Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH:14]=[O:15])=[CH:9][C:8]=1[O:16][CH3:17])(=O)=O.CCOC(C)=O.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:26]#[N:27])=[C:8]([O:16][CH3:17])[CH:9]=1)=[O:15]
Reactant: COc1cc(C=O)c(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(C)cc1C#N
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate (35.0 g, 117 mmol), zinc cyanide (55.1 g, 469 mmol) and tetrakis triphenylphosphine palladium (0) (20.34 g, 17.60 mmol) in DMF (300 mL) were stirred at 110° C. under nitrogen atmosphere for 8 hr. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxy-5-methylbenzonitrile. 1H NMR (CDCl3, 500 MHz) δ 10.39 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.02 (s, 3H), 2.66 (s, 3H); LC/MS: (IE, m/z) [M+1]+=176.06; tR=2.71 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC[O-].[Na+]>>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[O:24])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCCCc1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(CCCc1ccc(OC)cc1)C(=O)OCC
Yield: 82.2 %

Procedure:
17.2 g of 3-ethoxycarbonyl-6-(4-methoxyphenyl)-2-oxocaproic acid ethyl ester are prepared from 14.7 g of 5-(4-methoxyphenyl)-valeric acid ethyl ester and 11.8 g of diethyl oxalate, using sodium ethylate as the base, in a manner analogous to that in Example (1b).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][C:7]=2[O:6]1>C(Cl)(Cl)(Cl)Cl>[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Br:2])=[CH:8][C:7]=2[O:6]1
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)OCO2
Yield: 121.1 %

Procedure:
A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of 3,4-methylenedioxyphenethyl alcohol (15.0 g) (see Preparation 14) in carbon tetrachloride (200 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice), 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (100 g) using carbon tetrachloride as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a pale yellow oil (8.3 g, 40%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr
Yield: 96.4 %

Procedure:
A mixture of 3-chloro-2-methylanisole (2 g), N-bromosuccinimide (2.39 g) and 2,2′-azobis(2-methylpropionitrile) (32 mg) in carbon tetrachloride (15 mL) was heated at reflux for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (2.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Reactant: C#CC(=O)OCC
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)ns1
Temperature: 135 °C
Yield: 31.8 %

Procedure:
To a stirred solution of 5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one (42.80 g, 217.1 mmol) in o-dichlorobenzene (600 mL) was added ethyl propiolate (66.0 mL, 651 mmol). The mixture was heated overnight at 135° C. and concentrated. The residual oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 3-(4-fluorophenyl)isothiazole-5-carboxylate as a pale golden solid (17.35 g, 32%). The more polar, ethyl 3-(4-fluorophenyl)isothiazole-4-carboxylate isomer (generated in 57/43 ratio versus the desired product) was discarded.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
In a reaction vial, (imino-{5-methylsulfanyl-4-[3′-(2,2,2-trifluoro-1-hydroxy-ethyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 28, step c) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (31 mg, 0.072 mmol, Lancaster Synthesis, Windham, N.H.) were dissolved in DCM (2 mL). To that solution, wet DCM (1 mL, 4 μL H2O) was added slowly via a syringe. After 1 hr of stirring at rt, the reaction was evaporated and the residue was partitioned between Et2O (30 mL) and 10% Na2S2O3-saturated NaHCO3 (1:1, 15 mL). The aqueous layer was washed with an additional portion of Et2O. The combined organic washes were dried with MgSO4 and concentrated in vacuo to give 30 mg (quantitative yield) of the title compound that was used without purification. 1H-NMR (CDCl3; 400 MHz) δ 8.28 (br s, 1H), 8.26 (t, 1H, J=1.7 Hz), 8.08–8.13 (m, 1H), 7.99–8.04 (m, 1H), 7.96 (s, 1H), 7.91–7.95 (m, 1H), 7.82–7.86 (m, 1H), 7.62–7.71 (m, 2H), 2.59 (s, 3H), 1.51 (s, 9H). 19F-NMR (CDCl3; 400 MHz) δ −84.93 (s). ESI-MS (m/z) Calcd. for C25H23F3N2O5S3: 487.6 (M+H); found: 487.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][CH:15]=[CH2:16])([CH3:13])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C>C1C=CC=CC=1>[CH2:14]([C:4]1([CH3:13])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:18])[CH:12]=[C:3]1[O:2][CH3:1])[CH:15]=[CH2:16]
Reactant: C=CCC1(C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: C=CCC1(C)C(OC)=CC(=O)c2ccccc21
Yield: 24.9 %

Procedure:
To a solution of Example 123B (7.72 g, 36.1 mmol) in benzene (400 mL) was added celite (15 g), pyridinium dichromate (54.3 g, 144.3 mmol) and tert-butylhydroperoxide (70% in water) (19.9 mL, 144.3 mmol). The resultant solution was stirred at room temperature for 1.25 hours, followed by filtering the solution through a plug of celite (20 g) which was rinsed with benzene (100 mL). The combined filtrate was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with a mixture of 20% ethyl acetate in hexane followed by 50% ethyl acetate in hexane to provide the title compound as a light yellow oil (2.05 g, 25%). 1H NMR (300 MHz, DMSO-d6): δ 1.53 (s, 3 H), 2.77 m, 2 H), 3.82 (s, 3 H), 4.75 m, 2 H), 5.02 (m, 1H), 5.84 (s, 1 H), 7.42 m, 1 H), 7.65 (dt, J=8.1, 1.5 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.96 (dd, J=7.7, 1.5 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][CH:15]([N:19]=[C:20]=S)[CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:20]([NH:19][CH:15]([CH3:14])[CH2:16][CH2:17][CH3:18])[NH:1][C:2]=2[CH:7]=1
Reactant: CCCC(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CCCC(C)NC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4,5-dichlorobenzenesulfonamide and 2-pentyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 217-220° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (t, 3H, CH3), 1.14 (d, 3H, CH3), 1.20-1.55 (m, 4H, CH2CH2), 3.83 (m, 1H, NHCH), 7.33 (br., 1H, NH), 7.49 (br.s, 1H, ArH), 7.89 (s, 1H, ArH), 10.48 (br.s, 1H, NH); MS: m/e 335/337/339 (M+).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5])#[N:2].CO[CH:17]=[CH:18][C:19](=O)[CH3:20].N12CCN(CC1)CC2>COCCOCCO.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(F)ccc1NC(=O)CC#N
Reactant: COC=CC(C)=O
Agent: C1CN2CCN1CC2
Solvent: COCCOCCO
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-n1c(C)ccc(C#N)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
2-Cyano-N-(4-fluoro-2-methylphenyl)acetamide (2.0 g, 10 mmol) and 4-methoxybut-3-en-2-one (1.4 mL, 13 mmol) were suspended in 2-(2-methoxyethoxy)ethanol (20 mL), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10 mmol) was added. The mixture was stirred at 120° C. for 6 hr, and cooled to room temperature. The mixture was diluted with ethyl acetate (40 mL), and washed with saturated aqueous sodium hydrogen carbonate solution. Then the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (630 mg, 25%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][NH:4][C:3]1=[O:9].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])[C:3]1=[O:9]
Reactant: ClCCCCBr
Reactant: Cn1c(=O)cn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 4b (7.11 g; 0.056 mol) in DMF (70 ml) is added to a 60% suspension of sodium hydride (2.46 g; 0.062 mol) in DMF (25 ml). After stirring for 2 hours at room temperature, 1-bromo-4-chlorobutane (10.55 g; 0.062 mol) is added and the mixture is kept stirring overnight. After concentrating to dryness under vacuum, the residue is taken up in water (15 ml) and extracted with ethyl ether (2×50 ml). The organic phases, dried (Na2SO4) and concentrated to dryness under vacuum, give the oily compound 4c.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:11][CH:10]=3)[C:5]([CH3:16])([CH3:15])[CH2:6][CH2:7]2)[CH2:14][CH2:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35 mmol), triethyl amine (10 mL), anhydrous tetrahydrofuran, copper(I)iodide (0.080 g, 0.42 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), the title compound was obtained as an oil (0.67 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:10]2)[CH3:2].FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+].[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][NH:17][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[CH2:10]2)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Reaction time: 1 h
Yield: 86.3 %

Procedure:
1.77 g (5.00 mmol) of ethyl[2-(t-butoxycarbonylaminomethyl)-indan-5-oxy]acetate was dissolved in 6 ml of methylene chloride, to which was added 4 ml of trifluoroacetic acid under ice-cooling and stirred for 1 hour. The reaction mixture was diluted with 40 ml of methylene chloride. A solution of 40 ml water containing 8.37 g (60 mmol) of potassium carbonate was added thereto and stirred vigorously. 10 minutes after, 1.07 g (6.00 mmol) of phenylsulfonylchloride was added thereto, and stirred for further 1.5 hours. The organic phase was collected, dried and condensed, and the residue was purified by column gel chromatography (ethyl acetate:hexane=1:1) to obtain 1.68 g of a colorless oil. Yield: 88%
Reaction SMILES: [CH:1]([NH2:3])=[O:2].Br[CH:5]([CH3:23])[C:6]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)=O>O>[C:19]([C:10]1[CH:9]=[C:8]([C:6]2[N:3]=[CH:1][O:2][C:5]=2[CH3:23])[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: NC=O
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Product: Cc1ocnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 150 °C
Yield: 58.1 %

Procedure:
A mixture of 4.5 g of formamide and 2.25 g of 4-(2-bromopropionyl)-2,6-di-tert-butylphenol was heated to 150° C. for 1.5 hours. The reaction mixture was poured into water after cooling and then extracted twice each time with 30 ml of toluene. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue was recrystallized from aqueous methanol to provide 1.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazole.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[CH2:13][C@H:14]([OH:16])[CH3:15])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:16][C@@H:14]([CH2:13]/[CH:12]=[CH:11]/[C:7]2[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[CH3:15])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)Oc1cncc(/C=C/C[C@@H](C)O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
To a stirred solution of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (8.50 g, 38.46 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (14.67 g, 76.92 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to yield a dark-brown, viscous oil (11.75 g, 81.5%).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([OH:27])=O)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:25](=[O:27])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)N1CCCC1

Procedure:
Starting from (S)-N6-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-lysine and pyrrolidine, the expected product is obtained according to the procedure described in Steps A and B of Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[CH:18]/[N:19](C)C)/[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.O.[NH2:23]N>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[N:23][NH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)/C=C(\C(=O)c1cccc(Cl)c1)c1ccnc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(Br)c2)c1
Yield: 31.5 %

Procedure:
A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C14H9BrClN3: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][NH:8][C:7]1=[O:21])([O:3][CH2:4][CH3:5])=[O:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:27][O:21][C:7]1[CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][N:8]=1
Reactant: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CN=C1OC
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of 14.9 g 3-carboethoxy-5-[t-butyl(dimethyl)silyloxymethyl]-2-piperidone in 400 ml anhydrous dichloromethane at 4° C. were added 7.7 g of trimethyloxonium tetrafluoroborate. The mixture was first stirred for 90 minutes at 4° C. and then for 1 hour at 22° C. The resulting solution was poured into a saturated solution of sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to give 13.8 g of the title compound: 300-MHz 1H NMR (CDCl3) δ0.04 (s, 6H), 0.88 (s, 9H), 1.25 (t, J=7 Hz, 3H), 1.51-2.18 (m, 3H), 3.11-3.32 (m, 2H), 3.48-3.56 (m, 2H), 3.60-3.76 (m, 4H), 4.19 (t, J=7 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[CH3:21][NH:22][C:23]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:24]
Reactant: OCCSc1cccc2nccn12
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCCSc1cccc2nccn12
Yield: 85.2 %

Procedure:
To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1,2-a]pyridine (971 mg, 5 mmoles) and trietylamine (0.91 ml, 6.53 mmoles) in methylene chloride (40 ml) was added methyl isocyanate (0.65 ml, 11 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with saturtated saline and dried over anhydrous magnesium sulfater. After the solvent was distilled off, the residue was purified by column chromatography (eluent: methanol/chloroform=1:20) to obtain 1.07 g of the desired product (85.2%, colorless crystals).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([OH:39])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:28][CH:27]=3)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]([O:39][S:48]([CH3:47])(=[O:50])=[O:49])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:30][CH:31]=3)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)N(Cc1ccc(C(O)Cc2nn[nH]n2)cc1)c1ccc(C2=CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CS(=O)(=O)OC(Cc1nn[nH]n1)c1ccc(CN(C(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)-1-{4-[1-hydroxy-2-(2H-tetrazol-5-yl)ethyl]benzyl}urea (100 mg, 0.17 mmol) was dissolved in DCM (1 ml) and triethyl amine (27 μl, 0.195 mmol) was added. The mixture was cooled to 0° C. and methansulphonyl chloride (15 μl, 0.195 mmol) was added followed by 1,8-diazabicyclo[5,4,0]-undec-7-ene (29 μl, 0.195 mmol). The mixture was stirred at 0° C. for 2 hours, and at room temperature overnight, then diluted with DCM (20 ml) and washed with brine (20 ml). The organic solution was dried with anhydrous sodium sulphate and evaporated to dryness, to give pure title material as a white powder. Yield: 113 mg (100%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[CH:32][C:33]5[O:37][C:36]([CH2:38][CH3:39])=[N:35][C:34]=5[CH:40]=4)[N:24]=3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:41](O)[CH3:42]>[Pd]>[CH2:38]([C:36]1[O:37][C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:25]3[N:24]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH2:41][CH3:42])[CH2:16][CH2:15]5)=[N:18][CH:19]=4)[CH:28]=[CH:27][N:26]=3)=[CH:40][C:34]=2[N:35]=1)[CH3:39]
Reactant: CCO
Reactant: CCc1nc2cc(Nc3nccc(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)n3)ccc2o1
Agent: [Pd]
Product: CCc1nc2cc(Nc3nccc(-c4ccc(N5CCN(CC)CC5)nc4)n3)ccc2o1
Reaction time: 2 h

Procedure:
A suspension of 4-(2-(4-benzyloxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(2-ethylbenzoxazol-5-yl)-2-pyrimidineamine (100 mg, 0.19 mmol) and 10% palladium on charcoal (30 mg) in ethanol (25 ml) was stirred under an atmosphere of hydrogen at 50° for 2 h, then filtered through Celite® and evaporated. The residue was subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane, 1:5:94) to afford the title compound (25 mg) as a white solid m.p. 174-176°. δH (CDCl3) 1.15 (3H, t, J 7.2 Hz), 1.45 (3H, t, J 7.6 Hz), 2.49 (2H, q, J 7.2 Hz), 2.58 (4H, m), 2.96 (2H, q, J 7.6 Hz), 3.71 (4H, m), 6.71 (1H, d, J 9.0 Hz), 7.04 (1H, d, J 5.3 Hz), 7.40 (1H, br s), 7.41 (1H, d, J 8.7 Hz), 7.49 (1H, dd, J 2.1, 8.7 Hz), 8.09 (1H, d, J 2.1 Hz), 8.20 (1H, dd, J 2.4, 9.0 Hz), 8.36 (1H, d, J 5.3 Hz) and 8.87 (1H, d, J 2.1 Hz).