Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNOC
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 mg, 114 mmol), DIEA (41 mL, 228 mmol) methyl-m-tolyl-amine (44 mg, 0.36 mmol), and BOP (69 mg, 49 mmol), were reacted according to the procedure D for the synthesis of 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-picolinic amides at 50° C. The reaction mixture was quenched with 1 (M) HCl, extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: N([Si:4]([CH3:7])([CH3:6])[CH3:5])=[N+]=[N-].[CH:8]12[O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2.C([Br:18])C=C>ClC1C=CC=CC=1>[Br:18][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[O:14][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C=CCBr
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C1CCC2OC2C1
Solvent: Clc1ccccc1
Product: C[Si](C)(C)O[C@H]1CCCC[C@@H]1Br
Yield: 71 %

Procedure:
To a vial containing 0.03 grams of this (S)-catalyst was added a solution of azidotrimethylsilane (0.34 g, 2.95 mmol) and cyclohexene oxide (0.24 g, 2.45 mmol) in a mixture of allyl bromide (4.0 mL) and chlorobenzene (4.0 mL). After 48 h the volatiles were removed at reduced pressure and the residue was purified by flash chromatography on 220-400 mesh silica with 98% hexane and 2% ether as eluant. The product (1S,2S)-1-bromo-2-trimethysiloxycyclohexane (0.44 g, 71%) was isolated by distillation of the solvent at reduced pressure. Anal. for C9H19OSiBr: Calcd: C, 43.03; H, 7.62; Br, 31.80; found: C, 43.06; H, 7.69; Br, 31.78. 1H NMR: d 0.19 (s, 9 H), 1.24-1.46 (m, 3 H), 1.64-1.87 (m, 3 H), 2.01 (m, 1 H), 2.35 (m, 1 H), 3.66 (m, 1 H), 3.87 (m, 1 H). 13C NMR: d 24.15, 25.70, 34.96, 35.62, 58.44, 75.38. [a]D25=+39.0, c=1.02 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 120° C. on Cyclodex B stationary phase indicated that the enantiomeric excess of the product was 85%.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][C:10]1[C:15](O)=CC=C[CH:11]=1>>[C:10]([C:4]1[CH:5]=[C:6]([OH:7])[CH:1]=[C:2]([CH3:8])[CH:3]=1)([CH3:15])([CH3:11])[CH3:9]
Reactant: Cc1cccc(O)c1
Reactant: Cc1ccccc1O
Product: Cc1cc(O)cc(C(C)(C)C)c1
Yield: 80 %

Procedure:
Run D of Example 1 is repeated except that 3-cresol is substituted for the cresylic acid mixture. The process results in a selectivity of better than 80 percent of 5-t-butyl-3-cresol.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH3:16].C(=O)=O.O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:16])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: N
Agent: O=C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(N)=S)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.4 grams (0.032 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane in 80 ml of methanol in a 250 ml reaction flask equipped with magnetic stirrer, thermometer, dry-ice condenser and gas addition tube was added NH3 gas until an NH3 reflux was obtained in the condenser. The reaction mixture was stirred for 3 hours at room temperature while maintaining a gentle NH3 reflux in the dry ice condenser. The reaction mixture was then poured into 200 ml of water and the product extracted with methylene chloride. The methylene chloride extract was washed with 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure. The residue was slurried in pentane and the slurry filtered. The white solid filter cake was air dried and weighed 4.5 grams (57% crude yield). The product melted at 155°-157° C. with decomposition. The infrared spectrum of the product contained a strong band at 1525 cm-1 and 3 NH bands at 3180, 3250 and 3400 cm-1.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[C:5]([O:19][CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:5]1[C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(OC)cccc12
Product: COc1cccc2c1[nH]c(=O)n1c(=O)[nH]nc21
Temperature: 25 °C

Procedure:
1.02 g (0.0036 mol) of ethyl 2-hydroxy-8-methoxy-quinazolin-4-yl-carbazate in 65 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from methanol. Yield: 0.52 g (61%) of 7-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 308°-310° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>>[C:2]([C:3]1[CH:9]([C:9]2[CH:3]=[CH:2][N:1]=[CH:11][CH:10]=2)[C:25]2[C:21](=[N:22][NH:23][CH:24]=2)[NH:20][C:18]=1[CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1)#[N:1]
Reactant: O=Cc1ccncc1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C1CCCNC1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1ccncc1

Procedure:
The title compound was prepared from ethyl nipecotate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:7]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:30][C:11]1[C:6]([NH:5][CH2:4][C:3]([N:2]([CH3:29])[CH3:1])=[O:28])=[N:7][C:8]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[N:9][C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CN(C)C(=O)CNc1nc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A mixture of N,N-dimethyl-2-[6-phenyl-2-(4-trifluoromethyl-phenyl)-4-pyrimidinylamino]acetamide (15.9 g), N-chlorosuccinimide (6.4 g) and acetic acid (80 ml) is stirred at 90° C. for 1.5 hour. The reaction mixture is concentrated under reduced pressure, and water and chloroform are added to the residue. The mixture is neutralized with an aqueous sodium hydroxide solution (1 mol/L), and the chloroform layer is separated. The chloroform layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (16 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: COC(=O)CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CC1CCN(c2ncnc(C)c2C#Cc2ccc(N)nc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 2.0 g (8.17 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.90 g (9.81 mmol) piperidin-4-yl-acetic acid methyl ester using 3.50 mL (20.4 mmoL) DIPEA in 50 mL ACN. The reaction mixture is stirred for 1 h at 80° C. The solvent is removed under reduced pressure. The residue is taken up in DCM/MeOH and filtered over silica. After removal of the solvent and extractive work up 2.9 g (96%) of the desired product is obtained. The product is used without further purification for the next step.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]#[N:15])(=O)C.O.CO>C1COCC1>[NH2:15][CH2:14][C:7]1[C:8]([Cl:13])=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(Cl)cc(Cl)c1C#N
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCc1c(Cl)cc(Cl)cc1CO
Temperature: 75 °C

Procedure:
To a solution of 3,5-dichloro-2-cyanobenzyl acetate (11.7 mmol) in 50 mL THF was added a solution of BH3 (50 mmol, 1M in THF). The reaction mixture was heated to 75° C. for 7 h and then cooled to 0° C. Water was added followed by MeOH and the mixture was concentrated. The residue was taken up in water and EtOAc, acidified with 1N HCl solution and extracted with DCM. The aqueous phase was then basified with 1M NaOH solution and extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification with CC using DCM/Et3N (99/1) to DCM/MeOH/Et3N (90/10/1) gives the desired compound as pinkish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([SH:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:24][CH2:22][CH3:23])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(SCC)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step2) (0.5 g, 1.54 mmole) and ethanethiol (0.1 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The solution was maintained at 90° C. for 48 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 10-40% ethyl acetate in hexane to give light yellow solid (0.24 g, 43%): GCMS 366.00 (M+). 1H NMR (CDCl3/400 MHz) 7.60 (s, 1H), 7.27 (s, 1H), 6.77 (s, 1H), 5.67 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 2.96 (m, 2H), 1.40 (m, 3H), 1.35 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH:9]1[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.[CH3:25]OS(OC)(=O)=O>C1COCC1>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:19]([O:21][CH3:25])=[O:20])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][CH2:16]2
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (7.4 g, 25.3 mmol) in THF (40 mL) was added LiOH.H2O (1.06 g, 25.3 mmol). The reaction mixture was stirred at room temperature for 40 min. Me2SO4 (1.19 mL, 12.63 mmol) was added and the reaction was brought to reflux for 3 h. The reaction was cooled down to room temperature and THF was removed. The residue was diluted with CH2Cl2 (150 mL), washed with H2O (2×30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on ISCO (120 g) with 0-50% ethyl acetate in hexanes over 40 minutes to yield 2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a pale yellowish foam (3.56 g, 46%). This racemic mixture was separated by Chiral preparative HPLC using chiralpak OD 20μ column (5×50 cm, eluting with 5% (EtOH/MeOH (50:50))/Heptane with flow rate 50 mL/min). The later eluted peak is the desired (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white foam (1.1 g, 31%). HPLC retention time (Method B)=3.04 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, 9H), 2.67-2.99 (m, 2H), 3.59-3.74 (m, 1H), 3.70 (s, 3H), 3.74-3.86 (m, 1H), 5.35 (s, 0.5H), 5.51 (s, 0.5H), 5.70 (s, 0.5H), 5.76 (s, 0.5H), 6.64 (s, 1H), 6.67-6.76 (m, 1H), 7.31 (d, J=8.6 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:29][C:28](OC)([O:30]C)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C1C=CC=CC=1.CCCCCCC>[C:1]([NH:4][C:5]([CH:26]1[CH2:29][C:28](=[O:30])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: COC1(OC)CC(C(CCCCB2OC(C)(C)C(C)(C)O2)(NC(C)=O)C(=O)NC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
2-Acetamido-N-tert-butyl-2-(3,3-dimethoxycyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (5.21 g, 11.10 mmol) was dissolved in acetone (110 mL) and treated with p-toluenesulfonic acid (106 mg, 0.56 mmol). The reaction was stirred overnight at room temperature, then diluted with benzene (500 mL) and heptane (250 mL), washed successively with water and saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 50-75% ethyl acetate in heptane to afford the desired product (3.40 g, 73%). Rf 0.31 (75% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 6.83 (br s, 1H), 5.84 (br s, 1H), 3.45-3.33 (m, 1H), 3.09-2.82 (m, 6H), 2.02 (s, 3H), 1.54-1.05 (m, 25H), 0.77 (t, J=7.4 Hz, 2H). ESI MS found for C22H39BN2O5 m/z [423.1 (M+1)].
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S>CN(C)C=O.CO.[Cu]Br>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: [Cu]Br
Agent: S
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1ccncc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper(1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeOH, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide(g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:20])[C:6]=1[CH3:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:20])[C:6]=1[CH3:21]
Reactant: BrCc1ccccc1
Reactant: Cc1c(OCCO)ccc(-c2ccc(C(=O)O)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCCO)ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-bromo-2,3-dimethylphenoxy)ethanol (0.531 g), 4-carboxyphenylboronic acid (0.360 g), tetrakis-(triphenylphosphine)palladium(0) (0.125 g), cesium fluoride (1.645 g), water (2 mL), ethanol (2 mL) and 1,4-dioxane (8 mL) was stirred at 80° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid (0.62 g) as a crude product. A mixture of the crude 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid, benzyl bromide (0.445 g), and potassium carbonate (0.450 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford the title compound (0.033 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[O:6].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)C(CCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]([Cl:8])(Cl)[P:3]([Cl:6])([Cl:5])=[O:4].[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-:17].C([NH+](CC)CC)C>C(#N)C>[Cl:1][C:2]([Cl:8])([P:3]([Cl:6])([Cl:5])=[O:4])[CH2:9][CH:10]([Cl:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: O=P(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: [Cl-]
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: O=P(Cl)(Cl)C(Cl)(Cl)CC(Cl)c1ccccc1

Procedure:
11.8 g (0.05 mole) trichloromethane phosphonic dichloride, 7.8 g (0.075 mole) styrene, 134 mg (1 mmole) anhydrous cupric chloride and 206 mg triethylammonium chloride were brought into solution by 5 ml acetonitrile, and heated in the absence of air in a sealed ampoule at 110° during 3.5 hours. After cooling and opening of the ampoule, the reaction mixture was subjected to fractionation in vacuo, through a short Vigreux column. 9.1 g pure 1:1 adduct, 1,1,3-trichloro-3-phenyl-propane-1-phosphonic dichloride was obtained bp/0.05: 121°. Found: Cl: 50.8, Calc. for C9H8Cl5OP: 52.1%
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.[NH:25]1[CH2:27][CH2:26]1.O>O1CCCC1>[N:25]1([C:22]([C:9]2[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=3[CH:8]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: C1CN1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3c(c(C(=O)N4CC4)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
To a suspension of 260 mg (0.81 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]-imidazole-5-carboxylic acid in tetrahydrofuran (10 ml) were added 157 mg (1.0 mmol) N,N′-carbonyl-diimidazole (CDI) and the reaction was stirred at room temperature overnight 105 mg (2.4 mmol) Aziridine were added and the mixture was stirred for 16 h at room temperature. The reaction was poured into water and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=20:1) and crystallized from n-butanol to afford 56 mg (20%) of the title compound as a white solid. m.p. 201°-204° C.