Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH3:17])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1>CC(O)C>[CH3:17][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH3:2])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C@H:30]([CH2:33][C:34]([O:36][C:34](=[O:35])[CH2:33][C@H:30]4[C:29]5[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:20]6[CH:19]=[C:18]([C:4]7[C:5]([CH3:17])=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][C:3]=7[CH3:2])[CH:23]=[CH:22][CH:21]=6)=[CH:38][C:37]=5[O:1][CH2:31]4)=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reactant: O
Solvent: CC(C)O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)OC(=O)C[C@@H]2COc3cc(OCc4cccc(-c5c(C)cc(OCCCS(C)(=O)=O)cc5C)c4)ccc32)c1
Temperature: 55 °C

Procedure:
[(3S)-6-({2′,6′-Dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hydrate (0.5 hydrate) (100 mg) was dissolved in 2-propanol (2.5 mL) at 55° C. After filtration, n-heptane (2.5 mL) heated to 55° C. was added, and the mixture was allowed to gradually cool to 5° C. with stirring. The precipitated crystals were collected by filtration to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid anhydride as crystals (A form crystal) (about 60 mg).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH:4]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH2:32]([N-:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]/[CH:57]=[CH:58]\[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(NCC)C>ClCCl>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH2:4].[CH2:32]([N-:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]/[CH:57]=[CH:58]\[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC[N-]CCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O

Procedure:
1 g Boc-Dap(Fmoc)-N-palmityl-N-oleyl-amide raw product were dissolved in 8 ml anhydrous dichloromethane in a 50 ml round-bottom flask. 3 ml diethylamine were added and steered at room temperature (FIG. 4). Thin layer chromatography control of the reaction showed that after 4.5 hours the reaction of the starting product was completed. The volatile components were removed by a rotary evaporator and the residue is chromatography purified using 40 g silica gel 60 (Merck) using hexane/ethylacetate 5:1. The product was eluted using a step gradient consisting of ethylacetate, ethylacetate/methanol 4:1 and dichloromethane/methanol 4:1. 576 mg (0.85 mmol) Boc-Dap-N-palmityl-N-oleyl-amide were obtained as a yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[F:13].C([Mg]Br)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1>[F:13][C:3]1[CH:4]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[C:19]([OH:21])=[O:20]
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Reactant: O=C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)(F)F)cc1F
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (8 g, 30.8 mmol) in 170 mL of THF was cooled to −40° C., and then i-PrMgBr (0.4 mol/L in THF, 91 mL) was injected. After being stirred for 3 h, CO2 was injected for 2 h at 0° C. The mixture was washed with 1M HCl aqueous solution, separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was washed with petroether to give the title compound (6 g, 87% yield): 1H NMR (400 MHz, CDCl3): δ ppm 7.05-7.12 (m, 2H), 8.10 (t, J=8.4 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CN(C)C=O.C(OCC)(=O)C>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: N#CCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 0° C. solution of 4-hydroxyindole (20 g, 150 mmol) in 500 ml of dimethylformamide is treated with NaH (60% dispersion in mineral oil; 6.6 g, 165 mmol). After 30 minutes, bromoacetonitrile (11.5 ml, 165 mmol) is added, and the resulting mixture is allowed to slowly warm to ambient temperature and stir for 3 days. The reaction mixture is diluted with ethyl acetate and washed 3 times with H2O. The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by normal phase HPLC (SiO2; 5% step gradient of 0 to 20% ethyl acetate in hexanes) to give 25 g of (1H-indol-4-yloxy)acetonitrile (97%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:27](OC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH2:23][C:24]([NH2:26])=[O:25])=[O:20])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH:21]([C:19]([O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)=[O:20])[C@H:22]([C:27]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])[CH2:23][C:24](=[O:25])[NH2:26]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 19 h

Procedure:
16.7 g of H-Leu-OMe and 46.0 g of Z-Asn-ONP are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is allowed to stand for 19 hours at 25°C. Thereafter 1.2 liters of water are added and the crystalline precipitate is filtered off. The dipeptide derivative is dried at 40°C in vacuo and is then twice recrystallised from methanol-water. Melting point 180°-181°C; [α]20D = + 9° (c = 2.05 in chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].C(N(C(C)C)C(C)C)C>CS(C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Nc4ccccn4)n3)cc2s1
Temperature: 180 °C
Yield: 9.2 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), pyridin-2-amine (0.03 g, 0.3 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 g, 1.0 mmol) in DMSO (1 g, 13 mmol) was heated under microwave (CEM) at 180° C. and 200 W (Powermax® off). Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC to give a light yellow solid (10 mg). MS (ESI pos. ion) Found m/z: 363, (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(Cl)Cl>[Cl:8][CH2:7][C:4]1[N:3]=[C:2]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])[S:6][N:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: ClCc1nsc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(CCl)ns2)c(OC)c1
Reaction time: 8 h

Procedure:
A solution of 5-chloro-3-chloromethyl-[1,2,4]thiadiazole (3 g, 18 mmol, [74461-64-6]) in DCM (20 mL) was treated with DIPEA (1 eq), followed by 2,4-dimethoxybenzylamine (1 eq). After stirring overnight, the mixture was concentrated and purified by silica gel chromatography (10% MeOH/EtOAc) to afford (3-chloromethyl-[1,2,4]thiadiazol-5-yl)-(2,4-dimethoxy-benzyl)-amine, which was used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](OCC)=[O:12].CC[O-].[Na+].Cl>CCO.O>[OH:12][CH:11]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: CCOC=O
Reactant: O=C1Cc2ccccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2C1=CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a slurry of oxindole (1.33 g, 10.0 mmol) and ethyl formate (2.42 mL, 30.0 mmol) was added 4.85 mL of 21 wt. % NaOEt in EtOH. The thick solution was stirred for 30 min at room temperature and then heated at reflux for 30 min. The solution was acidified to pH=3 with 10% aqueous HCl and 5 mL H2O was added. The solid which formed was filtered and rinsed with H2O to give the title compound (1.34 g, 83%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH3:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][C:30]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.611 g (1.75 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 0.8 g (5.7 mmol) of potassium carbonate are dissolved in 50 ml dimethylformamide and mixed with water. The mixture is stirred for 72 hours at 90° C. Then the reaction mixture is poured onto water, the precipitate is filtered off and dried. After column chromatography on silica gel (eluant: ethyl acetate) colourless crystals are left.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])O.[NH4+].O>C(#N)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A mixture of 2.8 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate in 17 cm3 of acetonitrile [lacuna] to which is added 3.95 g of ammonium hydrogen carbonate and 35 cm3 of water at a pH in the region of 8. 0.017 g of type-II α-chymotrypsin is then introduced and the mixture is left stirring at room temperature for 1 hour 15 min, while measuring the pH regularly. After this reaction time, the pH is less than 8, a further 0.017 g of type-II α-chymotrypsin is added and stirring of the reaction medium is continued for 2 hours 45 min. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate; the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the form of white crystals melting at 110° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=C(C=CC=1)C(OO)=[O:16].O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]1[NH:3][C:4]2=[N+:5]([O-:16])[CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2ccc[n+]([O-])c2[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-methyl-7-azaindole (5 g, 37.8 mmol) in 1,2-dimethoxyethane (40 ml) is added m-chloroperoxybenzoic acid (10.4 g, of a 77% w/w solid, 46.6 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, at room temperature for 3 hours and then poured into water (400 ml). The solution is basified to pH 9-10 using saturated potassium carbonate solution. The aqueous is extracted with DCM (2×100 ml) and the organic portions are combined, dried (MgSO4) and concentrated in vacuo. Purification of the resulting crude by chromatography on silica eluting firstly with neat ethyl acetate followed by DCM/MeOH (10:1) yields the titled compound as a yellow powder. (MH+ 297 appears as a dimer)
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[C:14]([OH:16])(=[O:15])/[CH:13]=[CH:2]/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(/C=C/C(=O)O)ccc1O

Procedure:
Ferulic acid is a compound contained, as an ester thereof, in natural substances, particularly plants such as rice and adlay and may be obtained as a purified product from such a plant or a synthesized product industrially obtained. A ferulic ester is obtained in a hydrous ethanol fraction after rice bran oil obtained from rice bran is partitioned with hydrous ethanol and hexane at room temperature under weakly alkaline conditions. Ferulic acid can be obtained by hydrolyzing the ferulic ester obtained by the above-described process with sulfuric acid with heating under pressure and purifying the resultant hydrolyzate or by culturing Pseudomonas in a medium containing clove oil from buds and leaves of Syzygium aromaticum MERRILL et PERRY, Myrtaceae by steam distillation, or eugenol obtained by purifying the clove oil and subjecting the medium to isolation and purification. When ferulic acid is prepared by chemical synthesis, it may be prepared by, for example, a condensation reaction of vanillin and malonic acid (Journal of American Chemical Society, 74, 5346, 1952).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH:37]1[CH:36]=[C:33]([CH2:34][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:18]2[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)[CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:16][CH:17]=2)=[O:20])[C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:39][CH:38]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=Cc1ccccc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(NCCCCNCc1ccccc1OC(F)(F)F)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethoxybenzaldehyde (manufactured by Avocado Co., Ltd.) (0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (39.7 mg) of the subject compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([O:19][C:17]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C(=O)OC)nc1
Yield: 100.1 %

Procedure:
To a solution of methyl 5-bromopyridine-2-carboxylate (5.0 g, 23.1 mg) in dioxane (80 ml) was added Pd(PPh3)4 (1.34 g, 1.16 mmol) and tributyl(1-ethoxyethenyl)stannane (8.60 ml, 25.5 mmol). After stirring the reaction mixture at reflux temp for overnight, the mixture was diluted with ethyl acetate, washed with 10% KF solution (aqueous), filtered though celite, dried, concentrated, and separated by HPLC (8-70% EtOH in hexane) to give methyl 5-(1-ethoxyethenyl)pyridine-2-carboxylate (4.8 g). LCMS: [M+H]+=208.2
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].Cl.O1CCOCC1>O>[Cl:25][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([C:29]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:37])=[N:3][CH:4]=1
Reactant: CON(C)C(=O)c1cccnc1C
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(OC(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide (592 mg, 1.32 mmol) was placed in a dry 25 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (5 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (1.72 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 60 minutes, followed by the addition of N-methoxy-2,N-dimethyl-nicotinamide (379 mg, 2.11 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (6 mL, 24.0 mmol) and H2O (6.0 mL), and then stirred at 80° C. for two hours. The resultant solution was concentrated in vacuo and saturated sodium bicarbonate was added to adjust to neutral pH. The solution was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude sulfonamide was finally purified via automated flash chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 8.58 (d, 1H), 8.17 (m, 2H), 7.80 (d, 2H), 7.49 (d, 1H), 7.16 (m, 1H), 6.89 (d, 2H), 4.57 (sep, 1H), 2.34 (s, 3H), 1.33 (d, 6H); MS (ES) M+H expect 445.9. found 446.1.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH2:30]([C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(Cc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{2-benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (1.15 g, 2.30 mmol) in THF (15 mL) and MeOH (30 mL) was treated with 2.5N aqueous NaOH (10 mL). The solution was heated at 55° C. for 2 h, cooled to ambient temperature, and concentrated in vacuo. The residue was acidified with 5N aqueous HCl (5 mL) and partitioned between EtOAc (125 mL) and H2O (25 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to a colorless oil (1.1 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, 2H, J=7.6, 2.2 Hz), 7.44-7.40 (m, 3H), 7.27-7.15 (m, 5H), 6.77 (d, 1H, J=8.8 Hz), 6.69 (d, 1H, J=2.9 Hz), 6.62 (dd, 1H, J=8.8, 2.9 Hz), 4.12 (t, 2H, J=6.4 Hz), 3.93 (s, 2H), 2.96 (t, 2H, J=6.6 Hz), 2.35 (s, 3H), 1.45 (s, 6H); MS (ES) m/e 472 [M+1].
Reaction SMILES: [CH:1]1([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[N:20](CCC#N)[N:19]=[N:18][N:17]=4)[CH:15]=[C:10]3[N:9]=[C:8]2[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([NH:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:43][NH:42][C:40]([C:38]1[CH:37]=[CH:36][C:35]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[C:34]([CH2:33][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:8]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:11]4=[N:12][CH:13]=[C:14]([C:16]5[NH:17][N:18]=[N:19][N:20]=5)[CH:15]=[C:10]4[N:9]=3)=[CH:26][CH:27]=2)[CH:39]=1)=[O:41]
Reactant: N#CCCn1nnnc1-c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(COc2ccc(-c3nc4cc(-c5nnn[nH]5)cnc4n3C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
Intermediate 63 (50 mg, 0.12 mmol) in dimethylformamide was reacted with 2-(bromomethyl)-4′-cyano-N-methyl-1,1′-biphenyl-4-carboxamide (63a) (40 mg, 0.12 mmol), cesium carbonate (20 mg, 0.06 mmol) and the resulting suspension stirred under a nitrogen atmosphere at rt for 3h at which point ethyl acetate (30 mL) was added. The organic phase was washed with water (2×25 mL) and brine (1×), dried (Na2SO4), and concentrated on a rotary evaporator. The resulting residue was dissolved in 10% methanolic sodium hydroxide (5 mL) and water (2 mL) was added. The resulting solution was stirred at rt under a nitrogen atmosphere for 30 minutes at which point 10% hydrochloric acid was added until pH=2. This solution was extracted with ethyl acetate, dried (Na2SO4), and concentrated on a rotary evaporator and the residue purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (6 mg, 7%). 1H NMR (CD3OD) δ 9.16 (s, 1H), 8.7 (br s, 1H), 8.15 (d, 1H, J=1.46), 7.94 (dd, 1H, J=8.06, 1.83), 7.80 (d, 2H, J=8.42), 7.71 (br m, 2H), 7.65 (d, 2H, J=8.06), 7.49 (d, 1H, J=8.06), 7.17 (d, 2H, 6.59), 5.14 (s, 1H), 4.46 (br m, 1H), 2.96 (s, 3H), 2.83 (br m, 2H), 1.96 (br m, 4H), 1.75 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 610.24 (M+H); HPLC purity (ELSD)>95%.