Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]([CH2:28][CH3:29])=[N:16][C:11]=3[CH:12]=[N:13][C:14]=2[CH:15]=1)(=[O:4])=[O:3].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]([CH2:28][CH3:29])=[N:16][C:11]=3[C:12]([NH2:42])=[N:13][C:14]=2[CH:15]=1)(=[O:3])=[O:4]
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Reaction time: 0.42 h

Procedure:
2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate (0.625 g, 1.52 mmol) was dissolved in chloroform (15 mL). 3-Chloroperoxybenzoic acid (60% pure, 0.437 g, 1.52 mmol) was added in one portion, and the reaction was stirred for 25 minutes. Ammonium hydroxide (25 mL) was added. A precipitate formed, and the reaction was stirred until the precipitate dissolved. p-Toluenesulfonyl chloride (0.290 g, 1.52 mmol) was added in one portion, and the reaction mixture was stirred for an additional 16 hours. The layers were separated, and the aqueous fraction was extracted with dichloromethane followed by chloroform. The organics were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (eluting with a chloroform:methanol:ammonium hydroxide gradient) followed by recrystallization from acetonitrile provided 0.150 g of 4-amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate as an orange solid, mp 213.0-214.5° C.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-benzo[d][1,3]oxazine-2,4-dione (1.63 g, 10.0 mmol) in anhydrous DMF (20 mL) was added 4-trifluoromethyl-aniline (1.61 g, 10.0 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. It was then cooled to room temperature, diluted with ethyl acetate (150 mL), and the organic phase was washed with water (100 mL), 10% aq. NaOH solution (100 mL), water (150 mL), brine (150 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and the crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-N-(4-trifluoromethyl-phenyl)-benzamide as an off-white solid. Yield: 0.2 g (7%).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][C:34]([CH3:39])=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41]>C(O)(C)C>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][C:34]([CH3:39])=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1nc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2cc1F
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 0.48 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 4.7 mL of isopropyl alcohol, 0.44 mL of concentrated hydrochloric acid was added, the temperature was increased to 60° C. and the mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, and the solid was filtered off to obtain 0.33 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Yield: 75 %

Procedure:
1-Benzyl-3-(4′-hydroxymethylphenyl)indazole was reacted with succinic anhydride according the procedure described in Example 1 (d) to afford Compound 9 in a yield of 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10](O)=O.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=1.O.N>P(Cl)(Cl)(Cl)=O.CO>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10]1[NH:20][C:19]2[C:14]([N:13]=1)=[N:15][CH:16]=[CH:17][CH:18]=2
Reactant: Nc1cccnc1N
Reactant: COc1cc(SC)sc1C(=O)O
Agent: N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1cc(SC)sc1-c1nc2ncccc2[nH]1

Procedure:
6.83 g (33.4 mmoles) of 3-methoxy-5-methylthio-2-thiophene carboxylic acid (formula (II): R=CH3, R2 =SCH3) are refluxed together with 3.65 g (33.4 mmoles) of 2,3-diaminopyridine (formula III): R1 =H) in 80 ml of phosphorous oxychloride for 3 hours. The reaction mixture obtained is then introduced in portions into about 1.5 l of cold water, stirred well, filtered over Hyflo, made alkaline with potassium carbonate and some ammonia, and extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The dark residue is suspended in about 300 ml of methanol, an excess of methanolic hydrochloric acid is added, heated to boiling, activated charcoal is added, filtered, and the solution is concentrated to about 100 ml and allowed to cool. A yellow hydrochloride precipitate of (I) is removed by suction and washed with a small amount of methanol. For preparing the free base, these crystals are suspended in 28 ml of methanol, 1.2 g of a 25% aqueous solution of ammonia are added, 80 ml of water are added, and the yellow crystalline precipitate is removed by suction, washed with water and dried. Yield: 4.24 g (46%), m.p. (ethanol) 224° C. (dec.).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:2]
Reactant: ClCc1ccccn1
Reactant: C#CCNC(=NCCS)NC#N
Agent: Cl
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
The ethanolic solution of the product of Step A is reacted with about an equimolar amount of 2-chloromethylpyridine hydrochloride and about two equivalents of base to produce the title product.
Reaction SMILES: [CH2:1]([O:12][P:13]([OH:16])([OH:15])=[O:14])[C@H:2]1[O:7][C@H:6]([OH:8])[C@H:5]([NH2:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[C:17](N1C(=O)CCC1=O)(=[O:19])[CH3:18]>C1COCC1.O>[CH3:18][C:17]([NH:9][CH:5]1[CH:6]([OH:8])[O:7][CH:2]([CH2:1][O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:3]([OH:11])[CH:4]1[OH:10])=[O:19]
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O[C@@H]1O
Reactant: CC(=O)N1C(=O)CCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC1C(O)OC(COP(=O)(O)O)C(O)C1O

Procedure:
In one process, GlcN-6-P was acetylated in THF/water using N-acetylsuccinimide (NAS) to form GlcNAc-6-P. Acetic anhydride can also be used. That N-acetyl compound was treated with an enzyme preparation from Candida utilis containing N-acetylglucosamine phosphomutase (EC 2.7.5.2) and UDP-GlcNAc pyrophosphorylase (EC 2.7.7.23) to first form GlcNAc-1-P and then UDP-GlcNAc in the presence of UTP and inorganic pyrophosphatase (EC 3.6.1.1) to destroy the inorganic pyrophosphate formed.
Reaction SMILES: C(S[O:4][C:5](=O)[C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])C.C([SiH](CC)CC)C>CC(C)=O.[Pd]>[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[CH:5]=[O:4])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCSOC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of (2R)-N-BOC-proline ethylthioester, prepared in Step A, in acetone were added dropwise triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0° C. When no further gas evolution occurred, the reaction mixture was warmed to rt and then stirred for additional 30 min. The reaction solution was filtered though Celite, the filtrate concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (1.43 g, 93.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Temperature: 95 °C
Reaction time: 13 h
Yield: 17.2 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.5 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.4 g, 2 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.6 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 13 hours, M−1=404. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane and further purified by HPLC to give 0.12 g of the title compound as a pale yellow solid. MS (m/z)=406 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][SH:39]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][S:39][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=1)[N:15]=[CH:14][CH:13]=[CH:12]3
Reactant: COC(=O)CCS
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 20 (215 mg, 0.422 mmol) in CH2Cl2 (4.2 mL) and TFA (98 μL, 1.26 mmol) was added methyl-3-mercaptopropionate (56 μL, 0.506 mmol). The solution was stirred at ambient temperature for 5 hours when LCMS analysis indicated complete conversion of the starting materials to the products. The solution was dried under reduced pressure and azeotroped with CH2Cl2 three times to provide the product 23 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.30-2.38 (m, 4H), 3.63 (s, 3H), 4.04 (s, 3H),4.42 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=15 Hz), 5.49 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=5, 8 Hz), 7.59 (dd, 1H, J=4,9 Hz), 8.53 (d, 1H, J=8 Hz), 8.91-9.01 (m, 1H); 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 457.3 [MH+], 479.2 [M+Na].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(F)ccc1CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)ccc1CCC=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.1 %

Procedure:
To the solution of the product of example 133 (1.0 g, 4.3 mmol) in dichloromethane (100 ml), was added Pyridinium Chlorochromate (1.65 g 6.4 mmol) at 0° C. The mixture was stirred at room temperature for 5 hours. The result mixture was washed with water, and the organic layer was dried over Na2SO4. The product was purified by column chromatography to give the titled compound (555 mg, yield 58%)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
0.226 g (0.001 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.350 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chloro-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.28 g (77%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as colorless crystals; m.p. 67°-69°.
Reaction SMILES: [CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([CH:13]=[O:14])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([Mg]Cl)[CH2:29][CH3:30].C(OCC)C.[Cl-].[NH4+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(Cl)Cl>[C:13]([C:11]1[S:10][C:9]([CH2:15][CH3:16])=[C:8]([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1)(=[O:14])[CH2:28][CH2:29][CH3:30]
Reactant: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Reactant: CCC[Mg]Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC(=O)c1cc(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)c(CC)s1
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of methyl 4-{[cyclohexyl(2-ethyl-5-formylthiophen-3-yl)methyl]amino}benzoate (500 mg) synthesized in Example 287 (6) in tetrahydrofuran (10 mL) was added dropwise 2.0M n-propylmagnesium chloride-diethyl ether solution (1.63 mL) at −45° C., and the mixture was stirred for 2 hr under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil. To a solution of the obtained oil in methylene chloride (10 mL) was added Dess-Martin reagent (827 mg) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous sodium sulfite solution was added to quench the reaction, methylene chloride was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give the title compound (316 mg, 57%) as a colorless oil.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])C)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.S(=O)(O)[O-:17].[Na+].Cl>O>[CH2:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:17])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred 6% aqueous sodium hypochlorite solution in an oil bath to 55° C. is added 1-indane-5-yl-ethanone (1.0 g, 6.2 mmol). The solution is stirred at 55° C. for 2 h, followed by cooling to rt. Solid sodium bisulfite is added until the solution became clear. The mixture is diluted with water, followed by aqueous hydrochloric acid (6.0 M). The solid that forms is filtered and washed several times with water. The solid is dried under high vacuum at 60° C. for 5 h to afford Acid C6 as a white solid (0.96 g, 95%): 1H NMR (CDCl3) δ 8.0, 7.9, 7.3, 3.0, 2.1.
Reaction SMILES: [Li].C([O:4][C:5](=[O:18])[C:6](O)=[CH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)C.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].[OH-].[K+].Cl>C(O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[C:8]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:7][C:6]([C:5]([OH:4])=[O:18])=[N:28]1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)C(O)=CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [Li]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-(4-Chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester lithium salt I-6a (30.26 g, 116 mmoles) was suspended in 242 ml of ethanol. 2-Chlorophenylhydrazine hydrochloride (20.88 g, 116 mmoles) was added portionwise as a solid over 45 minutes while maintaining an internal temperature between 30–40° C. Note: Reaction mixture goes from a yellow suspension to a dark orange suspension. Reaction stirred for 3 hours while maintaining internal temperature between 25–35° C. An aqueous potassium hydroxide solution (148 ml of 1.8 M solution, 266 mmoles) was added over 20 minutes while maintaining an internal temperature between 20–30° C. The reaction mixture was held for 2.5 hours. Note: Within 30 minutes of potassium hydroxide solution addition, reaction turned almost clear, very dark rust orange in color. Aqueous hydrochloric acid (85 ml of 3.9 M solution, 331 mmoles) was added over 15 minutes while maintaining reaction temperature between 20–30° C. Note: Product precipitated during hydrochloric acid addition. The precipitated product was granulated for 16 hours at room temperature. The crude product was isolated by filtration and the filtercake was washed with 150 ml of water. Note: Filtercake was a yellowish orange solid. After air-drying for 30 minutes, the filtercake was suspended in 480 ml of methanol. This suspension was heated to reflux to give a clear dark orange solution (all solids in solution within 1 hour of reaching reflux) that was held at reflux for 8 hours. The solution was cooled over 4 hours to room temperature, during which time product had precipitated from solution. The reaction mixture was held at room temperature for 10 hours, followed by cooling to 0° C., and stirring for 1.5 hours. Collection of the precipitate by filtration, washing the resulting filtercake with 150 ml of ice-chilled methanol, and drying at 60° C. and 1 mm for 3 hours afforded 1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6b (29.28 g, 76%) as an off-white solid.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[Br:18][CH2:19]C#N>ClCCl>[Br:18][CH2:19][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CCBr
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: BrCc1nsc2nc3ccccc3n12
Yield: 76.9 %

Procedure:
A solution of 2-butyl-1,2,4-thiadiazolo[4,5-α]benzimidazole-3(2H)-one (15 g, 60.65 mmol) and bromoacetonitrile (18.19 g, 151.6 mmol) in dichloromethane (150 mL) was stirred for 48 h. A white precipitate was formed and the insoluble solid was filtered to give 12.50 g (77%) of the title compound: 1H NMR (CDCl3) δ 4.79 (s, 2H, CH2), 7.42 (t, 1H, ArH), 7.51 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.94 (d, 1H, ArH); mp 242-244° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[Cl:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.[C:57]([O:60][CH2:61]C)(=[O:59])C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:49][C:48]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[C:37]1[CH:38]=[C:39]2[C:31]([C:57]([O:60][CH3:61])=[O:59])=[C:32]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)[O:33][C:34]2=[N:35][CH:36]=1
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3Cl)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (28 mg, 0.067 mmol) was added to a stirring solution of palladium(II) acetate (7.5 mg, 0.034 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (75 mg, 0.17 mmol) in MeOH (0.6 mL) and DMSO (1.1 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (75 mg, 0.113 mmol, 67% yield) by LCMS. LC-MS retention time: 2.28 min; m/z (MH+): 427. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Product: O=C(Nc1cccc(Cl)c1)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid (3-chloro-phenyl)-amide was obtained starting from 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and 3-chloro-phenylamine. The desired product was obtained as a brownish orange powder. ESI−MS: m/z 301 (MH+); 1H-NMR (DMSO-d6): δ6.96-7.00 (1H, m), 7.27-7.29 (2H, m), 7.35 (1H, dd, J=1.3 Hz, 4.6 Hz), 7.98-7.99 (1H, m), 8.53 (1H, d, J=1.0 Hz), 8.74 (1H, d, J=4.6 Hz), 10.92 (1H, brs).