Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.C(O)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:32])([CH3:31])[CH:20]=[N:21][S@@:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:32])([CH3:31])[CH:20]([NH:21][S:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:23])[C:1]#[N:2])=[CH:15][CH:14]=1
Reactant: Cc1ccc([S@@](=O)N=CC(C)(C)c2ccc(Cl)cc2)cc1
Reactant: [C-]#N
Agent: CC[Al+]CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1ccc(S(=O)NC(C#N)C(C)(C)c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
The diethyl aluminum cyanide (43.5 mL of a 1.0M solution in toluene, 43.5 mmol) was added to isopropanol (28.9 mL, 377 mmol) and stirred at 10° C. for 15 minutes. This solution was cannulated into the (R)-4-methylbenzenesulfinic acid [2-(4-chlorophenyl)-2-methyl-propylidene]-amide (9.28 g, 29.0 mmol) as a solution in 290 mL of THF at −78° C. This solution was allowed to stir for 15 minutes at −78° C. then allowed to warm slowly to room temperature overnight. The solution was quenched with the addition of diluted NaHCO3 solution and extracted with ethyl acetate. The combined organic was washed with brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the 4-methyl-benzenesulfinic acid [2-(4-chlorophenyl)-1-cyano-2-methyl-propyl]-amide as a colorless oil (9.55 g, 95% yield). The material was heated to 110° C. (reflux) in concentrated HCl solution over the weekend. The solution was cooled to room temperature, washed with ether, then concentrated in vacuo to give the (S)-2-amino-3-(4-chlorophenyl)-3-methyl-butyric acid hydrochloride salt a white solid (1.61 g, 21%). 1H NMR (DMSO-d6, 400 MHz) δ 8.19 (brs, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.13 (s, 3H), 4.15 (s, 1H), 1.42 (s, 3H), 1.40 (s, 3H). LCMS (APCI+) m/z 228 [M+H]+; Rt=1.81 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][OH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[N:23]=[CH:24][C:25]([O:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])=[N:26][C:27]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.26 g), methyl glycolate (0.075 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.1 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[C:13](=[O:26])[CH2:12]3)[NH:7][C:6]=2[CH:27]=1.C(OC([N:38]1CCN(CC2C=CC(C#N)=CC=2)C(=O)C1)=O)C1C=CC=CC=1.ClC1C=CC2NC(CCl)=NC=2C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]([NH2:38])=[NH:23])=[CH:20][CH:19]=4)[C:13](=[O:26])[CH2:12]3)[NH:7][C:6]=2[CH:27]=1
Reactant: N#Cc1ccc(CN2CCN(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Agent: ClCc1nc2cc(Cl)ccc2[nH]1
Solvent: CO
Product: N=C(N)c1ccc(CN2CCN(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1

Procedure:
Hydrogen chloride gas is bubbled into an ice-cooled solution of 4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-benzonitrile (100 mg, 0.264 mmol), (prepared by deprotecting 4-(4-cyanobenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester, EXAMPLE 66, Part A, followed by alkylation with 6-chloro-2-chloromethylbenzimidazole) in 15 mL of methanol. The solution contained 3Å molecular sieves. The reaction mixture is stored at −30° C. The methanol is removed on the rotovap. Fresh methanol (20 ml) is added folowed by a stream of ammonia gas. The resulting mixture is heated to reflux for three hours. The reaction mixture is filtered at room temperature. The mother liquor is condensed and the resulting residue is purified by reverse phase HPLC (0-50% ACN/H2O). The product is isolated as a white solid with a melting point of 91-95° C. MS C20H21ClN6O m/z: 397, 399. Anal. cald. for C20H21ClN6O.3C2HF3O2: C, 42.26; H, 3.27; N, 11.37. Found C, 42.20; H, 3.44; N, 11.36.
Reaction SMILES: N1[CH:6]=[CH:5]C=CC=1.Cl.[C:8]([C:11]1[O:12][C:13](=[O:17])[C:14](=[O:16])[N:15]=1)([CH3:10])=[CH2:9].C([OH:20])C>>[C:14]([NH:15][C:11](=[O:20])[C:8]([CH3:10])=[CH2:9])([C:13]([O:12][CH2:5][CH3:6])=[O:17])=[O:16]
Reactant: C=C(C)C1=NC(=O)C(=O)O1
Reactant: CCO
Reactant: c1ccncc1
Agent: Cl
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In the same reaction vessel as used in Example 1, ethanol (230.4 g; 5.0 mol) and pyridine (39.6 g; 0.5 mol) were charged, and the reaction vessel was cooled at 0° C. in an ice bath. 2-Isopropenyloxazoline-4,5-dione hydrochloride (87.8 g; 0.5 mol) was added thereto in 30 minutes under stirring while keeping the reaction temperature at 0° to 10° C. After completion of the addition, excess ethanol was removed under reduced pressure. The reaction mixture was shaken with ethyl acetate (1,000 ml) and a large amount of water, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, followed by removal of ethyl acetate. Hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (30.5 g). Yield, 33%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[S:14][N:13]=[C:12]([CH3:15])[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9].[CH2:19]([S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH-].[Na+]>O1CCCC1>[C:8]([C:10]1[S:14][N:13]=[C:12]([CH2:15][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:42][CH:41]=2)[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9]
Reactant: Cc1nsc(C#N)c1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cc2nsc(C#N)c2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 23.5 %

Procedure:
Triethylamine (20.2 grams, 0.200 mol) was added to 200 ml of a tetrahydrofuran (THF) solution of 16.9 grams (0.100 mol) of 5-cyano-3-methyl-4-nitroisothiazole, and 74.6 grams (0.200 mol) of 4-dodecylsulfonylbenzoyl chloride was added dropwise. After heating under reflux for 8 hours, 200 ml of 1N aqueous sodium hydroxide solution was added dropwise. After heating under reflux for 3 hours, the reaction mixture was left to cool, poured into ice water and extracted with ethyl acetate. 5-Cyano-3-(4-dodecylsulfonylbenzoylmethyl)-4-nitroisothiazole (11.9 grams, 23.5 mmol) was obtained on refinement using silica gel column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[N:14]=1)=[NH:8].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C2CCCCCCCCC=2)CCCCCCNNN=1>C(#N)C>[CH2:26]([N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=2[O:24][CH3:25])=[NH:8])[S:11][CH:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Reactant: BrCc1ccccc1
Agent: C1=C(C2=NNNCCCCCC2)CCCCCCCC1
Solvent: CC#N
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2Cc2ccccc2)cs1
Yield: 50.6 %

Procedure:
177 mg N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine, Example 147 free base, 100 mg of benzyl bromide and 870 mg polymer-bound triazabicyclodecene (1.3 mmol/g, Argonaut) were shaken in 20 ml acetonitrile overnight at room temperature. Chromatography on silica gel (dichloromethane/methanol 0-5%) of the residue obtained following evaporation concentration yielded 112 mg of a white solid; ESI-MS [M+H+]=452.15.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[CH:17][C:18]([CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].C([NH+]1C2=NC3C(N=C2N(CC)C1C#CC=C1N(CC)C2=NC4C(N=C2N1CC)=CC=CC=4)=CC=CC=3)C>N1C=CC=CC=1>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[CH3:6][N+:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]#[C:18][CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31]
Reactant: CN1C(=CC(=O)C=C2C=Cc3ccccc3N2C)C=Cc2ccccc21
Agent: CCN1C(=CC#CC2N(CC)c3nc4ccccc4nc3[NH+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1C(=CC#Cc2ccc3ccccc3[n+]2C)C=Cc2ccccc21
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Phosphoryl chloride (1.0 ml) is added to a stirred suspension of 1,3-Bis(1-methyl-2-(1H)-quinolylidene)acetone (0.68 g, 0.002 mol) in pyridine (10 ml). The mixture is stirred for 5 min., then the solid is collected and washed with a little pyridine, then with ether. The dye is converted to its perchlorate salt by solution in methanol, followed by addition of aqueous sodium perchlorate solution. After recrystallization from acetonitrile, the yield of purified dye is 0.30 g (36%) with the melting point indistinct. The following two dyes were prepared by procedures similar to that described above: 1,3-Diethyl-2[(1,3-diethyl-1H-imidazo[4,5 -b]quinoxalin-2-(3H)-ylidene)-1-propynyl]-1H-imidazo[4,5 -b]quinoxalinium perchlorate. ##STR19## Recrystallized from acetonitrile. Purified yield 35%. mp >300°. 1,3,3-Trimethyl-2-[(1,3,3-trimethyl-2-indolinylidene)-1-propynyl]-3H-indolium perchlorate. ##STR20## Recrystallized from methanol. Purified yield 43% mp 194-7° dec.
Reaction SMILES: C([O:6][C:7]([C:9]1[CH:10]=[CH:11][C-:12](C)[CH:13]=1)=[O:8])(=O)CCC.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[OH-:21].[K+]>C(O)C>[C-:15]1([C:12]([CH2:11][CH2:10][CH2:9][C:7]([OH:6])=[O:8])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1.[Fe+2:20]
Reactant: CCCC(=O)OC(=O)c1cc[c-](C)c1
Reactant: [OH-]
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Solvent: CCO
Product: O=C(O)CCCC(=O)[c-]1cccc1
Yield: 194.7 %

Procedure:
An amount of 25.8 g of methyl-4-ferrocenoyl butyrate prepared according to the method of Preparation Example 1 (1) was reacted in ethanol with 11.5 g of potassium hydroxide, to obtain 24.0 g of 4-ferrocenoyl butyric acid represented by the following formula: ##STR58##
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][NH:3]1.[C:29]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:10]=2)[N:16]=1.[CH3:29][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[CH:7][C:2]1=[O:1]
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1cc[nH]c(=O)c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: Cn1ccc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)cc1=O
Product: O=C(Nc1cc2ccccc2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg of 2-[[(1,2-dihydro-2-oxopyridin-4-yl)methyl]amino]-N-(isoquinolin-3-yl)benzoic acid amide is introduced into 4 ml of a mixture that consists of toluene:methanol=1:3.5 and mixed with 0.2 ml of a 2-molar solution of trimethylsilyldlazomethane in hexane and stirred for 8 hours at room temperature. After repeated addition of 0.2 ml of trimethylsilyldiazomethane solution and 1 hour of stirring, the batch is evaporated to the dry state and chromatographed on silica gel with methylene chloride:ethanol=97:3 as an eluant. 20 mg of 2-[(−2-methoxypyridin-4-yl)methyl]amino]-N-(isoquinolin-3-yl)benzic acid amide and 10 mg of 2-[[(1,2-dihydro-1-methyl-2-oxopyridin-4-yl)methyl]amino]-N-(isoquinolin-3-yl)-benzoic acid amide are obtained.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1.CN([CH:19]=[O:20])C.O.O.C(O)(=O)C(O)=O>CCOCC.O.CCOC(C)=O>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Brc1c(C2OCCO2)oc2ccccc12
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1c(C2OCCO2)oc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
3-Bromo-2-(1,3-dioxolan-2-yl)-1-benzofuran (6.6 g 24.5 mmol) is dissolved in Et2O (100 ml) in a 3-neck, flame-dried, round-bottom flask under nitrogen and cooled to −78° C. tert-butylithium (31.7 ml, 53.9 mmol) is added dropwise, and the chilled solution is stirred 1 h. DMF (2.18 ml, 28.2 mmol) is dissolved in Et2O (25 ml) and also added dropwise, and the mixture is stirred at −78° C. for another 7 h. The reaction is warmed to rt, whereby oxalic acid dihydrate (6.18 g, 49.0 mmol) and water (25 ml) are added. The reaction continued stirring at rt overnight and is then diluted with water (125 ml) and EtOAc (175 ml). The layers are allowed to separate, and the aqueous is extracted with EtOAc (1×100 ml). The organics are combined, dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude material is chromatographed over 350 g slurry-packed silica, eluting with 30% ethyl acetate/hexane. The appropriate fractions are combined and concentrated to afford 3.84 g (72%) of 2-(1,3-dioxolan-2-yl)-1-benzofuran-3-carbaldehyde as a yellow/orange oil. MS (EI) m/z: 218 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=O.C(N(CC)CC)C.[C:31]1(=O)[CH2:36][CH2:35]CC[C:32]1=[O:37]>ClCCl.CN(C)C=O.CC(C)(O)C#N>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]([CH:19]2[C:18](=[O:22])[CH2:35][CH2:36][CH2:31][C:32]2=[O:37])=[O:17])[C:5](=[O:14])[N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O=C1CCCCC1=O
Reactant: Cc1cc(C(=O)O)c(=O)n(-c2ccccc2)n1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)C2C(=O)CCCC2=O)c(=O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methyl-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylic acid (0.56 g, 2.42 mmol) was stirred in anhydrous dichloromethane (13 ml) and 1 drop of anhydrous dimethylformamide was added. Oxalyl chloride (0.25 mL, 2.90 mmol) was added dropwise to the yellow solution. After 1.5 h the reaction was concentrated in vacuo. The residue obtained was dissolved in dichloromethane (20 ml). To the brown solution anhydrous triethylamine (1 ml), then cyclohexanedione (0.33 g, 2.90 mmol) was added, producing a reddish solution. A further 0.33 ml of anhydrous triethylamine was added. The reaction mixture was stirred at room temperature for 2 h (reaction monitored by LCMS), then acetone cyanohydrin (1 drop) and anhydrous triethylamine (0.67 ml) was added and the reaction was stirred overnight. LCMS indicated the desired product had been formed. The reaction mixture was concentrated in vacuo. The residue obtained was purified using column chromatography (SiO2, Toluene/Triethylamine/Dioxane/EtOH/Water 100:40:20:20:5 by volume) to afford the title compound as an orange oil (382 mg, 49%). 1H NMR (CDCl3) 2.05 (quin, 2H), 2.41 (m, 3H), 2.47 (br s, 2H), 2.73 (br s, 2H), 7.10 (s, 1H), 7.36 (m, 1H), 7.46 (m, 2H), 7.57 (m, 2H), 16.15 (br s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:14]([OH:22])(=[O:21])[CH2:15][C:16](C(O)=O)=O.Cl.[NH2:24][OH:25].Cl>[OH-].[K+].O>[OH:13][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([C:10]([OH:12])=[O:11])[CH2:16][C:15](=[N:24][OH:25])[C:14]([OH:22])=[O:21]
Reactant: NO
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: O=C(O)CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CC(O)(Cc1ccc(O)cc1)C(=O)O)=NO

Procedure:
To 10 ml of water in which were dissolved 3.18 g of potassium hydroxide, were added 1.0 g (5.55 mmol) of 4-hydroxyphenylpyruvic acid and 2.2 g (16.7 mmol) of oxalacetic acid, for reaction at ambient temperature for 72 hours (about pH 13 at the start of the reaction). Hydroxylamine hydrochloride salt of 1.54 g (22.2 mmol) was added to the reaction solution, for reaction at ambient temperature for 10 hours. The reaction solution was then adjusted to pH 2.6, using 6N hydrochloric acid, for extraction using ethyl acetate. The organic layer was rinsed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to dryness, to obtain 0.7 g (2.47 mmol) of 4-hydroxy-4-(4-hydroxyphenylmethyl)-2-hydroxyiminoglutaric acid as a crude product. Further, the crude product was recrystallized in methanol and toluene, to obtain 0.22 g (0.78 mmol) of 4-hydroxy-4-(4-hydroxyphenylmethyl)-2-hydroxyiminoglutaric acid in crystal. (NMR Measurement)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetamidomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at room temperature for 30 min, then heated to reflux. After heating for 18 h, the resultant slurry was cooled to room temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over MgSO4. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85°-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:31]([S:32]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:34])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 3-amino6methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0 mmol), as prepared in the preceding step, and N-methylmorpholine (840 μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. The solvent was concentrated to give a solid which was washed with ethyl acetate hexane (1:2, 60 mL) to give the title compound as a white solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H), 4.75 (s, 2H), 4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[O:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[N:36]1.O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:40]([C:39]1[O:35][N:36]=[CH:37][CH:38]=1)=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: O=C(Cl)c1ccno1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccno3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the solution, and the mixture was stirred at −78° C. for 20 min. Isoxazole-5-carbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (27 mg, yield 26%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH:47]([CH3:49])[CH2:46][C:45]=4[CH:50]=3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH:47]([CH3:49])[CH2:46][C:45]=4[CH:50]=3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc3c(c2)CC(C)O3)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc3c(c2)CC(C)O3)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.062 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.094 g, 50%).