Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1NC1CC1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCC(=O)Nc1ccccc1NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of N1-cyclopropylbenzene-1,2-diamine (221 mg, 1.49 mmol) and triethylamine (0.3 mL, 2.2 mmol) in DMF was added a solution of methyl 8-chloro-8-oxooctanoate (260 mg, 1.3 mmol) in DMF at 0° C. drop-wise. The reaction was stirred overnight at room temperature, diluted with ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The separated organic layer was concentrated to give crude methyl 8-(2-(cyclopropylamino)phenylamino)-8-oxooctanoate (390 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([N:27]=[C:28]=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([NH:27][C:28]([NH:33][CH2:31][CH3:32])=[O:29])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 42 %

Procedure:
1-[2-(R)-Isocyanato-3-(4-methoxyphenyl)-propionyl]-pyrrolidin-2-(S)-carboxylic acid benzyl ester (0.60 g) was dissolved under nitrogene in 20 mL of dichloromethane and ethyl amine was allowed to pass through at −20° C. for 5 minutes. The mixture was kept stirring for 16 h. The volatiles were pumped off and the remaining residue was purified by silica chromatography (dichloromethane/methanol 80/20) to give 0.29 g (42%) of the title compound as a colorless oil. (+)-APCI-MS: 454(MH+).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)([CH3:5])[CH3:4].[CH3:18][O:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:18][O:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:16]1[CH:17]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:3]([CH3:5])[CH3:4])[N:14]=[CH:15]1
Reactant: CC(C)Oc1ccccc1-c1c[nH]cn1
Reactant: COC(=O)CCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCn1cnc(-c2ccccc2OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Add sodium hydride (1.82 g, 38 mmol) to a suspension of 4-(2-isopropoxyphenyl)-1H-imidazole (5.01 g, 25 mmol) in THF (125 mL) at 0° C. under nitrogen, and warm the mixture to room temperature and stir for 1 hour. Cool the mixture to 0° C. and add 8-bromooctanoic acid methyl ester (5.98 g, 25 mmol) and tetra-n-butylammonium iodide (0.55 g, 1.5 mmol) and warm the mixture to room temperature to stir for 8 hours. Dilute the mixture with water (20 mL) and remove the solvent under reduced pressure. Dilute the residue with ethyl acetate (300 mL), wash with water (100 mL) and brine (100 mL), dry over sodium sulfate, and remove the solvent under reduced pressure to provide 8-[4-(2-isopropoxyphenyl)imidazol-1-yl]octanoic acid methyl ester (5.16 g, 57%), which is used in the next step without further purification.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:37][C:38]1[C:46]([O:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][C@H:50]([NH2:54])[CH2:49]2)=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[N:41][NH:42]2>CN(C)C=O>[CH3:3][CH:2]([CH3:4])[C:1]([NH:54][C@H:50]1[CH2:51][CH2:52][CH2:53][C@@H:48]([O:47][C:46]2[C:38]([CH3:37])=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][N:41]=[CH:40]3)[CH2:49]1)=[O:5]
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(O[C@@H]2CCC[C@H](NC(=O)C(C)C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Isobutyric acid (36.2 μL, 0.39 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (74.8 mg, 0.39 mmol), hydroxybenzotriazole (52.8 mg, 0.39 mmol) and triethylamine (0.18 ml, 1.28 mmol) were added to a solution of monohydrochloride (100 mg, 0.35 mmol) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example 411 in N,N-dimethylformamide (5 ml), and the resulting mixture was stirred overnight at room temperature. The reaction solution was partitioned by the addition of ethyl acetate, toluene and water, and then extracted twice with ethyl acetate-toluene (1/1). The extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 0/1) to obtain 2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (86.3 mg, 77%).
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([CH2:9][O:10]C2CCCCO2)[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][N:2]1[C@H:8]([CH2:9][OH:10])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2
Reactant: CN1[C@H](COC2CCCCO2)CCC12CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN1[C@H](CO)CCC12CC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a mixture of (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane (64 mg, 0.284 mmol) in 10 mL of methanol was added 4-methyl-benzenesulfonic acid (97.8 mg, 0.568 mmol, Aldrich). The reaction mixture was stirred at 50° C. overnight, and then concentrated in vacuo. The residue was treated with 10 mL of saturated Na2CO3 aqueous solution, and extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the desired product as yellow oil (32 mg, 80%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1([CH3:21])[C:14](C)(C)OB(CC(C)=C)O1.[F-].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][C:10](=[CH2:9])[CH2:21][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C=C(C)CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: ClCCl
Product: C=C(C)Cc1cnc(N)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromopyrazin-2-amine (1 g, 5.75 mmol) in was added 4,4,5,5-tetramethyl-2-(2-methylallyl)-1,3,2-dioxaborolane (1.360 g, 7.47 mmol), PdCl2(dppf)-DCM adduct (0.469 g, 0.575 mmol), CsF (2.62 g, 17.24 mmol), purge though nitrogen. The reaction mixture was stirred at 100° C. in oil bath for 3h. The reaction mixture was partitioned between EtOAc and water. The organic was washed with brine, dried and concentrated. The residue was dissolved in 1N HCl (10 mL) The aqueous layer was back extracted with EtOAc, The aqueous was then neutralized to pH=8, then extracted by EtOAc 3 times. The organic was then dried and concentrated. The crude product was used in next step reaction. LCMS (m/z): 150.5 (MH+), 0.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.[PH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: Nc1cccc(O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the (2,4-dichloro-phenoxyacetic acid (600 mg, 2.71 mmol) and 3-amino-phenol (592 mg, 5.43 mmol) in DMF (20.0 mL) were added benzotriazol-1-yl-N-oxy-trispyrrolidino)-phosphonium hexafluorophosphate (PyBOP) (2.8 g, 5.43 mmol), and N,N-diisopropylethylamine (DIPEA) (0.95 ml, 5.43 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=10:3:1) gave 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide as a white solid (837 mg, 99% yield)
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1cc(C#N)ccc1N
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCN(C(=O)CCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DMF solution (4.0 ml) containing the compound (0.501 g) obtained in Example 46-2 was added with 60% sodium hydride (76.0 mg) and the whole was stirred at room temperature for 30 minutes. The solution was cooled with ice and then 1-iodopropane (0.184 ml) was dropped thereto. The whole was stirred at room temperature for 23 hours. The solvent in the reaction solution was distillated off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (ethyl acetate/chloroform), thereby obtaining the subject compound (0.378 g) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: FC(F)(F)Sc1ccc(CCl)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A mixture of 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (16.2 mg, 0.050 mmol) with 4-(trifluoromethylthio)benzyl chloride (20.3 mg, 0.075 mmol), acetonitrile (1.0 mL) and chloroform (0.56 mL) was stirred at 60° C. for 15 hours, cooled, then loaded onto a VarianM SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-5-chlorobenzoyl) glycyl]aminomethyl]-1-[4-(trifluoromethylthio)benzyl]piperidine (Compd. No. 1616) (21.9 mg, 85%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 545.2 (M++H, C23H26ClF3N4O2S).
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[K+].[Br-]>CO>[CH:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C1NC(c2ccccc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=C1NC(C2CCCCC2)C1O
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone VIa and 15 mg of Rh-C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtered on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of VIIe as a white solid: White solid; mp 140°-140.5° C.; [α]D20 +65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (m, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm-1. Anal. Calcd for C9H15NO2 : C, 63.88, H, 8.93, N, 8.28. Found: C, 63.70, H, 9.00, N, 8.06.
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2:5].[P:6]([O-:10])([O-:9])([OH:8])=[O:7].[Ca+2]>O>[OH2:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[Ca+2:5]
Reactant: O=C([O-])[O-]
Reactant: O=P([O-])([O-])O
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Powdery calcium carbonate and a powdery dihydrate of calcium monohydrogenohosphate are weighed to get a Ca/P ratio of 1.45 to 1.67. The powdery mixture thus prepared is then added pure water at a temperature of 30° C. or higher to obtain an aqueous slurry having a concentration of about 10% by weight. Thereafter, the aqueous slurry is subjected to a rotational attrition by using a ball mill to conduct a mechanochemical reaction of the calcium carbonate with the dihydrate of calcium monohydrogenphosphate. The slurry is then dried completely at 80° C., followed by pulverization to yield a dry powder of calcium phosphate hydrate. The dry powder is calcinated at a temperature ranging from 720° to 1,150° C. for 1-10 hours or more to give calcium phosphate powder, which is molded in a desired shape and is sintered at a certain temperature to obtain a sintered body of calcium phosphate. The calcium phosphate and the sintered body thereof, thus prepared, have an assured biological safety in that the calcium phosphate is free from hemolysis, antigenicity and cytotoxicity.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][CH2:8][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)CBr)cc1
Yield: 83.5 %

Procedure:
To a solution of 1-p-tolyl-ethanone (0.5 g, 4.16 mmol) in dichloromethane-methanol (50 ml-20 mL) was added tetrabutylammonium tribromide (2.2 g, 4.58 mmol) at room temperature. The mixture was stirred until the orange color faded. The solvent was then distilled under reduced pressure and the resulting precipitate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash column chromatography to yield the desired product 2-bromo-1-p-tolyl-1-ethanone (0.74 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.89 (s, 2H), 7.37 (d, 2H), 7.89 (d, 2H); ESI-MS (MK): 213 and 215.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[CH:5][C:6]([N+:23]([O-])=[O:24])=[C:7]([CH:9]([O:16]C(=O)C(Cl)(Cl)Cl)C2C=CC=CC=2)[CH:8]=1.CN(C)C1C=CC([N+]([O-])=O)=C(C=1)COC(=O)C(Cl)(Cl)Cl>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[CH:5][C:6]([N:23]=[O:24])=[C:7]([CH:8]=1)[CH:9]=[O:16]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(OC(=O)C(Cl)(Cl)Cl)c2ccccc2)c1
Agent: CN(C)c1ccc([N+](=O)[O-])c(COC(=O)C(Cl)(Cl)Cl)c1
Product: CN(C)c1ccc(N=O)c(C=O)c1
Yield: 30 %

Procedure:
Photolysis of 5-dimethylamino-2-nitrobenzyltrichloroacetate (41) and α-phenyl-5-dimethylamino-2-nitrobenzyltrichloroacetate (42) appeared to be of particular promise. They have absorption maxima at 395 and 398 nm, respectively, with molar extinction coefficients of around 17000 M.cm−1. The photolysis of compound 41, with no substitution at the α-position, was slower than that of the esters having an α-substitution16,17. Thus irradiation at 0.2% concentration, at 365 nm, gave the expected photoproduct, 5-dimethylamino-2-nitrosobenzaldehyde (53), in 30% yield after 16 min. In addition, the amount of accompanying secondary photoproducts, around 10%, was the highest among the esters evaluated so far. On the other hand, irradiations at lower concentrations indicated that the inner filter effect was diminishing as the photolysis proceeded. This was not the case with any esters tested by us before. Preliminary illuminations of compound 41 with blue light, λ>395 nm, at 0.002% concentration, carried out with the high pressure mercury arc lamp equipped with appropriate filters, gave about 12% photoconversion after 16 min. This result indicates that the development of photolabile esters whose activation would require considerably less expensive sources of visible light is feasible.
Reaction SMILES: [CH2:1]1[C@:6]2([OH:10])[C:7]([O:9][C@@H:4]([CH2:5]2)[C@@H:3]([OH:11])[C@H:2]1[OH:12])=[O:8].Cl.C(=O)(O)[O-:15].[Na+].[Na+].[Cl-]>C1COCC1>[CH2:5]1[C@@H:4]([OH:9])[C@@H:3]([OH:11])[C@H:2]([OH:12])[CH2:1][C@@:6]1([C:7]([OH:15])=[O:8])[OH:10]
Reactant: O=C1O[C@H]2C[C@]1(O)C[C@H](O)[C@@H]2O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Temperature: 0 °C

Procedure:
A solution of 12.7 g (12.2 mmol) 1,3-O-dicarbotrichloroethoxy-4-O-dicarbotrichloroethoxycaffeoyl quinide in 870 ml THF is treated for 3 days with 9 ml concentrated HCl. After cooling to 0° C., the reaction mixture is adjusted to pH 2 by addition of solid sodium bicarbonate and is then saturated with NaCl. The organic phase is then separated and the aqueous phase is extracted with 2×20 ml ethyl acetate. After the combined organic phases have been dried over sodium sulfate, the solvents are evaporated. Treatment of the residue with a solvent mixture of THF and hexane in a ratio by volume of 1:20 gives 12.7 g 1,3-O-dicarbotrichloroethoxy- 4-O-dicarbotrichloroethoxycaffeoyl quinic acid in the form of an amorphous white powder (yield 99%) .
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)C>[N:21]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: O=c1cc(-c2cccc(F)c2)c2ccc(CBr)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Reaction time: 8 h

Procedure:
To a solution of 7-(bromomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (1.16 g, 3.5 mmol) in ethanol (35 mL), sodium azide (248 mg, 3.8 mmol) was added. The reaction mixture was then stirred overnight at reflux. After cooling, the reaction mixture was concentrated under reduced pressure and the crude residue was dissolved with CH2Cl2. Salts were removed by filtration and the filtrate was concentrated under reduced pressure to afford the tittle compound. 1H NMR (400 MHz, acetone-d6): 7.72-7.6 (m, 1H), 7.65 (d, 1H), 7.47-7.32 (m, 5H), 6.42 (s, 1H), 4.67 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27]([NH:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Nc1cccc(-c2ccc(F)cc2)c1
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccc(F)cc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-3-amine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid to give 5-chloro-2-([((2-[(4′-fluorobiphenyl-3-yl)amino]-2-oxoethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 78%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:22]([C:24]1[N:25]=[C:26]([C:37](O)=[O:38])[N:27]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:28]=1)#[N:23].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][NH:15][S:16](=[O:20])(=[O:19])[NH:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:37]([C:26]2[N:27]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:28]=[C:24]([C:22]#[N:23])[N:25]=2)=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Yield: 25 %

Procedure:
2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 30.7 mg, 0.100 mmol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 33.6 mg, 0.260 mmol) as described in Example 1, step (1) to obtain the title compound (14 mg, 25%) after purification on silica (20-50% EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C26H36N6O4SSi, 557.2 (M+H). found 556.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]>C(Cl)(Cl)Cl>[N:4]1([CH2:3][CH2:2][NH:1][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)NCCN1CCCCC1
Temperature: 25 °C

Procedure:
7.3 Grams of N-(2-aminoethyl)piperidine, 5.2 g of triethylamine and 100 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 15.8 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 16.3 g of the desired product. m.p. 48° C.