Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][S:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)C=Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
163 g of 2-(4-fluorophenyl)ethenesulfonyl chloride were dissolved in 1.5 l of toluene and, at RT, 69.64 g of phenol were added. Subsequently, at RT, 103 ml of triethylamine were added dropwise, during which the temperature rose to 44° C. The mixture was then stirred at RT for 90 minutes, left to stand for 16 hours and stirred at RT for a further 2 hours. The solvent was then removed in vacuo, and the crude product was taken up in 2.5 l of EA. Washing 3 times with 750 ml of a saturated aqueous NaHCO3 solution was followed by washing 3 times with 750 ml of 2 N aqueous HCl solution each time. After drying over Na2SO4, the solvent was removed in vacuo. The product was then stirred in 350 ml of HEP for 1 hour and, on cooling, the product crystallized and was washed with HEP and dried under medium vacuum. 145.0 g of white crystals were obtained, mp 108° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]([O:11][CH:12]([Cl:14])[CH3:13])=[O:10].[Cl-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60° C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[CH:27]=[CH:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:33][C:28]=2[CH:27]=[CH:26]1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc2occc2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5occc5c4)nc3c2)cc1

Procedure:
Compound 188 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzofuran-5-carboxaldehyde. [M+H]+ calcd for C24H20N4O2: 397.16; found: 397.52.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:15][C:14]1[C:6]([Cl:5])=[C:7]2[C:11]([CH2:20][CH2:21][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Thionyl chloride (5.73 mL, ˜79 mmol) and 2,3-dichloro-benzoic acid (commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene was heated to reflux until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to AlCl3 (7.0 g, ˜53 mmol) in dichloroethane at 10-20° C. Ethylene was bubbled through the mixture for 4 h. The mixture was stirred overnight and quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. The concentrate was added to a slurry of AlCl3 (9.0 g) and NaCl (2.4 g) at 130° C. The resulting mixture was stirred at 180° C. for 2 hours after which it was cooled to room temperature and quenched with ice followed by concentrated HCl. The mixture was extracted with CH2Cl2 (3×500 mL) and the combined organic extracts were concentrated and purified by column chromatography using 20% EtOAc:hexane eluant to give 6.8 g (80%) of 6,7-dichloro-1-indanone. Use of 6,7-dichloro-indan-1-one in Method NINETEEN produced 4-(4,5-dichloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 153).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=C1C(Cc2ccncc2)c2cccnc2N1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N(c2ccc(Cl)cc2)c2ncccc2C1(Cc1ccccc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1,3-dihydro-1-(4-chlorophenyl)-3-(4-pyridinylmethyl)-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 8.93 mmol) and 20 ml 1N NaOH was treated with enough MeOH to effect solution. The mixture was treated with benzyl chloride (1.24 g, 9.82 mmol) and stirred at room temperature for 24 h. The resulting solid was collected by filtration, washed with water, and dried in vacuo to give the desired product in 87% (3.30 g) yield; mp 182°-185° C.; IR(nujol): 1727 cm-1 (CO); 1H NMR(CDCl3TMS): d 3.29 (dd, 2H, Phe-CH2), 3.4-3.-7 (g, 2H, Pyr-CH2), [6.75 (d, J=8.8, 2H), 6.9 (m, 2H), 7.1 (m, 6H), 7.35 (d, J=8.4, 2H), 7.61 (d, J=7.3, 1H), 8.05 (d, J=6.6, 1H), 8.33 (d, J=6.2, 2H), Ar]; mass spec m/e 426(M+1). Anal calcd for C26H20N3OCl, MW 425.92: C, 73.32; H, 4.73; N,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(OCC)C>[C:13]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:10]=[CH:11][CH3:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC=NNc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC=NN(C(=O)c1ccccc1)c1ccc(OC)cc1
Reaction time: 24 h

Procedure:
Combine N-(4-methoxyphenyl)-N'-ethylidene hydrazine (6.0 g, 43 mmol), benzoyl chloride (5.2 mL. 44 mmol), pyridine (3.7 mL, 46 mmol), and diethyl ether (25 mL). After 24 hours, add diethyl ether (100 mL), remove the solid by filtration and dry in vacuo to give N-benzoyl-N-(4-methoxyphenyl)-N'-ethylidene hydrazine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[CH2:13]O)=[CH:4][CH:3]=1.Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>O1CCCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2/[CH:13]=[CH:17]/[C:16]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: OCc1nnsc1-c1ccc(F)cc1
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1nnsc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
[5-(4-Fluorophenyl)-1,2,3-thiadiazol-4-yl]methanol (0.75 g) was dissolved in tetrahydrofuran (30 ml) and activated manganese dioxide (3 g) was added. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated. Ethyl diethylphosphonoacetate (0.50 g) and N,N-dimethylformamide (10 ml) were added to the residue. To this mixture was added sodium hydride (60% in oil, 80 mg) at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into an aqueous dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil. A 6N aqueous hydrochloric acid solution (10 ml) and acetic acid (5 ml) were added to this yellow oil and the mixture was stirred for 3 hrs. with heating under reflux. The reaction mixture was concentrated, poured into water, and the precipitated solids were filtered, washed with water and dried to give (2E)-3-[5-(4-fluorophenyl)-1,2,3-thiadiazol-4-yl]acrylic acid (190 mg, yield: 21%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.41 (s, 1H), 7.49 (m, 2H), 7.56 (m, 1H), 7.80 (t, J 7.8, 1H), 7.95 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.60 (d, J 6.8, 1H), 8.72 (t, J 5.8, 1H), 9.56 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[O:17][CH:18]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)[CH2:19][CH2:20][CH2:21][N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1>CC#N.C(Cl)(Cl)Cl>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH:18]([O:17][C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:19][CH2:20][CH2:21][N:22]2[CH2:29][CH:28]3[O:30][CH:24]([CH2:25][N:26]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:27]3)[CH2:23]2)=[CH:38][CH:37]=1)#[N:36]
Reactant: COc1ccc(OC(CCCN2CC3CNCC(C2)O3)c2ccc(C#N)cc2)cc1OC
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1CC2CN(CCCC(Oc3ccc(OC)c(OC)c3)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of ethyl isocyanate (18.8 mg, 0.25 mmol) in MeCN (2 mL) was added, together with K2CO3 (34.5 mg, 0.25 mmol), to a solution of 4-[1-(3,4-dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (Preparation H; 109.4 mg, 0.25 mmol) in chloroform (0.5 mL). The reaction mixture was stirred at rt for 4 days before being added to a solid phase extraction plug (SiO2, 0.5 g). The plug was washed with CHCl3:MeCN (2.5 mL of 80:20), and the product was finally eluted with CHCl3:MeOH (3×2.5 mL of 95:5) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]C(CC)C.[C:31](=[O:33])=[O:32]>CCOCC.O>[CH3:15][C:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[C:31]([OH:33])=[O:32])[CH2:6][CH2:7]1)=[O:12])([CH3:17])[CH3:16]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)cc21
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2ccc(F)c(C(=O)O)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 6-fluoro-2,3-dihydro-1H-indole-1-carboxylate (8.7 g, 0.037 mol) in Et2O (150 mL) at −78° C. was added TMEDA (7.2 mL, 0.048 mol) and a solution of 1M sec-BuLi (44 mL, 0.044 mol) dropwise. The reaction mixture was stirred for 1 h at −78° C. and then poured onto crushed CO2 (250 mL). The mixture was allowed to warm to room temperature overnight. The suspension was diluted with water (200 mL) and diethyl ether (50 mL), and the layers were separated. The aqueous fraction was acidified with 1M HCl and extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure giving 8.0 g (77%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(=S)=S>[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Acetyl chloride (1 to 1.2 eq) and AlCl3 (1 to 1.2 eq) are mixed with carbon disulfide, 3-bromoanisole dissolved in carbon disulfide is added thereto. The resulting mixture is stirred for 10 to 16 h at room temperature, to obtain 1-(2-bromo-4-methoxyphenyl)ethanone of formula 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[OH:16].[C:18]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[O:16][CH3:18]
Reactant: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl)quinolin-4-ol (Step 1, 3.54 g, 13.3 mmol, 1 eq.) in acetone (75 mL) was added anhydrous K2CO3 (3.88 g, 28.0 mmol, 2.1 eq.), followed by iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.). The resulting mixture was stirred at reflux for 1.5 hours. An additional aliquot of iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.) was added and reflux was continued for an additional 1 hour. The reaction was cooled to room temperature, poured onto ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give 3.72 g (100% yield) of the desired product as a yellow solid, which was used in subsequent reactions without further purification. An analytical sample was prepared by recrystallization from hexane/ethyl acetate; MP=198-200° C.; MS (ES) m/z (relative intensity): 280 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Yield: 105.4 %

Procedure:
1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (O2.007; 1.63 g) was dissolved in THF (150 ml), and phenyltrimethylammonium tribromide (2.2 g) was added at RT while stirring. After stirring at RT for 2 h, the mixture was admixed with water, neutralized with sodium hydrogencarbonate solution and extracted three times with EA. The alkaline water phase was extracted 3× with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, neutralized with sodium hydrogencarbonate and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 1.27 g of the title compound were isolated. LC-MS rt: 1.65 min [M+H]+: 354.9 (met. b)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(CCN(C)C)C.[Li]CCCC.[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](N(OC)C)=[O:47])[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](=[O:47])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: c1cscn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)c1nccs1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of thiazole (0.035 mL, 0.5 mmol) and TMEDA (0.068 mL, 0.45 mmol) in anhydrous THF (1.0 mL) cooled to −60° C. is added n-BuLi (0.17 mL, 0.43 mmol). After stirring for 20 min at −60° C., a solution of N,β,β-trimethyl-L-phenylalanyl-N1-{(1S,2E)-1-isopropyl-4-[methoxy(methyl)-amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (52 mg, 0.1 mmol, from Example 52, in anhydrous THF (0.5 mL) is added. The purple reaction mixture is stirred for 2 h from −60° C. to room temperature, quenched with saturated aqueous ammonium chloride (1.5 mL). The reaction mixture is extracted with ethyl acetate three times. The combined organic layers are dried (Na2SO4), filtered and concentrated. The residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile) to give 56 mg (86%) of desired product as a yellow solid. HRMS (ESI) calcd for C30H44N4O3S [M+H] 541.3207, found 541.3203.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([F:8])[CH2:6][OH:7])[CH3:2].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([F:8])[CH2:6][O:7][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(F)CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(F)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A crude product of 2-fluoro-3-hydroxypropionic acid ethyl ester (13.06 g) was dissolved in dichloromethane (300 ml). Imidazole (17.2 g, 252.57 mmol) and tert-butyldiphenylsilyl chloride (25 ml, 96.14 mmol) were added to the solution under cooling on ice, and the reaction solution was stirred for 18 hours while raising the reaction solution temperature to room temperature. Saturated sodium bicarbonate water was added to the reaction solution and the resultant was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 17.98 g (three steps, 57%) of the title compound in the form of a colorless clear oily product.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=O)[CH3:12]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:11](\[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)/[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)c1cccnc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: C/C(=N/Nc1ccc(Br)cc1)c1cccnc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromophenylhydrazine hydrochloride (11.5 g, 50 mmol) in anhydrous ethanol (200 mL) is added 3-acetylpyridine (6.1 g, 50 mmol). The mixture is heated to 90° C. and stirred for 3 h, cooled to room temperature and filtered through a sintered glass funnel. The solid is washed with ethanol and placed under high vacuum overnight to give N-(4-bromo-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazine hydrochloride as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]1=[O:33])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CCCC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide, 0.35 g of glutaric anhydride and 0.85 ml of triethylamine in 30 ml of dry toluene was heated at reflux under a nitrogen atmosphere for 7 hours. The mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was then evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,6-dioxopiperidino)valeramide in the form of a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>CO.O>[F:14][C:12]([F:13])([F:15])[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1
Reactant: CC(=O)OCc1cc(C(F)(F)F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methyl acetate (1.0 g, 3.2 mmol) in methanol (10 mL) was added a 1.0 M solution of sodium hydroxide in water (10 mL). After being stirred at room temperature overnight, the solution was diluted with 20 mL of water and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum. Chromatography on silica gel eluting with hexanes/EtOAc (1:1) afforded the title compound (0.34 g) as a clear oil. MS (M+H) 178.1.