Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[CH3:24].[C:25](=O)([O-])[O-].[K+].[K+]>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][CH3:25])=[O:20])=[CH:17][C:16]=2[CH3:24])=[CH:9][CH:10]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(O)cc2)c(C)c1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 1.61 g (8.7 mmol) of 4-methoxymethoxy-phenylboronic acid and 1.8 g (9.7 mmol) of 4-bromo-3-methylbenzoic acid with 26.7 mL of 2.0M potassium carbonate and 1.54 g of tetrakis(triphenylphosphine)-palladium, followed by deprotection-esterification in methanol, the desired product is obtained in the form of a colourless oil (m=2.06 g; Y=98%).
Reaction SMILES: CC(C1C=C2C[CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])(C)[CH2:16][CH2:15][CH2:14][C:13]3(C)C2CC1)C.C(OC(=O)CCCCCCCCCCCCC)(C)C.C(OCC1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH:19](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Agent: CCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O=C(OCc1ccccc1)c1ccccc1
Product: CCCCCCCC=O

Procedure:
The foregoing formula may require a solubilizing agent, e.g., the methyl ester of dihydroabietic acid (commercial name: HERCOLYN D® benzyl benzoate isopropyl myristate and/or C12 -C14 isoparaffin hydrocarbons.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[O:8][C:7](C3C=CC=CC=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22]C1CC2N(C)C(CCC2)C1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:8]1[C:4]2=[CH:3][CH:2]=[CH:16][C:15]([C:17]([NH2:22])=[O:19])=[C:5]2[N:6]=[CH:7]1
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(F)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 215.9 %

Procedure:
A mixture of 6-fluoro-2-phenylbenzo[d]oxazole-4-carboxylic acid (30 mg, 0.12 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (32 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide (42 mg, 91%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J=7.5 Hz, 1H), 8.23-8.22 (m, 2H), 7.96 (d, J=10.5 Hz, 1H), 7.63-7.55 (m, 3H), 7.42 (d, J=7.0 Hz, 1H), 4.62-4.53 (m, 1H), 3.13-3.11 (m, 2H), 2.67-2.60 (m, 2H), 2.54 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.46 (m, 3H), 1.18-1.13 (m, 2H); 19F NMR (282 MHz, CDCl3) δ-113.93; MS (ESI+) m/z 394 (M+H); HPLC>99% (AUC), tR=12.78 min.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:25]=[C:24]([CH:26]=O)[O:23][N:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:48]>O1CCCC1.C(OCC)(=O)C>[ClH:48].[CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][N:15]([CH2:26][C:24]4[O:23][N:22]=[C:21]([C:20]([F:29])([F:28])[F:19])[CH:25]=4)[CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Reactant: O=Cc1cc(C(F)(F)F)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cccc(C2=CCN(Cc3cc(C(F)(F)F)no3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A mixture of N-cyclopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide free base (5b) (133 mg, 0.545 mmol), 3-(trifluoromethyl)isoxazole-5-carbaldehyde (75) (270 mg, 0.818 mmol) and acetic acid (0.037 ml, 0.654 mmol) in tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (347 mg, 1.636 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. The reaction was quenched with saturated NaHCO3 solution (10 ml), extracted with ethyl acetate (50 ml×3), washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 75/25 to 85/15) to give the desired free base. This was diluted with ethyl acetate and HCl solution (4 N in 1,4-dioxane) was added to the solution. The resulted solid was triturated with hexane to give N-cyclopropyl-6-(1-((3-(trifluoromethyl)isoxazol-5-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinamide hydrochloride (76) (33 mg, yield 14%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 8.52 (brs, 1H), 8.00 (m, 1H), 7.92 (m, 1H), 7.77 (m, 1H), 7.47 (m, 1H), 6.93 (s, 1H), 4.77 (m, 2H), 3.93 (m, 2H), 2.83-3.20 (m, 5H), 0.72 (m, 2H), 0.64 (m, 2H); MS: 393 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]#[N:11].[Cl-].[Cl:13][C:14](Cl)=[N+:15]([CH3:17])[CH3:16]>ClCCl>[C:10]([C:3]1[C:4]([CH:7]([CH3:9])[CH3:8])=[N:5][S:6][C:2]=1[N:1]=[C:14]([Cl:13])[N:15]([CH3:17])[CH3:16])#[N:11]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CC(C)c1nsc(N)c1C#N
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Reaction time: 5 h
Yield: 61.3 %

Procedure:
A mixture of 142 g of 5-amino-4-cyano-3-isopropylisothiazole and 610 ml of dichloromethane was treated with 138 g of N-(dichloromethylene)-N,N-dimethylammonium chloride. The reaction mixture became warm during addition of the N-(dichloromethylene)-N,N-dimethylammonium chloride and was cooled in an ice-water bath to 31°. The reaction temperature was maintained at 30°-35° for one-half hour after addition was complete. The reaction mixture was then heated under reflux for an additional 44 hours. Nitrogen gas was then passed through the refluxing solution for 5 hours. The reaction mixture was allowed to cool to 15°-20° and filtered. The filter cake was washed with 150 ml of dichloromethane and dried to yield an unidentified white solid, mp 162°, which was discarded. The filtrate was washed with two 100-ml portions of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to near dryness under reduced pressure. The residue was dissolved in 2250 ml of hot hexane, filtered hot and allowed to cool to room-temperature. The hexane solution was decanted from an oil which separated on cooling. The hexane solution was placed in a cooler overnight. The cold solution was filtered and dried to yield 133.7 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 68°-71°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](O)=[O:29])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH3:63][O:64][NH:65][CH3:66].CN1CCOCC1.Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[O:29])[N:65]([O:64][CH3:63])[CH3:66])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N(C)OC)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 107.2 %

Procedure:
To 10 mL of a tetrahydrofuran solution containing 600 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-carboxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 420 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 108 mg of O,N-dimethylhydroxylamine hydrochloride and 112 mg of N-methylmorpholine were added, and stirred at room temperature for 22 hours. Hydrochloric acid was added to the reaction mixture to make acidic, the organic layer was separated, washed sequentially with water, aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate], to give 0.69 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methoxy)(methyl)carbamoyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:14]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>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.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]=[CH:15][CH:16]=[CH:17]3)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1I
Reactant: OB(O)c1ccc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Yield: 39.1 %

Procedure:
A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), quinolin-6-ylboronic acid (0.381 g, 2.2 mmol), K2CO3 (0.553 g, 4.0 mmol), dimethoxyethane (20 mL), and water (5 mL) was heated under reflux overnight. Solvents were removed under reduced pressure. The residue was diluted with sat'd NH4Cl (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), concentrated in vacuo and purified by chromatography to afford ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 39% yield) as a colorless oil. MS (ESI) m/z: 312.0 (M+H+).
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: O=Cc1ccccn1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccccn2)ccc2ccccc12
Yield: 46 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and pyridine-2-carbaldehyde in 46% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][C:18]#N)=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[OH-:20].[Na+].C(O)C.[OH2:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][C:18]([OH:25])=[O:20])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O
Reactant: N#CCc1cccc2c(-c3ccc(Cl)cc3)onc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cccc2c(-c3ccc(Cl)cc3)onc12
Yield: 38 %

Procedure:
A mixture of 3.9 g (0.015 mole) of 3-(4-chlorophenyl)-2,1-benzisoxazol-7-acetonitrile, 10 ml of 20% sodium hydroxide and 75 ml of 95% ethanol was heated at reflux under a nitrogen atmosphere for 17 hr. The mixture was poured into 600 ml of water and filtered. The filtrate was treated with charcoal and filtered through Celite. The filtrate was adjusted to pH 7 with concentrated hydrochloric acid and the mixture filtered. The filtrate was made acidic with concentrated hydrochloric acid and a solid precipitated. The solid was collected by filtration and recrystallized from 2-propanol to yield 1.6 g (38%) of pale-yellow needles, m.p. 200°-202° C. with decomposition.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][CH2:14][P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])(=[O:19])[O:16][CH2:17][CH3:18].C[O:29][C:30](=O)[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(O)(=O)C.[Cl-].[Na+]>C1COCC1>[C:36]([O:35][C:33]([NH:32][CH2:31][C:30](=[O:29])[CH:14]([P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])(=[O:19])[O:16][CH2:17][CH3:18])[F:13])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(C)(OCC)P(=O)(CF)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCOC(C)(OCC)P(=O)(OCC)C(F)C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (2.5 mL, 14.5 mmol, 3.5 eq) in THF (30 mL) at −10° C. was added dropwise (about 10 minutes) n-BuLi (1.4 M in hexanes, 9.0 mL, 14.5 mmol). After 10 minutes, the reaction was cooled to −78° C., and a solution of ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate (2.0 g, 8.26 mmol, 2 eq) in THF (10 mL) was added dropwise over 10 minutes. After the addition the reaction mixture was stirred at −78° C. for 1 h. A solution of N-Boc-glycine methyl ester (0.8 g, 4.1 mmol) in THF (10 mL) was added dropwise over 10 minutes such that the internal temperature was maintained below −70° C. After the addition was complete the reaction was stirred at −78° C. for 1 h. The reaction was quenched with acetic acid (1 mL, 14.5 mmol) and then warmed to room temperature. Saturated aqueous sodium chloride (75 mL) was added to the reaction and the organic phase separated. The aqueous phase was then extracted with ethyl acetate (2×75 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure affording the crude product as a pale yellow oil (2.69 g). The crude product was purified by column chromatography (2×35 cm column), eluting with 40% ethyl acetate in hexane. This method afforded ethyl (3-(N-(tert-butoxycarbonyl) amino)-1-fluoro-2-oxopropyl)(1,1-diethoxyethyl)phosphinate as a clear colorless oil (0.73 g, 44%). 1H NMR (300 MHz, CDCl3) δ 5.78-5.24 (m,2H), 4.52-4.08 (m, 4H), 3.94-3.50 (m, 4H), 1.62-1.51 (m, 3H), 1.50-1.32 (m, 3H), 1.42 (s, 9H), 1.30-1.12 (m, 6H).
Reaction SMILES: [C:1]([N:6]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][O:8][C:7]1=[O:17])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:18](O)(C(F)(F)F)=O.[CH2:25]([N:32](C[Si](C)(C)C)[CH2:33]OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:25]([N:32]1[CH2:33][CH2:4][C@:2]([CH3:18])([C:1]([N:6]2[C@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][O:8][C:7]2=[O:17])=[O:5])[CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C(C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[C@]1(C(=O)N2C(=O)OC[C@H]2c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 683.5 %

Procedure:
To a solution of (R)-3-methacryloyl-4-phenyloxazolidin-2-one (135.00 g, 583.79 mmol) and TFA (4.497 mL, 58.379 mmol) in dry toluene (50 mL) at <10° C. was quickly added dropwise N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (194.16 mL, 758.93 mmol), and the mixture was stirred at ambient temperature overnight. The reaction was filtered and the filtrate was extracted with 4N HCl (3×250 mL). The aqueous layer was washed with ethyl acetate (250 mL) then made basic with solid K2CO3 to pH 10. The basic aqueous layer was extracted with ethyl acetate (4×400 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide (R)-3-((S)-1-benzyl-3-methylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (145 g, 399 mmol, 68% yield) as a dark oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[NH2:3].[C:13](/[C:15](=[CH:21]\OCC)/[C:16]([O:18][CH2:19]C)=[O:17])#[N:14].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH3:19][O:18][C:16]([C:15]1[CH:21]=[N:3][N:2]2[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6](=[O:8])[NH:14][C:13]=12)=[O:17]
Reactant: CCO/C=C(\C#N)C(=O)OCC
Reactant: NNc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h then cooled. Water (5 mL) was added and the mixture was stirred at ambient temperature for 1 h then filtered. The solid was washed with H2O, EtOH and Et2O then dried.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([OH:33])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([O:33][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl iodide (162 mg, 0.67 mmole) was added at 0° C. to a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (197 mg, 0.45 mmole) and K2CO3 (93 mg, 0.67 mmole) in DMF (4 ml). The mixture was stirred at 0°-5° C. for 1 hour and diluted with ethyl acetate (30 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (5 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in dioxane and lyophilized to afford 242 mg (97%) of the dioxane solvate of the title compound. Silica gel TLC: Rf 0.25 (1:1 CHCl3 -ethyl acetate). Estimated purity 85% (by HPLC). Mp. 90°-95° C.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:35][N:34]=1>O1CCCC1>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:10])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:35][N:34]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCCc1cncc2ccccc12
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cncc3ccccc23)c2ccc(OC)cc2)cc1
Yield: 29.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.841 g) and 4-isoquinolinebutanamine (0.39 g) in tetrahydrofuran (8 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate-hexane; 3:1) and then was crystallized from ethyl acetate-ether to provide 0.284 g of (E)-N-[4-(4-isoquinolinyl)butyl]-5,5-bis(4-methoxyphenyl)-2,4-pentadienamide, mp 91°-93° C.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C:40]2=[O:58])C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([C:40](=[O:58])[O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(=O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(=O)[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 80.3 %

Procedure:
To a solution of 48 (5 mg, 6.3 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (10 mg) and 1,2-dichlorobenzene (12 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LCMS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by passing through silica gel in a pipette (5% MeOH in DCM) to give 49 (2.2 mg, 80%). 1H NMR (300 MHz, CD3OD) δ 7.35 (s, 1H), 7.20 (s, 1H), 7.09 (s, 4H), 4.24-4.29 (m, 1H), 4.07 (t, J=10.5 Hz, 1H), 4.06 (s, 2H), 3.81 (dd, J=2.1, 12.0 Hz, 1H), 3.61-3.71 (m, 2H), 3.43 (t, J=9.9 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]([CH:4]1[C:8]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH3:15])([CH3:14])[O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[F:32][CH:30]([F:31])[C:26]1[C:25]([C:33]([NH:13][C:9]2[C:8]3[CH:4]([CH:1]([CH3:3])[CH3:2])[O:5][C:6]([CH3:15])([CH3:14])[C:7]=3[CH:12]=[CH:11][CH:10]=2)=[O:34])=[C:24]([F:23])[N:28]([CH3:29])[N:27]=1
Reactant: CC(C)C1OC(C)(C)c2cccc(N)c21
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1OC(C)(C)c2cccc(NC(=O)c3c(C(F)F)nn(C)c3F)c21
Reaction time: 4 h
Yield: 78 %

Procedure:
In a 25 ml round bottom flask, a solution of 3-isopropyl-1,1-dimethyl-1,3-dihydro-2-benzofuran-4-amine (62 mg, 0.301 mmol, 1 eq) in 5 ml of DCM is cooled to 0° C. and triethylamine (0.05 ml, 0.361 mmol, 1.2 eq) is added. A solution of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (70 mg, 0.331 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (78%)