Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=O)[C:12]3=[O:21])[C:6]=2[CH:22]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[N:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=4)[C:12]3=[O:21])[C:6]=2[CH:22]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1csc2ccc(Cl)cc12
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 1-[(5-chloro-1-benzothien-3-yl)methyl]-2H-indole-2,3-dione (50 mg, 0.15 mmol) and 3-trifluoromethylaniline (0.020 mL, 0.15 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 1:3 ethyl acetate and hexane as the eluent giving the desired product as a yellow solid (13 mg, 0.030 mmol, 18%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (298 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-methyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-ylacetate (670 mg, yield 85%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[CH:17]=[CH:18][C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[C:2]=[O:3])=[CH:12][C:11]=1[CH:17]=[CH:18][C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(Cl)OC(=O)C=Cc1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(Cl)OC(=O)C=Cc1cc(N=C=O)ccc1Cl

Procedure:
108.8 g of trichloromethyl chloroformate were added to a suspension of 130 g of 4-chloro-3-(α-chloroethoxycarbonylethenyl)-aniline in 1200 ml of toluene. The stirred mixture was refluxed for 16 hours. After the resulting precipitate had been separated off, the solvent was removed under reduced pressure, the residue was stirred with petroleum ether and the precipitate was removed and dried.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][C:7](=[O:10])[CH2:8]Br)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[N-:17]=[N+:18]=[N-:19].[Na+]>>[C:1]1(=[O:16])[N:5]([CH2:6][C:7](=[O:10])[CH2:8][N:17]=[N+:18]=[N-:19])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)CN1C(=O)c2ccccc2C1=O
Yield: 95 %

Procedure:
A suspension of (3-phthalimidoacetonyl)bromide, ethylene ketal (70.0 g, 210mmole) and sodium azide (33.0 g, 504 mmole) in 25 ml. of dimethyl sulfoxideis heated on a steambath under nitrogen for 4 days. The above mixture is poured onto ice and extracted with chloroform (3×, 500 ml). The chloroform extract is washed with water (2×), saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation of chloroform in vacuo gives a white oil which on trituration with hexane crystallizes to afford 59 g, (95%) of (3-phthalimidoacetonyl)azide, ethylene ketal as white prisms of melting point 90.5°-92° C.An analytical sample recrystallized from ethyl acetate hexane has a meltingpoint 92.5°-93.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.500 g, 3.06 mmol) in acetone (0.4M, 7.5 mL) cooled to 0° C. was added KOH (0.258 g, 4.60 mmol). After 15 minutes at 0° C., (bromomethyl)benzene (0.400 mL, 3.37 mmol) was added. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (50% EtOAc/hexanes) providing 256 mg (33%) of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:27])[C@H:19]([CH3:26])[NH:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:10]>CN(C)C=O>[CH2:9]([NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:27])[C@H:19]([CH3:26])[NH:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH3:10]
Reactant: O=C1CCCC(=O)O1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)N
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CCCC(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
1.7 g of glutaric anhydride was added to a solution of 4.0 grams of alanyl-alanyl proline ethylamide in 25 ml of dimethylformamide and the reaction solution heated for 1 hour at 60 degrees C. Then, the solution was evaporated and the resultant non-crystalline evaporation residue dissolved in 30 ml of ethyl acetate. After 48 hours of standing at 3 degrees C., 3.6 g of separated product was filtered off with a melting point of 154 to 156 degrees C. ([α]D20 -137.3 degrees (c 0.3; 50% methyl alcohol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.B>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M/THF, 4 eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 0° C. and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95% yield.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O:23][B:24](OC)[O:25]C.Cl>C(OCC)C>[CH2:15]([O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[B:24]([OH:25])[OH:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(OCc2ccccc2)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of butyl lithium (1.6M in hexane) (50 ml) was added dropwise to a stirred solution of the product from step (i) (23 g) in diethylether (300 ml) at −70° C. After 1 h a further 18 ml of butyl lithium was added, left for 0.75 h, then trimethylborate (10 ml) added and the mixture warmed to RT and left for 16 h. 2M Hydrochloric acid (100 ml) was added, stirred for 1 h then the organic layer separated and extracted with aqueous sodium hydroxide solution. The basic layer was acidified with 2M hydrochloric acid solution, extracted with diethylether which was dried and evaporated under reduced pressure. The residue was triturated with iso-hexane and filtered. Yield 10.8 g
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[CH2:32][CH2:33]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.1 g, 5.28 mmol) in DMF (10 mL) is added triethylamine (1.47 mL, 10.57 mmol), followed by 1-hydroxy-7-benzotriazole (0.755 g, 5.55 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.06 g, 5.55 mmol). After stirring 15 min at RT, 1-(3-nitro-phenyl)-piperazine (1.09 g, 5.28 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and brine (50 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (cyclohexane/ethylacetate 0-80%) to give 2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-ethanone (1.24 g, 59%). 1H-NMR (400 MHz, MeOD): δ=2.31 (s, 3H), 3.31-3.40 (m, 2H), 3.41-3.49 (m, 2H), 3.77-3.85 (m, 4H), 5.25 (s, 2H), 6.43 (s, 1H), 7.38-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.69-7.72 (m, 1H), 7.80-7.81 (s, 1H). MS: m/z=398 (M+1).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[CH:29])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35](=[O:37])=[O:36]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[C:29][C:35]([OH:37])=[O:36])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=C=O
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (45 ml) was added dropwise to a solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (132 g) in tetrahydrofuran (1 l.) keeping the temperature below -40°. The mixture was stirred at -60° for 2 hours and then carbon dioxide gas was passed through the solution for 30 minutes with cooling in an acetone/solid carbon dioxide bath. The mixture was allowed to warm to 0° while the passage of carbon dioxide gas was continued and then it was quenched with water (1 l.) and the layers separated. The aqueous layer was extracted into ether (500 ml) and the combined organic layers were washed with water, diluted with dichloromethane, washed with 1M HCl, dried over MgSO4 and evaporated. The residue was triturated with methanol and the resulting solid collected, washed with cold (-20°) methanol and dried to give 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoic acid, (83.7 g), m.p. 150°-152°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[C:13]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[CH2:14][C:15]([CH3:17])=O>CO>[CH2:20]([O:19][C:13]([CH:14]=[C:15]([NH:11][CH:4]1[CH2:3][C:2]([CH3:12])([CH3:1])[CH2:7][C:6]([CH:9]([NH:10][C:15]([CH3:17])=[CH2:14])[C:13]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])([CH3:8])[CH2:5]1)[CH3:17])=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(=O)CC(=O)OCC(C)C
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Solvent: CO
Product: C=C(C)NC(C(=O)OCC(C)C)C1(C)CC(NC(C)=CC(=O)OCC(C)C)CC(C)(C)C1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To isophoronediamine (139.23 g, 0.819 mol) in methanol (700 ml) was slowly added with stirring isobutyl acetoacetate (262.31 g, 1.660 mol) in methanol (700 ml) over 45 minutes, during which the temperature increased from 22° C. to 30° C. The reaction mixture was allowed to stand at 21° C. overnight (15 h). Further methanol was added, and removal of solvent and drying (91° C./100 Pa) gave 1-(1-isobutoxycarbonyl-2-prop-1-enylamino)-3-(1-isobutoxycarbonyl-2-prop-1-enylaminomethyl)-3,5,5-trimethylcyclohexane (IIMTCH) as a clear light yellow viscous syrup (366.80 g, 100%), which set to a soft gum on standing and was identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][C:23](=O)[CH:24]=[CH2:25])[CH:17]=[CH:18][CH:19]=1>[OH-].[K+]>[CH2:1]([C@:5]12[CH2:6][CH2:7][C:8]3[C:17]4[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=4[CH2:20][CH2:21][C:22]=3[C:23]1=[CH:24][CH2:25][C:9]2=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Reactant: CCCCC1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Product: CCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC2=O
Yield: 32.5 %

Procedure:
Condense n-butylcyclopentane-1,3-dione (2.8 g) in 0.12% methanolic potassium hydroxide solution (8 cc) with 6-m-methoxyphenylhex-1-en-3-one (5 g) by heating the mixture at 80° for 10 hours. Evaporate the solvent under reduced pressure and heat the residue with toluene-p-sulfonic acid (2 g) in benzene (50 cc) for 45 minutes using a Dean-Stark trap to effect double cyclodehydration. Add ether to the cooled reaction mixture, and evaporate the washed and solution; recrystallize ether solution;recrystallize the residue from ethanol to obtain 13β-butyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (1.9 g), m.p. 53°-55°; ultraviolet absorption peak at 312 mμ (ε29,200).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11]Br)=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)oc1CBr
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)c1cc(Br)oc1CNCc1ccc(OC)cc1

Procedure:
A solution of 5-bromo-2-bromomethyl-furan-3-carboxylic acid methyl ester (1.74, 5.88 mmol) and p-methoxy benzylamine (0.76 mL, 5.88 mmol) in MeOH (30 mL) is stirred at 85° C. for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 4:1 petroleum ether:ethyl acetate followed by 1:1 petroleum ether:ethylacetate. The title compound is isolated (643.8 mg).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:31]([F:34])([F:33])[F:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N+:28]([O-])=O)[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Zn]>[NH2:28][CH:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[C:13]=2[C:31]([F:33])([F:34])[F:32])[CH:18]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(CCC(=O)O)[N+](=O)[O-])ccc3c2C(F)(F)F)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(N)CCC(=O)O)ccc3c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Zinc (0.194 g, 2.96 mmol) was added to a solution of 4-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-nitro-butyric acid (0.102 g, 0.212 mmol) in acetic acid (3.00 mL, 52.8 mmol). The mixture was stirred for 2 hours at room temperature. HPLC analysis showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The resulting crude product was dissolved in DMSO (4 mL) and purified by HPLC. The product was dried for 2 days under vacuum to give 28 mg of the title compound as a white solid (26% yield). MS: m/z=435.66 [M-16]+. 1H NMR (MeOD, 400 MHz): δ=8.24-8.30 (m, 1 H), 8.09-8.14 (m, 1 H), 7.92-7.96 (m, 1 H), 7.56-7.65 (m, 2 H), 4.45-4.57 (m, 2 H), 2.65-2.69 (m, 2 H), 2.26-2.46 (m, 4 H), 2.18-2.26 (m, 2 H), 1.87-1.97 (m, 2 H), 1.45-1.58 (m, 2 H), 1.18-1.31 (m, 2 H), 1.06-1.17 (m, 1 H), 0.92 (s, 9 H)
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@@H:4]1[NH2:5].C(N([CH2:19][CH3:20])CC)C>CN(C=O)C>[C:3]([NH:5][C@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])(=[O:2])[CH2:4][CH2:6][C:19]#[CH:20]
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: C#CCCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of D-mannosamine hydrochloride (863 mg, 4.0 mmol), N-succinimidyl 4-pentynoate 9 (781 mg, 4.0 mmol), triethylamine (1.67 ml, 12.0 mmol) in DMF (31 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (CHCl3/MeOH 8:1) to give N-4-Pentynoylmannosamine, 10 (898 mg, 87%); 1H-NMR (500 MHz, D2O) 2.37 (t, 2.63H, J=2.5 Hz), 2.48-2.63 (m, 10.5H), 3.38-3.42 (m, 1H), 3.52 (t, 1H, J=10 Hz), 3.63 (t, 1.63H, J=10 Hz), 3.69-3.91 (m, 7.89H), 4.05 (dd, 1.63H, J=4.5 and 10 Hz), 4.35 (dd, 1.63H, J=1.5 and 4.5 Hz), 4.47 (dd, 1H, J=1.5 and 4.5 Hz), 5.03 (d, 1H, J=1.5 Hz), 5.13 (d, 1.63H, J=1.5 Hz); 13C-NMR (125 MHz, D2O)□ 14.78, 14.91, 34.62, 34.79, 53.67, 54.50, 60.91, 60.93, 67.01, 67.28, 69.25, 70.56, 70.71, 72.47, 72.50, 76.80, 84.04, 84.45, 93.36, 93.67, 175.68, 176.41; ESI-TOF-HRMS m/e calculated for (M+H)+ C11H17NO6260.1129; found 260.1120.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([NH2:28])=[S:27])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:28]=[C:26]([NH:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[S:27][CH:2]=1)[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 56 mg (0.33 mmol) ethyl 4-chloroacetoacetate and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with diethyl ether yielding 115 mg (98%) {2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester as an off-white solid. MS ISP (m/e): 373.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.68 (s, 1H), 9.26 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.46 (d, 1H), 7.22 n(d, 1H), 6.79 (s, 1H), 4.09 (q, 2H), 3.83 (s, 3H), 3.67 (s, 2H), 2.33 (s, 3H), 1.19 (t, 3H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:53][O:52][C:48]1[CH:47]=[C:46]([CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH:51]=[CH:50][CH:49]=1
Reactant: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1
Yield: 31.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3-methoxyphenethyl)-1-piperidinecarboxamide (0.110 g, 0.14 mmol) was reacted according to Procedure H to yield (eluant: 5:1 chloroform-methanol) the title compound (0.025 g, 0.044 mmol).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(F)cc1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 41 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-fluorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM. Yield: 41% (after two steps)
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22]/[C:23](=[CH:25]/[CH2:26][OH:27])/[CH3:24])[CH3:19]>[Cl-].[Zn+2].[Cl-]>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([O:27][CH2:26]/[CH:25]=[C:23](/[CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])\[CH3:24])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: [Cl-]
Agent: [Zn+2]
Product: C=CC(=O)N1Cc2ccccc2SC(OC/C=C(\C)CCC=C(C)C)C1
Yield: 68.3 %

Procedure:
The above-mentioned 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g), geraniol (0.9 g) and zinc chloride (0.8 g) were reacted in the same manner as in Experimental Example 9 to give 4-acryloyl-2-geranyloxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g).