (0.739 g, 4.51 mmol, 1.20 equiv), bis(triphenylphosphine)palladium(II) chloride (0.264 g, 0.376 mmol, 0.100 equiv) in acetonitrile (6 mL) and 1.0M sodium carbonate aqueous solution (6 mL) was heated in the microwave to 160° C. for 2 min. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (20 mL). The collected organic was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (2.5% methanol in dichoromethane) afforded product as a sticky solid (567 mg, 63%). 1H NMR (500 MHz, CDCl3), δ: 7.74 (m, 1H), 7.68 (m, 1H), 7.36-7.48 (m, 4H), 6.79 (dd, J=7.2, 1.3 Hz, 1H), 4.46 (br s, 2H), 3.01 (m, 1H), 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-(trifluoromethyl)benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclobutylethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.81, 7.66, 7.51, 7.34, 3.86-3.66, 3.40-3.34, 2.33, 2.03, 1.86-1.57. 13C NMR (75 MHz, CDCl3) δ 166.0, 162.8, 159.8, 145.5, 138.9, 135.9, 129.8, 128.5, 127.5, 127.3, 125.6, 125.2, 112.7, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 496.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][O:6][CH2:7][CH2:8]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:10]2[CH2:8][CH2:7][O:6][CH2:5][CH:4]2[C:3]([O:2][CH3:1])=[O:25])(=[O:13])=[O:12])=[CH:15][CH:16]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(COCCBr)C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonylamino)-propionic acid methyl ester (0.15 g, 0.35 mmol) dissolved in DMF (2 mL) and cooled in an ice bath was added potassium carbonate (0.16 g, 1.15 mmol) and the reaction was stirred at room temperature for 1 hour. After removing the solvent, the residue was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 0.09 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester as an oil. Yield˜73.8%. Electrospray Mass Spec 354.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:30])[CH:36]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.926, m/z=472.2; 1H NMR (CD3OD) 1.31 (s, 3H), 1.41 (s, 1H), 1.58 (d, 3H), 2.30 (m, 2H), 2.34 (m, 1H), 2.43 (m, 1H), 2.61 (d, 2H), 2.81 (s, 3H), 3.21 (m, 1H), 5.62 (m, 1H), 7.08 (m, 2H), 7.29 (d, 2H), 7.41 (m, 2H), 7.79 (d, 2H), 8.09 (m, 1H), 8.19 (s, 1H), 8.68 (d, 1H).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Subsequently, Ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-neopentyloxybenzonitrile (80.5 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. After ice-cooling, the reaction mixture was filtrated and the solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g), melting point: 55–56° C.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 115 °C
Yield: 40 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride was dissolved in dimethyl sulfoxide (1.0 mL). 2-Chloro-5-(trifluoromethyl)pyridine (28.0 mg, 0.154 mmol, 1.5 equivalents) and sodium carbonate (65.5 mg, 0.618 mmol, 6.0 equivalents) were added, and the resulting suspension was heated to 115° C. for 14 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges, eluting with 25:75 to 0:100 heptanes:ethyl acetate to give the titled compound (16 mg, 40% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.42 (s, 1H), 7.96 (dd, J=14.0, 1.2 Hz, 2H), 7.67 (dd, J=9.0, 2.4 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H), 5.48 (t, J=4.0 Hz, 1H), 4.81 (d, J=14.6 Hz, 1H), 4.37-4.32 (m, 1H), 4.19-4.10 (m, 1H), 4.04 (dd, J=13.9, 2.2 Hz, 1H), 3.73 (dd, J=13.8, 4.1 Hz, 1H), 3.54-3.36 (m, 1H), 3.04 (dd, J=14.5, 9.4 Hz, 1H), 2.75 (dd, J=6.6, 3.6 Hz, 2H), 2.55 (dd, J=13.8, 5.1 Hz, 1H), 2.05-1.95 (m, 2H), 0.98-0.91 (m, 4H); 1H NMR (400 MHz, pyridine-d5) δ ppm 8.63 (s, 1H), 8.16 (d, J=1.1 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.52 (t, J=4.0 Hz, 1H), 4.82 (d, J=14.5 Hz, 1H), 4.53-4.24 (m, 3H), 3.92 (dd, J=13.6, 4.1 Hz, 1H), 3.40 (ddd, J=14.7, 10.2, 1.9 Hz, 1H), 3.07 (dd, J=14.5, 9.4 Hz, 1H), 2.89-2.72 (m, 2H), 2.65-2.47 (m, 1H), 2.11-1.91 (m, 2H), 1.10-0.97 (m, 2H), 0.97-0.81 (m, 2H); MS (ESI+) m/z 434.1 (M+H)+; [α]D24.8=−3.2 (c=0.41, CH3OH).
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC4(CC3)OCCO4)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)O
Solvent: O
Product: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC(=O)CC3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 70.4 %

Procedure:
A mixture of N-{[8-(benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.21 g) and acetic acid (15 mL) was added at 80° C. for 24 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.79 g, yield 71%) as a colorless amorphous solid from a fraction eluted with tetrahydrofuran-methanol (1:1, volume ratio). MS: 568 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36].C[O-].[Na+:40]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O-:37])=[O:36].[Na+:40]
Reactant: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
6-Chloro-7-(4-(4-(trifluoromethylthio) phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (58.7 mg, 0.106 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (213 μL, 0.106 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (60.0 mg, 0.105 mmol, 98.3% yield) as a solid. MS (apci) m/z=552.0 (M+2H-Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][CH2:43][CH:36]12)[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:42]4[CH2:41][CH:37]5[CH:36]([N:35]([CH2:33][CH3:34])[CH2:40][CH2:39][CH2:38]5)[CH2:43]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: CCN1CCCC2CNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC2CN(CCCOc3cc4c(Nc5ccc(F)c(Cl)c5)ncnc4cc3OC)CC21
Temperature: 80 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.50 g), K2CO3 (5.00 g) and 1-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.90 g) in 25 mL of DMF was stirred for 7 h at 80° C., and then cooled down. The resulted mixture was poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.75 g, 38.60%), HPLC: 98.30%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 514.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.03 (t, J=4.6 Hz, 3H), 1.52-1.62 (m, 2H), 1.97-2.00 (m, 3H), 2.07-2.09 (m, 2H), 2.08-2.11 (m, 4H), 2.40 (q, J=4.6 Hz, 2H), 2.51-2.56 (m, 1H), 2.57-2.61 (m, 2H), 2.88-2.92 (m, 2H), 3.94 (s, 3H), 4.18 (t, J=8.6 Hz, 2H), 7.19 (s, 1H), 7.44 (t, J=10.4 Hz, 1H), 7.82 (s, 2H), 8.13 (t, J=6.8 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]3=[O:26])=[C:11]([N+:27]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:27][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]1=[O:26]
Reactant: [H][H]
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2N)C1=O

Procedure:
Prepared by reduction of 1-(4'-cyano-3-nitro-4-biphenylyl)- 3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one with hydrogen at 5 bars in the presence of 5% palladium/charcoal in ethyl acetate at ambient temperature.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 444 (M+H+, 100).