Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-]>CO.O>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([O:23][CH3:1])=[O:22])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20% aqueous solution of cesium carbonate was slowly added to a mixture of 14.2 g of 10 in 230 ml of methanol and 23 ml of water, until the mixture was neutral (about 50 ml of the carbonate solution). The solvent was evaporated under reduced pressure. The residue was placed in 50 ml of dimethylformamide and stripped twice. The residue was placed in 150 ml of dimethylformamide and 50 ml of methyl iodide was added to the mixture, which then was stirred overnight at room temperature. The mixture was filtered, and a large volume of methylene chloride was added to the filtrate. The filtrate was washed with a large volume of water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane, the mixture was filtered, and the solvent was evaporated from the filtrate to give 13, as a tan solid, m.p.: 46°-48° C.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH3:24][S:25]([Cl:28])(=[O:27])=[O:26]>CC(C)=O>[ClH:28].[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: CC(C)=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccccc3)CC21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylarnine (Preparation 8, 1.00 g, 3.26 mmol) in acetone (5 ml) at 0° C. was added methanesulfonyl chloride (0.28 ml, 3.58 mrol) and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration to afford the title compound as a white crystalline solid (1.19 g, 87%).
Reaction SMILES: [N+](C1C=CC(C[N:9]2[CH:12]([CH2:13][CH2:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[CH:11]([N:20]3[C@@H:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][O:22][C:21]3=[O:31])[C:10]2=[O:32])=CC=1)([O-])=O.[C:35]([O-:38])(=[O:37])[CH3:36].[I-].[Li+]>C(OCC)(=O)C>[C:25]1([C@H:24]2[CH2:23][O:22][C:21](=[O:31])[N:20]2[CH:11]2[CH:12]([CH2:13][CH2:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[NH:9][C:10]2=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:35]([OH:38])(=[O:37])[CH3:36]
Reactant: O=C1C(N2C(=O)OC[C@@H]2c2ccccc2)C(CCc2ccco2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(=O)O
Product: O=C1NC(CCc2ccco2)C1N1C(=O)OC[C@@H]1c1ccccc1

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 1 using 2.60 g (5 mmol) of p-nitrobenzyl-3-[(S)-4-phenyloxazolidin-2-one-3-yl]-4-[2-furylethyl]-azetidin-2-one-1-ethanoate, 20 ml of ethyl acetate and 2.0 g (15 mmol) of lithium iodide. The reaction mixture was allowed to react for approximately 71/2 hours at reflux temperature to provide 1.54 g of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:35]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Nc1ccc(-c2ccncc2)cc1Cl
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(-c5ccncc5)cc4Cl)cc23)CC1

Procedure:
The title compound was prepared in a similar manner to Example 1 from 2-chloro-4-(pyridin-4-yl)aniline (D11, 0.18 g, 0.88 mmole), 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (D2, 0.15 g, 0.66 mmole), triphosgene (0.10 g, 0.34 mmole) and triethylamine (0.3 ml). This was obtained as a pink-white solid (0.20 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32]CC)=O)=O)[CH2:13][CH2:12]1.O.[NH2:36][NH2:37]>C(O)C>[NH2:36][N:37]1[C:30](=[O:32])[C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[N:23]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1
Reactant: NN
Reactant: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Solvent: O
Solvent: CCO
Product: Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Reaction time: 4 h
Yield: 51 %

Procedure:
In 120 ml of ethanol, 8.0 g of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate as synthesized in above Step 4-1-C was dissolved, and to the solution 60 ml of hydrazine monohydrate was added, followed by 4 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 3.8 g (51%) of 3-amino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]c1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E and substituting 5-methyl-2(1H)-pyridone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.42 Hz, 1H) 7.88 (d, J=2.18 Hz, 1H) 7.42 (dd, J=8.58, 2.03 Hz, 1H) 7.28 (dd, J=9.36, 2.50 Hz, 1H) 7.15 (s, 1H) 6.62 (d, J=9.36 Hz, 1H) 3.59-3.69 (m, 1H) 3.15-3.25 (m, 1H) 3.01-3.10 (m, 1H) 2.77-2.85 (m, 1H) 2.60-2.67 (m, 1H) 2.33-2.56 (m, 3H) 2.12 (s, 3H) 1.93-2.03 (m, 1H) 1.79-1.88 (m, 1H) 1.68-1.77 (m, 1H) 1.45-1.64 (m, 2H) 1.16 (s, 3H). MS: (M+H)+=380.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][C:3]=2[O:2]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C1COCC1.CCOCC>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[O:14])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3-(3,4methylenedioxyphenyl)-propionic acid (501 mg, 2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28 mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C. After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg, 2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture. After 30 min the temperature was allowed to warm up to rt and stir for 24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1 N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a solid. The residue was taken up in Et2O, filtrated and washed with Et2O gave the title compound as a white solid (62%) in a 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([CH2:6][C:7](OCC)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[C:12]1([CH:20]=[C:18]([OH:19])[CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13]>>[OH:13][C:12]1[CH:20]=[C:18]([OH:19])[CH:17]=[C:15]2[C:14]=1[C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7](=[O:8])[O:16]2
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCc1cc(=O)oc2cc(O)cc(O)c12

Procedure:
condensing ethyl butyrylacetate and phloroglucinol in the presence of an acid catalyst to form 5,7-dihydroxy-4-propylcoumarin;
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[ClH:39].CCOCC>O1CCOCC1>[ClH:39].[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cccc(OC(F)F)c4)c3)c(F)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
(S)-tert-butyl 2-(4-(1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylate (102 mg, 0.2 mmol) was dissolved in dioxane (0.75 ml) and a solution of HCl in dioxane (4M, 0.75 ml, 3 mmol) was added. The reaction mixture was stirred for 90 min at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(3-(difluoromethoxy)phenyl)-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-1H-pyrazole-4-carboxamide hydrochloride (84 mg, 91%) as a white solid. MS (ISP): 433.2 ([M+H]+).
Reaction SMILES: [CH3:1]C(C)[O-].[Na+].[Na].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[NH:11][C:12]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(OC)(OC)(=O)=O>C(O)(C)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[N:11]([CH3:1])[C:12]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CC(C)[O-]
Reactant: N#CCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)[nH]1
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
To a refluxing solution of sodium isopropoxide in isopropanol (prepared by refluxing 0.69 g. (0.030 mole) of sodium in 70 ml. of isopropanol) is added 7.0 g. (0.025 mole) of 4-chloro-5-(p-chlorobenzoyl)-pyrrole- 2-acetonitrile prepared according to Example VIII, after which a solution of 3.78 g. (0.030 mole) of dimethyl sulfate in 10 ml. of isopropanol is added dropwise. When addition of the dimethyl sulfate solution is complete, the whole is refluxed for a half-hour and then poured into 1 liter of ice water. Filtration of the resulting mixture yields a grey solid, which is washed well with water and is then chromatographed with benzene on alumina. The chromatographed material is finally recrystallized from isopropanol to yield 4-chloro-5-(p-chlorobenzoyl)-1-methyl- pyrrole-2-acetonitrile as a beige solid; m.p. 139°-142° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:12][C@H:10]1[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (20.05 g, 107 mmol, MC09PH1559, Pharmacore) and triethylamine (22.34 mL, 161 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (200 mL) was cooled to −30° C. and methanesulfonyl chloride (9.94 mL, 129 mmol, Sigma-Aldrich Chemical Company, Inc.) was added dropwise over 20 min period. The mixture was stirred at room temperature for 12 h, washed with 200 mL water, then 200 mL 10% aq. citric acid followed by brine, dried over Na2SO4 and evaporated to give the title compound (29 g, 109 mmol, 102% yield). It was used in the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][C:12]1[C:14]2[C:15](=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])[C:21](=[O:23])[NH:2][N:3]=1
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(Br)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
Hydrazine hydrate (0.110 mL, 1.48 mmol) was added to methyl 4-(2-(3-bromophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (49) (0.470 g, 1.34 mmol) in acetic acid (20 mL). The resulting solution was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a beige solid (0.253 g, 56.7% yield); 1H NMR (400.132 MHz, MeOD) δ 2.18 (3H, s), 2.50 (3H, s), 4.03 (2H, s), 7.04-7.11 (2H, m), 7.25 (2H, m); m/z (LC-MS, ESI+), RT=1.84 min (M+H=333.97).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1.O>[CH:1]1([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[NH:11][C:17]2=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccnc1NC1CC1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2nccnc2n1C1CC1
Yield: 41.4 %

Procedure:
To a solution of N2-cyclopropylpyrazine-2,3-diamine (2.0003 g, 13.32 mmol) in THF (66.6 ml) at 50° C. was added CDI (8.64 g, 53.3 mmol, Fluka) and stirred. The reaction flask was place in an ice bath until temperature reached 0° C. The flask was raised and water (10 mL) was added dropwise to quench. (Note: if exothermic reaction was detected then flask was placed back into ice bath until it stopped.) The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. NMR showed product and imidazole. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 1% to 6% MeOH in CH2Cl2, to provide the title compound (0.9715 g, 5.51 mmol, 41.4% yield). LCMS showed product peak at 1.00 min (m+1=177.1) 1H NMR (400 MHz, DMSO-d) δ ppm 0.94-1.02 (m, 2 H) 1.02-1.08 (m, 2 H) 2.89-3.00 (m, 1 H) 7.84-7.89 (m, 1 H) 7.89-7.94 (m, 1 H) 11.87 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([O:37]C)=[O:36])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([OH:37])=[O:36])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)Cc1ccc(CCNC(=O)c2ccc(Oc3cc4c(cc3C#N)C(C(=O)O)CCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a stirred solution of methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (83 mg, 0.16 mmol) in methanol (1 mL) at ambient temperature was added a 2M solution of sodium hydroxide (0.40 mL, 0.80 mmol). After stirring at ambient temperature for 1 hour the solution was concentrated, and the residual solid was redissolved in water (5 mL). The pH was adjusted to 4.5 to precipitate the product, and chloroform (5 mL) was added. After stirring the multiphase mixture for a few minutes, the product separated as a thick oil on the side of the flask. The chloroform/water mixture was decanted away and the residue dried under vacuum to afford 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as a light yellow glass (23 mg, 28% yield). MS (apci) m/z=500.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[NH:12]1[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:15]=2[CH:14]=[CH:13]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[C:15]=3[CH:14]=[CH:13]2)(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(c1cc(Cl)c(Cl)s1)n1ccc2c(N3CCNCC3)nccc21

Procedure:
4,5-Dichloro-thiophene-2-sulfonyl chloride (32.4 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (0.3 mg). LC/MS RT: 1.119 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 92%. MS: 418 (M+1).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:12]=2[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=1>[Fe].O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]([O:27][CH3:28])=[CH:13][CH:14]=[C:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1-c1cccc(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(N)cc2)cc1-c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed iron powder (586 mg, 10.5 mmol), ethanol (12 mL) and water (3.8 mL). The mixture was heated to 85° C. in an oil bath and then I-270 (1.05 g, 3.00 mmol) was added and the reaction was continued at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. To the filtrate was added water (60 mL) and extractions were performed with ethyl acetate (2×60 mL). The organic portions were combined, washed with brine (60 mL), dried (MgSO4) and concentrated to produce 862 mg of I-271 as a pale orange viscous oil in 89% yield. MS (APCI+): 324.1 (M+1); LC-MS: 97%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:27]N(C=O)C.CO>C(Cl)Cl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([O:18][CH3:27])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (440 mg) and thionyl chloride (0.131 ml) in methylene chloride (8 ml) was added DMF (0.14 ml) and the solution was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature before the addition of methanol (5 ml) and stirring continued for 2.5 hours. The reaction mixture was concentrated and then dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2×), brine, dried (magnesium sulfate) and concentrated to yield the crude methyl 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoate as a brown solid (419 mg); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.87 (s, 3H), 6.65 (d, 1H), 7.11 (d, 1H), 7.23 (d, 1H), 7.57-7.62 (m, 3H), 7.80 (s, 1H), 7.97 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M+Na+ 332.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Li+].[Cl-].C([Cu])#N.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>C1COCC1>[Cl:1][C:2]1[C:7]([C:19]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[O:20])=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(Cl)c1ccco1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1.0 M solution in THF, 1.1 mL, 1.1 mmol) was slowly added at −20° C. and the reaction mixture was stirred at the same temperature for 30 min. Then, furan-2-carbonyl chloride (261 mg, 2.0 mmol) was dropwise added at −20° C. and the resulting mixture was allowed to warm up slowly to 25° C. overnight. The reaction mixture was quenched with a sat. aq. NH4Cl solution (30 mL), extracted with diethyl ether (5×30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:1) furnished 8b as a colourless solid (172 mg, 71%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[CH3:36]O>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH3:36])=[O:17])=[O:7])=[CH:29][CH:28]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: CO
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound was isolated as a mixture of two isomers in 88.3% purity by HPLC.