Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]([OH:6])([C:4]#[C:5][CH2:10][C:9]([CH3:11])=[CH2:8])[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: C=C(C)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: C=C(C)CC#CC(C)(C)O
Yield: 65 %

Procedure:
The coupling reaction was conducted in the manner described in the procedure of Example VI using the following reagents: 1.00 mL (10.3 mmoles) of 2-methyl-3-butyn-2-ol, 1.10 mL (11.1 mmoles) of 3-chloro-2-methylpropene, 2.34 g (16.9 mmoles) of anhydrous potassium carbonate, 89 mg (0.90 mmole) of cuprous chloride, and 165 mg (0.72 mmole) of benzyltriethylammonium chloride. Isolation of the product in the usual manner afforded 925 mg (65%) of the named alcohol, thereby demonstrating the lack of need for a solvent in this coupling reaction.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]([OH:8])[CH2:6][CH:7]=1.C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Cl:22][CH2:2][C:3]1[CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]([OH:8])[CH2:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)CC1C(CO)=CCC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(O)CC1C(CCl)=CCC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-hydroxymethyl-1-hydroxycyclopent-3-en-2-yl]acetic acid, Ʊ-lactone, the compound of formula (1), (188 mg, 1.22 mmol) in 10 ml of methylene chloride was added 4-dimethylaminopyridine (119 mg, 0.97 mmol), followed by p-toluenesulfonyl chloride (280 mg, 1.46 mmol) and triethylamine (123 mg, 1.22 mmol). After stirring for 2 hours at room temperature, the mixture was diluted with diethyl ether (80 ml), filtered and the filtrate washed successively with aqueous 10% copper sulfate (50 ml), 10% aqueous sodium bicarbonate (50 ml) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 70/30) to give 165 mg of [3-chloromethyl-1-hydroxycyclopent-3-en-2-yl]acetic acid, Ʊ-lactone, m.p. 33°-34° C., the compound of formula (2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=O)[C:8](=[O:17])[CH:7]=[CH:6]2)#[CH:2].[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH2:24])[S:22][CH:23]=1>>[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH:24][C:14](=[O:16])[CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[CH:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:17])[S:22][CH:23]=1
Reactant: C#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: C#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Br)c2-c2ncn[nH]2)c1

Procedure:
The title compound was synthesized from 2-(6-ethynyl-2-oxoquinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.563, method [7], MS (ESI) 454.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.07 (d, J=9.35 Hz, 1H), 8.01-7.97 (m, 1H), 7.68-7.63 (m, 1H), 7.50 (d, J=8.80 Hz, 1H), 7.30 (s, 1H), 6.80 (d, J=9.9 Hz, 1H), 5.27 (s, 2H), 4.23 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([NH2:19])(=[O:18])=[O:17]>O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]2[C:6](=[O:2])[NH:19][S:16](=[O:18])(=[O:17])[C:8]=2[CH:9]=1)([O-:15])=[O:14]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C1NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 42 h
Yield: 68 %

Procedure:
To a solution of CrO3 (20.8 g, 208 mmol) in water (150 mL) was slowly added concentrated sulfuric acid (190 mL). To the resulting mixture was added 2-methyl-5-nitrobenzenesulfonamide (10.0 g, 46.3 mmol) and the mixture was stirred at rt for about 42 h. The mixture was filtered and the filter cake was washed with water (100 mL). The solid was dissolved in 10% aqueous NaHCO3, filtered and the filtrate acidified with 2 N HCl (pH=1). The precipitate was collected by filtration and washed with water (2×50 mL) to provide 6-nitro-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[d]isothiazol-3-one (7.2 g, 68%). 1H NMR (DMSO-d6) δ: 8.42-8.53 (m, 2H), 8.00 (s, 1H), 3.70 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][OH:35])=[N:6][N:7]2[CH2:32][CH3:33]>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=[O:35])=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1nc(CO)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1nc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a yellow solution of 5-chloro-1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)cinnolin-4(1H)-one (6 g, 8.45 mmol) in Dichloromethane (DCM) (100 mL) was added manganese dioxide (12.11 g, 118 mmol), and the mixture was stirred at r.t. overnight. Solid was filtered off and washed with DCM. The filtrate was concentrated to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (4 g, 4.79 mmol, 56.7% yield) as a crude dark brown solid. LCMS: (M+H)+: 509.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH3:31])[C@@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN[C@@H]1CCCNC1=O
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)[C@@H]1CCCNC1=O

Procedure:
(3R)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidin-2-one (Example 87) was reacted with 37% aqueous formaldehyde using an analogous method to that described for the equivalent step in Example 86 to give the title product; 1H NMR Spectrum: (DMSO d6) 1.77 (m, 3H); 2.02 (m, 1H); 2.40 (s, 3H); 3.09 (m, 2H); 3.29 (dd, 1H); 3.95 (s, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.40 (brs, 1H); 7.48 (t, 1H); 7.55 (m, 1H); 8.35 (s, 1H); 8.42 (s, 1H); 9.76 (s, 1H). Mass Spectrum: (M+H)+ 444.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:41].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
[2′-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester (1.09 g, 2.0 mmol) in CH2Cl2 (10 mL) was treated with 4N HCl in 1,4-dioxane (6 mL, 24.0 mmol) at room temperature, until complete conversion was seen by analytical LCMS. The mixture was concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nncn2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nncn3C)c2)nc1
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)benzoate (0.37 g, 1.20 mmol) in THF (5 mL) was added lithium hydroxide (86 mg, 3.60 mmol) in 5 mL of water. After 16 h, the reaction was acidified to pH 1 by 1 M HCl. The solution was concentrated and dried under vacuum to give the hydrochloride salt of the title compound (0.43 g). MS 295.0 (M+1).
Reaction SMILES: C1(=O)N([CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:25])[CH2:16][CH2:17][N:18]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]2=[O:24])[C:7]([O-:9])=[O:8])C(=O)CC1>OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].CS(C)=O>[CH2:21]1[C:22](=[O:23])[N:18]([O:9][C:7]([CH2:6][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH2:16][CH2:17][N:18]2[C:19](=[O:24])[CH:20]=[CH:21][C:22]2=[O:23])=[O:25])=[O:8])[C:19](=[O:24])[CH2:20]1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCCCC(C(=O)[O-])N1C(=O)CCC1=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Product: O=C(CCN1C(=O)C=CC1=O)NCCCCCC(=O)ON1C(=O)CCC1=O

Procedure:
To a sample bottle (8 mL volume), it was charged by 0.39 mL of human CO hemoglobin (Hb) solution (509 μM), and diluted with 1.61 mL of phosphate buffered saline solution (PBS) to be 0.1 mM 2 mL. Next, 7.6 mg of succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH, manufactured by Pierce Corporation) was dissolved in 0.25 mL of dimethyl sulfoxide (DMSO) to prepare 80 mM dimethyl sulfoxide (DMSO) solution of succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH). To the above human hemoglobin (Hb) solution (2 mL), it was added with 0.047 mL of succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH) solution (succinimidyl-6-(β-maleimidopropionamido)hexanoate/human hemoglobin (SMPH/Hb) =18 (mol/mol)), while stirring (100 rpm), and stirred at room temperature for 30 minutes. From the resultant reaction solution, unreacted succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH) was removed by the same method as the method described in Preparation Example 2 in Example 1. Specifically, 2.1 mL of human hemoglobin (Hb) solution was moved to a centrifugal concentrator (Vivaspin 20), diluted with about 18 mL of phosphate buffered saline solution (PBS) to ten times, and then concentrated to about 1.0 mL ( 1/10) at 4000 rpm, for 30 minutes and at 4° C. To that, it was added with 19 mL of phosphate buffered saline solution (PBS), and concentrated to about 1.0 mL under the same conditions. By repeating this dilution/concentration operation three times, unreacted succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH) was removed. Lastly, a sample in a tube was moved to a sample bottle (8 mL volume), and the total volume was adjusted with phosphate buffered saline solution (PBS) to 2.0 mL. The human hemoglobin-crosslinker conjugate (Hb-SMPH) concentration became 0.1 mM.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11](=[O:22])[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[H][H]>C(OCC)(=O)C.[Pd]>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11](=[O:22])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: O=C1C(=Cc2ccccc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of the compound of step D (26.6 g, 69.2 mmole) in 250 mL of ethyl acetate in a 500 mL Parr shaker flask was added 10% palladium on carbon catalyst (1.3 g). The mixture was hydrogenated at 40 psi until hydrogen uptake ceased after about 3 hours. The mixture was filtered through celite (a tradename for diatamaceous earth) to remove the palladium catalyst, and chromatographed over silica gel (hexane-ether); 25.1 g (94% yield) of the title product was obtained
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:8][CH2:9][CH2:10][N:11]=[N+]=[N-])[CH2:7][CH2:6]1.[ClH:15]>[Pd].C(O)C>[ClH:15].[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:7]1
Reactant: COC(=O)CC1(CCCN=[N+]=[N-])CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)CC1(CCCN)CC1

Procedure:
At room temperature, a mixture of 389 mg (1.97 mmol) of methyl[1-(3-azidopropyl)cyclopropyl]acetate, 40 mg of 10% palladium on carbon and 1.97 ml (1.97 mmol) of 1 M hydrochloric acid in 10 ml of ethanol were hydrogenated under atmospheric pressure overnight. After the reaction had ended, the mixture was filtered and the filtrate was concentrated to dryness. This gave 313 mg (1.51 mmol, 76% of theory) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH:13]=O)[N:12]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH2:13][NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]=1
Reactant: NC1CCCCC1
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-n2cc(CNC3CCCCC3)nc2-c2ccccc2Cl)cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxaldehyde (62 mg, 0.20 mmol) in methanol (7 mL) was added cyclohexylamine (58 μL, 0.5 mmol). The mixture was stirred overnight, and cooled to 4° C. NaBH4 (40 mg, 1.1 mmol) was added. The mixture was stirred at rt for 1 h, and concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC (50% EtOAc in hexane) to give N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]methyl}-N-cyclohexylamine (65 mg, 81% yield): LC-MS m/z (400.7 MH+), retention time 2.32 min (method 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22]C(=O)C)[CH:17]=1.[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1
Reactant: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
N-(4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 20-5 (3.45 g, 10.1 mmol) was dissolved in methanol (50 mL), a 2 M sodium hydroxide solution (50 mL) was added at room temperature, and the mixture was heated and stirred at 70° C. for 3 hours. Water and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate three times and the combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=49:1-24:1). The target fraction and the mixture fraction were concentrated under vacuum separately from each other, the mixture fraction was purified again with silica gel column chromatography (ethyl acetate:methanol=1:0-9:1), and then the resultant was combined with the above-described target fraction to obtain the title compound (2.60 g, 86%).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N+:8]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>O>[Cl:22][C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=1
Reactant: [O-][n+]1cccc(-c2ccccc2)c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To 922 mg of 2,3-diphenylpyridin-1-oxide, 3 ml of phosphorus oxychloride was added, followed by stirring at 100° C. for 15 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate and then washed with an aqueous 5% potassium carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 428 mg of the desired compound as an oily substance.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]4[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 805.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield)
Reaction SMILES: FC1C=CC(S(N2C3=NC=CC=C3C(CC(O)=O)=C2C)(=O)=O)=CC=1OC.C[O:28][C:29](=[O:58])[CH2:30][C:31]1[C:39]2[C:34](=[N:35][CH:36]=[CH:37][CH:38]=2)[N:33]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[C:45]([C:55]#[N:56])[CH:44]=2)(=[O:42])=[O:41])[C:32]=1[CH3:57]>>[C:55]([C:45]1[CH:44]=[C:43]([S:40]([N:33]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:39]3[C:31]([CH2:30][C:29]([OH:58])=[O:28])=[C:32]2[CH3:57])(=[O:42])=[O:41])[CH:48]=[CH:47][C:46]=1[N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)#[N:56]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(N3CCOCC3)c(C#N)c2)c2ncccc12
Agent: COc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1F
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(C#N)c1

Procedure:
The titled compound is prepared analogously to [1-(4-fluoro-3-methoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (Example 102) by replacing [1-(4-fluoro-3-methoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester with [1-(3-cyano-4-morpholin-4-yl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester. (MH+ 441)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH2:18]Cl)[CH3:16]>CC(C)=O>[Br:1][C:2]1[C:3]([O:8][CH2:18][O:17][CH2:15][CH3:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncccc1Br
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCOc1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a round-bottomed flask was added 3-bromo-2-hydroxypyridine (5 g, 28.7 mmol) and potassium carbonate (9.93 g, 71.8 mmol) in Acetone (300 mL). The suspension was stirred at ambient temperature for 30 min and then treated with the drop-wise addition of chloromethyl ethyl ether (2.78 mL, 30.6 mmol) via addition funnel. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate partitioned between EtOAc and water. The combined organic layers were washed with water, saturated solution of sodium bicarbonate and brine, dried over Mg2SO4, filtered and concentrated. The crude material was to afford 2.46 g of desired product as a clear oil which was used without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].[NH4+].[Cl-]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][N:16]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 6.8 %

Procedure:
LiHMDS (1.0M in THF, 4.0 mL, 4.0 mmol) was added dropwise to a stirred solution of 5-fluoropyridin-2-ylamine (224 mg, 2.0 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere at −78° C. After 15 min stirring at −78° C., a solution of 2,4-difluoro-1-nitrobenzene (0.22 mL, 2.0 mmol) in THF (5 mL) was added and stirring at −78° C. was continued for 30 min. The mixture was slowly warmed to 0° C. then the reaction mixture poured into a saturated solution of NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as an orange solid (34 mg, 7%). LCMS (Method C): RT 3.81 min [M+H]+ 252.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: O=C([O-])c1ccc(O)cc1O
Reactant: C=CC(Cl)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
154.0 g of potassium 2,4-dihydroxybenzoate and 122.3 g of vinylbenzyl chloride were added to 500 ml of dimethylsulfoxide, and stirred at 40° C. for 3 days to react. Then, 1,000 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from a benzene-hexane mixture solvent yielded 140 g of vinylbenzyl 2,4-dihydroxybenzoate (m.p. 52°-54° C.).