Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:4]=2[CH:3]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(CNCC2CCCCC2)CCCCC1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:36]([O:35][C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:8][C:4]=2[CH:3]=1)[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)ccc2n1COCC[Si](C)(C)C
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc2c(c1)nc([C@@H]1CCCN1C(=O)OC(C)(C)C)n2COCC[Si](C)(C)C
Temperature: 60 °C
Yield: 83 %

Procedure:
To (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.973 g, 5.99 mmol), ethyl acrylate (0.714 mL, 6.59 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.104 g, 0.359 mmol), N,N-dicyclohexylmethylamine (1.461 mL, 6.89 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.18 mmol) dissolved in THF (18 mL) had nitrogen bubbled through the solution for 15 minutes to remove the oxygen, and then the mixture heated at 60° C. for 2 hours. After cooling to room temperature the solution was filtered through diatomaceous earth and washed with EtOAc. The filtrated was then concentrated to a residue, and then the residue was dissolved in dichloromethane and extracted with water. The organic layer was then dried and concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 2.56 g, (83%) of the title compound. MS (ESI) m/z 516 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
A mixture of 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (2.95 g, 9.46 mmol), piperazine (10.60 g, 123 mmol) in dioxane (50 mL) is heated overnight at 110° C. Water is added and the reaction mixture is extracted with ethyl acetate. The combined ethyl acetate layers are washed with brine, dried and concentrated. The crude material is purified by chromatography eluting with dichloromethane-5% methanol. Fractions containing product are combined and concentrated to afford 1-(4-tert-butylphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (2.4 g, 70% yield) as a light cream solid. TLC (silica gel, dichloromethane-10% methanol) Rf 0.27; ESI/MS 362 (M+H), RT 3.27 min; NMR 10.14 (1H, s); 8.12 (1H, d, J=3 Hz); 8.09 (2H, d); 7.68 (2H, d); 7.47 (2H, m); 6.91 (1H, d, J=6 Hz); 3.20 (4H, m); 2.53 (4H, m); 2.25 (1H, br s); 1.36 (9H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([CH3:9])[O:3]1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC1C=C(Br)C=CC=1)C1C=CC=CC=1.[Mg].Cl>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([C:6]2([OH:8])[CH2:5][CH:4]([CH3:9])[O:3][CH:2]([CH3:1])[CH2:7]2)[CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: CC1CC(=O)CC(C)O1
Agent: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethyltetrahydropyran-4-one (2.2 g) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxybromobenzene (5 g), magnesium (0.5 g) and tetrahydrofuran (20 ml)] in tetrahydrofuran and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 5° C., ice (5 ml) and 2N hydrochloric acid solution (25 ml) were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of toluene and ethyl acetate as eluent. There were thus obtained two isomers of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:34]=1
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Yield: 65.8 %

Procedure:
A mixture of 0.58 g of 1-(6-iodohexyl)-2,3-bis (phenylmethoxy)benzene, 0.18 g of 3-hydroxybenzoic acid methyl ester and 0.25 g of potassium carbonate in 15 mL of acetone was stirred at reflux for 18 hours. Workup as in Example 16 and purification by HPLC using toluene gave 0.40 g (66% yield) of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12](=[O:16])[CH2:13][CH2:14]Cl)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C=CC(O)=CC=1)O.C(N(CC)CC)C>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12](=[O:16])[CH:13]=[CH2:14])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)CCCl)CC1
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=CC(=O)[C@H]1CC[C@H](CCCCC)CC1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
12.23 g of 1-(trans-4-pentylcyclohexyl)-3-chloropropan-1-one and 112 mg of hydroquinone were dissolved in 120 ml of absolute dioxan in a sulphonation flask with stirrer, thermometer, reflux condenser, dropping funnel and nitrogen gasification [in an analogous manner to Chem. Ber. 109 (1976) 3426 and 111 (1978) 2825] and 12.6 g of triethylamine were added dropwise within 10 minutes. The mixture was subsequently stirred at 80° C. for 3.5 hours, cooled to 15° C., the precipitated triethylamine hydrochloride was filtered off under suction, back-washed with 50 ml of dioxan and the solvent was evaporated on a rotary evaporator. The oil obtained was taken up in 100 ml of chloroform, washed firstly with 100 ml of 5% sodium hydrogen carbonate solution and then with 100 ml of water (the aqueous phases were each extracted with a small amount of chloroform), dried over sodium sulphate and freed from solvent. The oily 1-(trans-4-pentylcyclohexyl)-2-propen-1-one obtained was further processed without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([I:23])C(=O)C1>CN(C=O)C.C(Cl)Cl>[I:23][C:6]1[N:5]([CH3:14])[C:4](=[O:15])[C:3]([O:2][CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(I)n(C)c(=O)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a solution of Intermediate 1 (101 mg, 0.478 mmol) in DMF (0.5 mL) was added NIS (108 mg, 0.478 mmol) at rt. The reaction was stirred at rt for 3 days. An additional equivalent of NIS (67 mg, 0.30 mmol) was added and the reaction mixture heated at 60° C. overnight. The reaction was allowed to cool, diluted with DCM (40 mL) and the organic portion washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of DCM and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 19A (81 mg, 50% yield) as a yellow solid.
Reaction SMILES: CN(C)CC(O)=O.C([O-])(=O)C.[Na+].Br[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:17]([O:19][CH3:20])=[O:18].[CH:26]([N:29]([CH:34]([CH3:36])[CH3:35])[C:30](=[O:33])[CH:31]=[CH2:32])([CH3:28])[CH3:27].Cl>ClCCl.CN1CCCC1=O>[CH:34]([N:29]([CH:26]([CH3:28])[CH3:27])[C:30](=[O:33])/[CH:31]=[CH:32]/[C:14]1[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25])([CH3:36])[CH3:35]
Reactant: C=CC(=O)N(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Agent: CC(=O)[O-]
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(/C=C/C(=O)N(C(C)C)C(C)C)c1
Temperature: 130 °C
Yield: 68.9 %

Procedure:
A stirred suspension consisting of N,N-dimethylglycine (6.0 mmol), anhydrous sodium acetate (40 mmol), methyl 3-bromo-4-methoxybenzoate (20 mmol, 4.90 g), N,N-diisopropylacrylamide (24 mmol, 3.72 g), bis-(benzonitrile)-palladium-II chloride (1.5 mol %), and 20 ml of N-methyl-2-pyrrolidinone was heated at 130° C. until no starting material could be detected by tlc (starting material methyl 3-bromo-4-methoxybenzoate: Rf 0.73; N,N-diisopropylacrylamide: Rf 0.46; solvent system (1)). After cooling to room temperature 50 ml of an aqueous 2N HCl solution was added. The reaction was diluted with dichloromethane (50 ml) and the precipitated grey palladium metal was filtered off. The organic phase was washed with five portions (50 ml each) of 2N aqueous hydrochloric acid, dried (MgSO4) and evaporated to dryness. The remaining off-white solid was recrystallized from ethyl acetate/n-hexane to give 4.40 g (E)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)acrylamide in 69% yield, m.p. 139-140° C., tlc: (1) Rf 0.40. NMR (CD2Cl2): 21.22, 22.10, 46.39, 48.87, 52.59, 56.61, 111.42, 123.39, 123.78, 125.54, 130.32, 132.53, 135.07. MS (EI, DI, 105° C.): 319 (M+−, 22), 304 (6%), 276 (8%), 219 (100%), 187 (18%), 160 (7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[N:3]1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O1CCOCC1>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:20][C:2]([CH3:1])([CH3:12])[N:3]=[C:4]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: Cc1ccccc1C1=NC1(C)C
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: C1COCCO1
Product: Cc1ccccc1C1=NC(C)(C)OC1c1ccc(N(C)C)cc1

Procedure:
3.3 g of 2,2-dimethyl-3-(o-tolyl)-2H-azirine and 2.5 g of p-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 290 ml of 1,4-dioxane (with the light source described in Example 2). After removing the solvent in a water-jet vacuum, the residue was chromatographed on aluminum oxide (neutral, activity 1), the elution was carried out with n-heptane/ether (9:1). Crystallization from ethanol/water gave 5-[p-(dimethylamino)phenyl]-2,2-dimethyl-4-(o-tolyl)-3-oxazoline which melted at 89°-90° C. after drying for 16 hours at 30° C. and 13 Torr.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]([NH:27][NH2:28])=[O:26])[N:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:28][NH:27][C:25](=[O:26])[CH2:24][N:22]1[N:21]=[N:20][C:19]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:23]1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)Cn1nnc(N2CCOCC2)n1
Solvent: CC(=O)O
Product: O=C(Cn1nnc(N2CCOCC2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 73 mg of the title compound (76%) as a yellow powder in 86.7% purity by HPLC (Rt: 3.84, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:18]=[CH:17][CH2:16][C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:19][CH:20](O)[CH3:21].C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:30]([CH:20]([CH3:21])[CH2:19][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([CH2:16][CH:17]=[CH:18][C:7]=3[F:6])=[C:14]2[CH:13]=[N:12]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ncc2c1=CC1=C(F)C=CCC=21
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Cn1ncc2c1=CC1=C(F)C=CCC=21)N=[N+]=[N-]
Yield: 95.7 %

Procedure:
1 ml (12.9 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g (6.46 mmol) of (RS)-1-(7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.6 ml (25.8 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.84 g (12.9 mmol) of sodium azide and the reaction mixture was heated to 90° for 5 hours while stirring. After cooling, the solution was poured into 70 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 1.59 g (96%) of (RS)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20](O)[CH:21]=[C:22]([CH3:24])[CH:23]=1.O>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:5])=[O:4]
Reactant: COc1cc(C)cc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Trifluoromethanesulphonic anhydride (2.02 ml, 12.0 mmol) was added dropwise to a stirred solution of 3-methoxy-5-methylphenol (1.50 g, 10.9 mmol) in pyridine (20 ml) at −20° C. under nitrogen. The reaction was warmed to 0° C., stirred for 90 minutes and re-cooled to −20° C. More trifluoromethanesulphonic anhydride (1.01 ml, 6.00 mmol) was added dropwise. The reaction was allowed to warm to room temperature, stirred for 14 hours and cautiously poured into water (100 ml). The aqueous phase was extracted with ether (150 ml) and the organic phases were washed with water (3×75 ml), 0.2M hydrochloric acid (3×75 ml), 1.0M aqueous sodium carbonate solution (2×75 ml), water (75 ml) and brine (75 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (2.86 g) as a pale brown oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:44](=[O:46])[CH3:45])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 0.312 g of 3ξ-hydroxy-7β-phenylacetylamino-cepham-4ξ-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0° C. and after addition of 50 ml of toluene is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; a silica gel plate of 100 cm length is used and development is carried out with a 1:1 mixture of toluene and ethyl acetate. 3ξ-Acetoxy-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester of Rf=0.47 is obtained, melting at 162°-164° C. after crystallisation from a mixture of methylene chloride and pentane; [α]D20 =+55°±1° (c=0.492 in chloroform); ultraviolet absorption spectrum (in 95% strength ethanol): λmax =253 mμ (ε=700), 258 mμ (ε=820) and 265 mμ (ε=660): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.66μ, 5.77μ, 5.97μ, 6.28μ and 6.71μ.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[F:19][C:20]([F:25])([F:24])[C:21]([CH3:23])=[CH2:22].C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[F:19][C:20]([F:25])([F:24])/[C:21](/[CH3:23])=[CH:22]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C=C(C)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(/C=C(\C)C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
To a mixture of methyl 4-iodobenzoate (2.62 g, 10 mmol), Et3N (5 mL), acetonitrile (6 mL), Pd(OAc)2 (100 mg, 0.4 mmol) was added 2-trifluoromethylpropene (2.20 g, 20 mmol). The mixture was sealed and heated at 125° C. for 20 h. After cooling, the mixture was treated with sat. aq. Na2CO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography on silica gel to give methyl (E)-4-(3,3,3-trifluoro-2-methylprop-1-enyl)benzoate.
Reaction SMILES: [ClH:1].CCO.[CH2:5]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21](/[CH:25]=[CH:26]/[C:27]([NH:29][O:30]C3CCCCO3)=[O:28])=[CH:20][N:19]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO>[ClH:1].[ClH:1].[CH2:5]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])=[CH:20][N:19]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NO
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 2N HCl-EtOH solution (1.2 ml) was added to a mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (30 ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-hydroxyacrylamide dihydrochloride (90 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)=C)C=CC=CC=1.C1COCC1.[Li:20]CCCC.[C:25]1([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Li])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCCCCC.CO>[C:25]1([C:31]([Li:20])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [Li]CCCC
Reactant: [Li]CCCCCC(c1ccccc1)c1ccccc1
Agent: C=C(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C(CCCCC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Into a flask equipped with a mechanical stirrer and under a constant flow of argon was injected 0.8 ml (0.0044 mole) of 1,1-diphenylethylene followed by 100 ml of THF and 0.0038 mole of 1.6 M n-BuLi in hexane. The blood red color of diphenylhexyllithium developed immediately and the solution was stirred at room temperature for five minutes. It was then cooled to -74° C. and 3.2 ml (0.024 mole) of GMA was added dropwise from a hypodermic syringe. The red color discharged to a faint yellow after about 0.5 ml had been added, and the temperature rose to -70° C. until addition was complete (about 5 minutes). The temperature then returned to -74° C. and 10 ml (0.09 mole) of MMA was added dropwise at such a rate that the temperature did not exceed -69° C. (about 15 minutes). Following that, another 3.2 ml of GMA was added, the solution was stirred at -72° C. for 10 min, 1 ml of methanol was injected and the solution was poured into 1 liter of hexane. The stringy white polymer was collected and dried; yield, 15.0 g (97%).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]([NH:25][C:26](=[O:43])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=2)=[C:27]([CH:32]=1)[C:26]([NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1Nc1ccc(SC)cc1
Agent: [Li+]
Agent: [OH-]
Product: CSc1ccc(Nc2ccc(Cl)cc2C(=O)NC(Cc2ccc(-c3ccccc3Oc3ccccc3)cc2)C(=O)O)cc1

Procedure:
A solution of (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.154 g, 0.307 mmol), prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester and 2-amino-5-chlorobenzoic acid by the general procedure A) was reacted with 4-(methylthio)phenylboronic acid (0.130 g, 0.768 mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using DCM containing 25% hexane to give 0.075 g of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester as an oil. This ester was treated with LiOH (0.019 g, 0.441 mmol) by the general procedure I to give 0.049 g of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.