Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[S:25][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-thiophene-carboxaldehyde (8.75 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:31][C:32]1[C:36]([C:37]2[CH:38]=[C:39]([S:47]([NH:50][CH:51]3[CH2:55][CH2:54][CH2:53][CH:52]3[C:56](O)=[O:57])(=[O:49])=[O:48])[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=2)=[C:35]([CH3:59])[O:34][N:33]=1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:25]1([NH:30][C:56]([C@H:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[NH:50][S:47]([C:39]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[C:37]([C:36]3[C:32]([CH3:31])=[N:33][O:34][C:35]=3[CH3:59])[CH:38]=2)(=[O:49])=[O:48])=[O:57])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2C(=O)O)c2cccnc2c1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)N[C@@H]2CCC[C@@H]2C(=O)NC2CCCC2)c2cccnc2c1

Procedure:
To a mixture of HATU (38 mg, 0.10 mmol), cyclopentanamine (9 mg, 0.10 mmol), and 1S,2R)-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxylic acid (21 mg, 0.05 mmol) in anhydrous DMF (1 mL), was added slowly Hunig's base (30 uL, 0.16 mmol) with stirring until the starting material acid disappeared (about 1 hr). The reaction mixture was acidified with aqueous citric acid to pH 2-3, then subjected to preparative HPLC to give (1S,2R)—N-cyclopentyl-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxamide.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=O)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1nc(CN2CCOCC2)cs1)N(C1CCCCC1)C1CCCCC1
Yield: 30 %

Procedure:
1,1-Dicyclohexyl-3-(4-morpholin-4-ylmethyl-thiazol-2-yl)-urea was prepared in 30% yield (30 mg) as described in general procedure A from 1,1-dicyclohexyl-3-(4-formyl-thiazol-2-yl)-urea (101 mg, 0.3 mmol) and morpholine (30 uL, 0.3 mmol) using sodium triacetoxyborohydride as the reducing reagent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1.C(O)=O>C(N(CC)CC)C.[Pd]>[NH2:13][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([NH:8][CH3:9])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CNc1cccc(N)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
59.5 mg of palladium at a concentration of 10% on charcoal are added to 0.014 mole (2.8 g) of 4-chloro-2-amino-6-methylaminonitrobenzene in 5.3 ml of triethylamine, and 1.16 ml of formic acid are then run in dropwise. A high exothermicity is noted. The reaction mixture is heated to 80° C. for 40 minutes. After dilution of the reaction mixture with ethanol, the catalyst is removed by hot filtration. The filtrate, evaporated under reduced pressure, enables a dry extract to be obtained. After dilution of the dry extract with water, the expected product precipitates. After being filtered off and washed with water, the precipitate is dried under vacuum in the presence of phosphorous pentoxide. After two recrystallizations from isopropanol in order to remove a gum, the product melts at 70° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:23]([CH:26]([CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)C(OCC)=O)([OH:25])=[O:24]>C1CCCCC1>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:26](/[C:23]([OH:25])=[O:24])\[CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:8][N:9]=1
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)O
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Solvent: C1CCCCC1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1
Temperature: 27.5 °C
Yield: 57.5 %

Procedure:
Methyl 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate (32 gm) and ethyl 2-carboxy-3-(2-thienyl)propionate (57.15 gm) are added to cyclohexane (292 ml) under stirring at 25-30° C., the contents are heated to reflux (80-85° C.) for 2 hours under dean stark to separate the traces of water. The reaction mass is cooled to 50° C. and then slowly added a freshly prepared catalyst solution of propanoic acid (22.93 ml) in cyclohexane (53 ml) and piperidine (10.66 ml). The resulting mass is heated to reflux (80-85° C.) for 20 hours, and to the reaction mass drop wise was added a 50% NaOH solution (64 gm of NaOH in 256 ml of water) after reflux at 50° C. and then the reaction mass is heated to reflux for 2 hours. The reaction mass is cooled to 60° C., the layers separated, to the aqueous layer was added ethanol (192 ml) and then the pH of the mass is adjusted to 5.0 to 5.1 at 60° C. with 6N HCl solution (66 ml of HCl and 66 ml of water). The resulting mass was cooled to 20-25° C. and stirred for 2 hours. The mass was filtered, washed with water (100 ml) and then dried at 70-75° C. to give 26 gm of crude eprosartan free base (HPLC purity: 98.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ccc(CO)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CBr)cc1F
Reaction time: 1 h
Yield: 99 %

Procedure:
The mixture of [3-fluoro-4-(methylsulfanyl)phenyl]methanol (9.00 g, 52.26 mmol) and carbon tetrabromide (19.06 g, 57.49 mmol) in CH2Cl2 (200 mL) was added triphenylphosphine (15.08 g, 57.49 mmol) at 0° C. After 1 hour, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/10) to provide the subtitle compound (12.16 g. 94% yield) as an oil.
Reaction SMILES: Br[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)(C)C>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(N)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In a 100 mL round bottomed flask were placed ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (990 mg, 3.1 mmol) and isopropyl alcohol (20 mL). To the mixture was added thiourea (590 mg, 7.8 mmol) and the reaction was then refluxed for 16 h with stirring. The mixture was allowed to cool to rt and was then concentrated under reduced pressure. The residue was suspended in EtOAc (50 mL) and then washed with a saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL), and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residual off-white yellowish crystalline solid was essentially pure by LCMS and was used in the next step without further purification. LC/MS (FA) ES+ 296. 1H NMR (d6-DMSO, 400 MHz): δ: 7.80 (2H, br s), 7.32 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 4.14-4.20 (4H, m), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N)c(C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,4-dimethylaniline (10 mmol) in 5 mL of conc. H2SO4, fuming HNO3 (90%; 0.6 mL) was added dropwise at 0° C. The resulting mixture was stirred for 12 h at RT and then slowly poured into ice. The solid was collected by filtration and dried to yield 2,4-dimethyl-5-nitroaniline as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](OC)=[O:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:22][CH:20]([CH3:21])[CH3:19])=[O:11])[CH:3]=1
Reactant: CC(C)O
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4,5,6-trichloropicolinate (14.19 grams (g), 59.0 millimoles (mmol)) was slurried in 2-propanol (150 milliliters (mL)) in a 250 mL round bottom flask equipped with a Dean-Stark trap and a reflux condenser. Sulfuric acid (98% H2SO4; 8.07 g, 82 mmol) was added, and the reaction mixture was heated to reflux. After 20 hours (h) at reflux, the majority of the 2-propanol (100 mL) was distilled overhead. The pot solidified upon cooling to room temperature. The resulting solid was stirred with ethyl acetate (EtOAc; 500 mL) and saturated (satd) aqueous (aq) sodium bicarbonate solution (NaHCO3; 500 mL). The organic layer was separated, washed with brine and then filtered through Celite. The organic extract was concentrated to 150 mL by rotary evaporation. Hexane (100 mL) was added, and the solution was stored at −20° C. overnight. Crystals were collected, washed with hexane and dried in air (7.58 g, mp 104.6-105.7° C.). A second crop was obtained by concentration of the filtrate to give a total of 10.36 g (65%) 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H, pyridine H), 5.16 (septet, J=6.3 Hz, 1H, CHMe2), 1.34 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 161.9 (CO2R), 150.6, 145.9, 145.0, 133.1, 125.4 (C3), 70.7 (CHMe2), 21.7 (Me). Anal. Calcd for C9H8Cl3NO2: C, 40.26; H, 3.00; N, 5.22. Found: C, 40.25; H, 3.02; N, 5.22.
Reaction SMILES: CCCCCC.[H-].[K+].[OH:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:28][C@H:29]1[O:31][CH2:30]1)(=O)=O>C1COCC1>[O:31]1[CH2:30][C@H:29]1[CH2:28][O:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ccccc2-c2c(OC[C@@H]3CO3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A stirred suspension of hexane washed potassium hydride (0.204 g, 5 mmol) in THF was treated in one portion with 4-hydroxy-9-fluorenone (1.0 g, 5.1 mmol). To the purple suspension was added (S)-glycidyl nosylate (1.0 g, 5 mmol) and the mixture was stirred at ambient temperature overnight. The reaction was partitioned with EtOAc. The organic phase was washed with H2O, brine and dried (Na2SO4). The solvent was removed in vacuo to provide crude product. Purification by flash chromatography (CH2Cl2-hexane 3:1) provided 0.210 g of product as a yellow solid.
Reaction SMILES: BrBr.C(OC([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=O)[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.[C:27]([NH2:30])(=[S:29])[CH3:28].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:28][C:27]1[S:29][C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[N:30]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Reactant: CC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Bromine (1.0 mL, 18 mmol) was added to a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (6.0 g, 18 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in N,N-dimethylformamide (50 mL) and to the solution was added thioacetamide (1.4 g, 19 mmol) and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (200 mL) and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. 2N-hydrochloric acid (30 mL) was added to the resulting solid and the mixture was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, the mixture was basified with a 2N aqueous solution of sodium hydroxide (200 mL) and a saturated aqueous solution of sodiumhydrogen carbonate. The resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.8 g of the title compound (yield 54%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11](=[S:13])[NH2:12])[NH:7][CH:8]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)=O>C(O)C.O1CCOCC1>[F:28][C:23]1[CH:22]=[C:21]([C:19]2[N:12]=[C:11]([CH2:10][CH2:9][C:6]3[NH:5][C:4]([CH2:3][C:2]([CH3:16])([CH3:1])[CH2:14][CH3:15])=[CH:8][N:7]=3)[S:13][CH:18]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Reactant: CCC(C)(C)Cc1c[nH]c(CCC(N)=S)n1
Solvent: CCO
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cnc(CCc2nc(-c3ccc(F)c(F)c3)cs2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(2,2-Dimethylbutyl)-1H -imidazol-2-yl]propanethioamide (58 mg, 0.24 mmol) in ethanol (1 mL) was added to 2-bromo-1-(3,4-difluorophenyl)ethanone (56 mg, 0.24 mmol) in anhydrous 1,4-dioxane (4 mL). After stirring at rt overnight, the reaction mixture was concentrated to give a residue, which was purified by reverse phase HPLC (KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O over 12 min) to afford the title compound. LC-MS: m/e 376 (M+H).
Reaction SMILES: C(N(CC)CC)C.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:18])[CH3:17]>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.C(OCC)(=O)C>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])=[CH:23][CH:22]=1)(=[O:18])[CH3:17]
Reactant: CCOP([O-])OCC
Reactant: CC(=O)OCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(COC(C)=O)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 9.7 mL (0.057 mole) of triethylamine and 2.4 grams (0.002 mole) of tetrakis(triphenylphosphine)palladium(0) was stirred, and 7.3 mL (0.057 mole) of diethyl phosphite was added. To this was added 13.2 grams (0.057 mole) of 4-bromophenylmethyl acetate. The reaction mixture was warmed to about 100° C., where it stirred for 30 minutes. The reaction mixture was cooled, and 200 mL of ethyl acetate was added. The resultant solid was collected by filtration, and washed with 50 mL of ethyl acetate. The combined wash and filtrate were concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 3:7 heptane:ethyl acetate as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.1 grams of 4-(diethylphosphono)phenylmethyl acetate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Reactant: Cc1cccc(B(O)O)c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Temperature: 50 °C
Yield: 39.6 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 790 mg, 3.55 mmol), 2,3-dimethylphenylboronic acid (Aldrich; 522 mg, 3.48 mmol), copper(II) acetate (646 mg, 3.55 mmol) and triethylamine (500 μL, 3.55 mmol) in 1,2-dichloroethane (5.5 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[O:21][CH:22]=1>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][C:23]=1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Product: C1=C(c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)CCc2ccccc21
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole to give 2-(3,4-dihydro-2-naphthyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 99-100° C.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C(N(CC)CC)C.[CH:14](/[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=2)[NH:24][N:23]=1)=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.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>[CH3:3][O:2][P:1]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:6])[O:4][CH3:5]
Reactant: O=S(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)C(F)(F)F
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Temperature: 85 °C
Yield: 6.4 %

Procedure:
40.7 μl (1.09 eq; 0.444 mmol) of dimethyl phosphite, 61.9 μl (1.09 eq; 0.444 mmol) of triethylamine and 18.8 mg (0.04 eq; 0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 150 mg (1 eq; 0.407 mmol) of trifluoromethanesulfonic acid 3-((E)-styryl)-1H-indazol-5-yl ester in solution in 5 ml of dimethylformamide are added. The medium is heated at 85° C. overnight. 41 μl of dimethylphosphite, 62 μl of triethylamine and 20 mg of tetrakis(triphenylphosphine)palladium(0) are added to the medium, which is heated for a further two hours. 100 μl of dimethylphosphite, 100 μl of triethylamine and 30 mg of tetrakis(triphenylphosphine)palladium(0) are then added to the medium, which is heated overnight at 105° C. After filtration of the catalyst through filter paper, the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 8.6 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid dimethyl ester, along with 27.2 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid monomethyl ester (Example 13).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Step 3, 0.9 g, 3.25 mmol) in DCM (5 ml) EDCI (0.747 g, 3.89 mmol) and HOBt (0.527 g, 3.89 mmol) were added at about 0° C., after 10 minutes morpholine (0.6 ml, 6.5 mmol) and Et3N (2.3 ml, 16.26 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.6 g; Yield: 53.4%; 1H NMR (300 MHz, CD3OD): δ 7.40-7.22 (m, 5H), 5.19 (d, 1H, J=8.7 Hz), 5.08 (q, 2H, J=12.0 Hz), 3.95 (q, 1H, J=9.0 Hz), 3.79-3.38 (m, 8H), 2.80 (t, 1H, J=8.4 Hz), 2.49-2.35 (m, 1H), 2.34-2.20 (m, 1H), 1.33 (s, 3H), 0.89 (s, 3H); Mass: [M+1]+ 347 (10%), [M+Na]+ 346 (100%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:12]([C:13]2[CH:14]=[C:15]([S:23](Cl)(=[O:25])=[O:24])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)=[C:11]([CH3:27])[O:10][N:9]=1>C(OCC)(=O)C>[CH:1]1([NH:6][S:23]([C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[C:13]([C:12]3[C:8]([CH3:7])=[N:9][O:10][C:11]=3[CH3:27])[CH:14]=2)(=[O:24])=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)Cl)c2cccnc2c1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cyclopentyl amine (0.4 mL, 4 mmol) was added to a solution of 7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonyl chloride (500 mg, 1.55 mmol) in ethyl acetate (15 mL). The reaction was stirred at room temperature for 15 minutes before being partitioned between an aqueous solution of citric acid and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf=0.07 in 2:1 hexanes ethyl acetate) afforded N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.