Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)=[O:15]
Reactant: CNOC
Reactant: COc1ccc2cc(C(=O)O)cnc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the intermediate from step D (1.5 mmol) and N,O-dimethyhydroxylamine hydrochloride (219 mg, 2.25 mmol), in dichloromethane (20 mL) was added triethyl amine (1.04 mL, 7.5 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (840 mg, 1.8 mmol). After stirring the reaction mixture at room temperature for 3 hours, it was quenched by the addition of 1N HCl (10 mL). The resulting mixture was extracted with DCM. The organic layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 70% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 9.15 (d, J=1.8 Hz, 1H), 8.5 (d, J=1.8 Hz, 1H), 8.0 (s, 1H), 7.7 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.24 (dd, J=2.5, 9.0 Hz, 1H), 3.96 (s, 3H), 3.57 (s, 3H), 3.43 (s, 3H). LC-MS: 1.6 min; (M+H)=247.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH2:40])[C:27]2[C:32]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:39])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:10])(=[O:11])[NH2:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][C:15]([NH:40][CH:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)[C:27]1[C:32]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:39])=[O:17]
Reactant: COc1ccc(C(N)c2c(C)cccc2N2CCCCC2)cc1
Reactant: COc1cc(CC(=O)O)c(Br)cc1S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(NC(=O)Cc2cc(OC)c(S(N)(=O)=O)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture containing (2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid 12f from Example 12 (18 mg, 0.06 mmol), 1-(4-methoxyphenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methylamine 8c from Example 8 (25.9 mg, 0.08 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA (0.06 ml, 0.3 mmol) in a solvent mixture of THF (1 mL) and DMF (0.3 mL) was stirred under argon at RT for 1 hour. The mixture was then diluted with EtOAc (7 mL) and the organic layer was washed with 1.0 M aqueous HCl (2 mL), saturated NaHCO3 (2 mL), dried over Na2SO4, concentrated to a minimum volume (˜1 mL) and purified by preparative TLC (eluent EtOAc:hexane:AcOH 60:40:1) to obtain 31 mg of the semi-pure final inhibitor (˜85% purity by 1H-NMR). The pure inhibitor 2-(2-bromo-5-methoxy-4-sulfamoylphenyl)-N-[1-(4-methoxyphenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methyl]acetamide 301 (Table 3) was isolated after further purification by C18 reversed phase HPLC.
Reaction SMILES: [CH3:1][C:2]1([C:17]([OH:19])=O)[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1.S(Cl)([Cl:22])=O>C(Cl)Cl>[CH3:1][C:2]1([C:17]([Cl:22])=[O:19])[CH2:6][C:5]2[C:7]([CH3:16])=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: CC1=C2OC(C)(C(=O)O)CC2C(C)C([N+](=O)[O-])=C1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)Cl)C2

Procedure:
0.5 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 20 ml of methylene chloride and 0.27 g of thionyl chloride were added, followed by heating at reflux for 2 hours. After returning the temperature to room temperature, the solvent was distilled off to obtain 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride. To 0.33 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 0.23 g of triethylamine and 15 ml of DMF, a solution prepared by dissolving 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride in DMF was added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and a crystal was collected by filtration. The crystal was dissolved in chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 0.54 g of the objective product.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([NH:7][CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)(=[O:6])=[O:5].CNCC(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>[Cu]I.CN(C=O)C>[CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([N:7]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:35])([CH3:34])[C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=1)(=[O:6])=[O:5]
Reactant: CC(C)CS(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)c1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
To a flame-dry 50-mL round-bottomed flask was added 2-methyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide (0.100 g, 0.176 mmol, Example 210), N-methylglycine (3.0 mg, 0.040 mmol, Aldrich, St. Louis, Mo.), CuI (0.02 g, 0.09 mmol, Aldrich, St. Louis, Mo.), and potassium phosphate (0.08 g, 0.37 mmol, Aldrich, St. Louis, Mo.). After the mixture was stirred for 10 min, iodobenzene (0.030 g, 0.14 mmol, Aldrich, St. Louis, Mo.) and DMF (3.0 mL) were added. The resulting mixture was heated at 110° C. for 24 h. Additional CuI was added (7.0 mg, 0.035 mmol) and the reaction was heated at 110° C. for an additional 6 d. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and the crude product was purified by column chromatography (24 g of silica gel, 20 to 40% EtOAc in hexanes) to afford 2-methyl-N-phenyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide (0.032 g) as a mixture of two isomers:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.O.[CH3:20]O>>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: COc1c(Br)cc(C(=O)O)c(O)c1F
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(OC)c(F)c1O
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (0.70 g) in methanol (15.0 mL) was added dropwise thionyl chloride (0.39 mL) under ice-cooling. The reaction solution was stirred at 70° C. for 15 hr under argon atmosphere, and then overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.52 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C:46]([CH3:51])([CH3:50])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C:46]([CH3:51])([CH3:50])[C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)C(C)(C)N)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid to give the title compound. LC/MS (M+H)+: 620. Ret. time: 1.35 min. (Condition G); analytical HPLC Ret. time: 6.55 min (Condition Q).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 410.08 g/mol.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH2:22][CH2:21][O:17][N+:18]([O-:20])=[O:19])#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (5 ml), 2-nitroxyethylamine nitrate (0.57 g, 3.4 mmol) was added, and sodium methoxide (0.18 g, 3.4 mmol) was further added gradually. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.44 g, 0.20 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CC([O-])(C)C.[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1ncc2cc[nH]c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2cnc(Cl)nc21
Yield: 60 %

Procedure:
To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.54 mmol) in 25 mL THF was added t-BuOK (1.1 g, 9.81 mmol) and ethyl 2-bromoacetate (1.31 g, 7.84 mmol). The mixture was stirred and heated to reflux temperature for 2 h. After cooling the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to yield a crude product which was used in next step without further purification (940 mg Yield 60%). LCMS (m/z): 240.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH:35]([O:38]C1N=C(C(O)=O)C=C(C)N=1)([CH3:37])[CH3:36]>>[CH:35]([O:38][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)([CH3:37])[CH3:36]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: Cc1cc(C(=O)O)nc(OC(C)C)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(OC(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Isopropoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isopropoxy-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.95 min; [M+H]+=472.21.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([CH:41]=1)[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([C:38]([N:13]2[CH2:12][CH2:11][C@@H:10]3[C@@H:15]([N:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH2:9]3)[CH2:14]2)=[O:39])[CH:41]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 8.11-7.84 (m, 2H), 7.81-7.58 (m, 1H), 7.52-6.40 (m, 4H), 4.70-4.26 (m, 1H), 4.23-3.67 (m, 4H), 3.67-3.40 (m, 1H), 3.12-1.53 (m, 7H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26]([C:37]([O:39]N1C(=O)CCC1=O)=[O:38])[C@@H:27]([CH3:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[CH3:36][C@@H:27]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:26]([NH:25][C:47]([O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:48])[C:37]([OH:39])=[O:38].[NH2:1][C@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2.83 g of H-Glu-OBzl dissolved in 40 ml of acetonitrile were added 3.3 ml of triethylamine and 5.00 g of Boc-Thr(Bzl)-OSu under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and the resulting solution was washed with 30 ml of water twice. The ethyl acetate layer was dried with anhydrous magnesium sulfate. The solvent was removed by distillation to dry the ethyl acetate layer, whereby 5.50 g (yield: 87.2%) of the above objective compound was obtained as a powder form product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.C(O)(=O)C>CCO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:25][CH:24]=[CH:23][C:22]3[CH:21]=[CH:20][C:19]([N:18]([CH3:29])[CH3:17])=[CH:28][CH:27]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CC=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(4-Carboxyphenyl)-3-methyl-2-pyrazolin-5-one (2.18 gm, 0.010 mol), 4-dimethylaminocinnamaldehyde (1.75 gm, 0.010 mol) and glacial acetic acid (10 ml) were mixed together to form a slurry. It was heated to reflux with stirring, held at reflux for five minutes and then cooled to RT. EtOH (20 ml) was added to the reaction mixture which was heated again to reflux, held there for five minutes and cooled to RT. The product was isolated by filtration, washed in succession with ethanol and ligroin, and dried. The reaction was repeated twice on the same scale and the products obtained were all combined. They were treated further by first slurrying in refluxing EtOH (150 ml), isolating the solid by filtration while hot, and then slurrying in refluxing MeOH (200 ml) and isolating it again, while hot, by filtration. The mp was 282°-284° C. The NMR and IR spectra were consistent for the structure assigned. The C,H and N elemental analyses were in agreement with those calculated for the empirical formula of the dye.
Reaction SMILES: CO[C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:37])(=[O:36])[NH:11][C@H:12]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OC)=[O:25])=[CH:18][CH:17]=1.[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:32]([O:31][C:29](=[O:30])[C@@H:12]([NH:11][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:38])[NH:39][C:40]1[NH:45][CH2:44][CH2:43][CH2:42][N:41]=1)(=[O:37])=[O:36])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:25])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:18][CH:17]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)OC)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1C(=O)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
75 mg (0.13 mmol) of 2-((1S)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-ethylsulfamoyl)-benzoic acid methyl ester was dissolved in 1 ml of dimethylformamide and 68 mg (0.69 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 54 mg. MS (ES+): m/e=683.3 (M+H+).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[Br:13]/[CH:14]=[C:15]1\[CH2:16][CH2:17][CH2:18][C@@:19]2([CH3:26])[C@H:24]\1[CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2.C(=O)([O-])O.[Na+]>CS(C)=O>[Br:13]/[CH:14]=[C:15]1\[CH2:16][CH2:17][CH2:18][C@@:19]2([CH3:26])[C@H:24]\1[CH2:23][C:22](=[O:25])[CH:21]=[CH:20]2
Reactant: C[C@]12CCC/C(=C\Br)[C@@H]1CC(=O)CC2
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@]12C=CC(=O)C[C@H]1/C(=C/Br)CCC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
To a solution of ortho-iodoxybenzoic acid (1.56 g, 5.57 mmol) in dimethyl sulfoxide (17 ml), (E,4aR,8aR)-8-(bromomethylene)-octahydro-4a-methylnaphthalene-2(1H)-one (Compound 25: 955 mg, 3.71 mmol) was added, and the resulting mixture was stirred at 80° C. for 18 hours. The resulting mixture was cooled to room temperature, and 5% aqueous sodium hydrogen carbonate solution was added thereto. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with water and saturated brine. Further, the combined aqueous layer was extracted with ethyl acetate which was then washed with water and saturated brine. The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained crude product (976 mg) was purified by flash column chromatography to obtain (4aR,8E,8aR)-8-(bromomethylene)-4a,5,6,7,8,8a-hexahydro-4a-methylnaphthalene-2(1H)-one (443 mg, 46.8%). 1H NMR (CDCl3) δ: 6.76 (d, J=9.9 Hz, 1H), 5.88 (d, J=9.9 Hz, 1H), 5.74 (t, J=1.5 Hz, 1H), 2.95-3.10 (m, 1H), 2.66 (ddd, J=11.7 Hz, 5.7 Hz, 1.5 Hz, 1H), 2.45 (d, J=12.0 Hz, 1H), 2.43 (d, J=6 Hz, 1H), 1.50-1.90 (m, 5H), 0.98 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)O
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 1.15 ml of isopropanol were reacted to obtain 1.46 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+63.5°±3° (c=0.3% in benzene).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=O>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
By using 48.6 g of the thus-prepared catalyst (0.18% by weight based on glucose, calculated as palladium metal), an aqueous solution of glucose was reacted at a temperature of 30° ± 3° C and a pH of 10.0 in the same manner as described in Example 1 except that air was used instead of the oxygen gas employed in Example 1. Twenty one hours were required for completion of the reaction, and a liquid reaction mixture having a light brown color was obtained. The content of gluconic acid in the solid obtained by concentration of the liquid reaction mixture was 89.6 wt.% and the saccharide residual ratio was 5.3 wt.%.
Reaction SMILES: [N+:1](=[C:3]([C:8](=O)[CH2:9][O:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[N-:2].[NH4+]=[S:14]>>[CH3:11][O:10][CH2:9][C:8]1[S:14][N:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCC(=O)C(=[N+]=[N-])C(=O)OC
Product: COCc1snnc1C(=O)OC
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Methyl 2-diazo-4-methoxy-3-oxobutanoate (4.5 g, 0.026 mol) was cooled in an ice bath and ammonium sulfide (8.0 g, 0.12 mol) (40-48%) was added drop-wise over 2 minutes. White precipitate formed. The slurry was stirred for 30 minutes, and then purified by flash chromatography to give the desired product (4.2 g, 85%) as a light oil, that crystallized readily upon standing. 1H NMR (400 MHz, CD3OD): δ□ 5.02 (s, 2H), 3.98 (s, 3H), 3.57 (s, 3H). MF=C6H8N2O3S; LCMS calculated for C6H9N2O3S (M+H)+: m/z=189.0.