Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@@H:26](O)[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl.O>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([F:38])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@@H](O)CC2)c(C(=O)O)s1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](F)CC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (102 mg, 0.23 mmol) in dry CH2Cl2 (2 mL) is added DAST (Diethylaminosulphurtrifluoride) (90 μL, 0.69 mmol), and the mixture is stirred for 4 h at room temperature. Then it is diluted with CH2Cl2, water is added to the mixture, and it is vigorously stirred for 20 min. Organic fraction is separated, dried over Na2SO4, concentrated, and the residue is purified by preparative HPLC to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([F:32])[CH:25]=1>CN(C=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH:10]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:26]([F:32])[CH:25]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCCCC(=O)CC(=NOC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A mixture of 5.0 g (21.8 mmol) of ethyl 2-methoxyimino-4-oxooctanoate (from Example 1, Step A), 3.6 g (26 mmol) of anhydrous potassium carbonate, and 70 mL of dry DMF was stirred under N2 at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated dropwise with a solution of 5.9 g (21.8 mmol) of 4-bromo-2-fluorobenzyl bromide in 20 mL of dry DMF. The mixture was allowed to warm slowly to room temperature and was stirred under N2 for 48 hours. The mixture was partitioned between 400 mL of ethyl acetate and 400 mL of 0.2N HCl. The organic layer was washed twice with H2O and then dried over Na2SO4. The filtered solution was concentrated, and the residual oil was flash chromatographed on silica gel. Gradient elution with 5-20% ethyl acetate in hexane afforded 3.51 g (39%) of the title compound as an oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 416, 418 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.1 Hz, 3H), 1.2-1.4 (m, 5H) including 1.25 (t, J=7.1 Hz, 3H), 1.55 (m, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.97 (dd, J=14, 10 Hz, 1H), 3.36 (dd, J=14, 5 Hz, 1H), 3.95 (s, 3H), 4.15-4.35 (m, 3H), 6.98 (dd, J≈8, 8 Hz, 1H), 7.15 (apparent d, J=8.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22]C2C=CC=CC=2)[N:3]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(Sc3ccccc3)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
30.83 g (80 mmol) of N-{4-[2-amino-3,5-dicyano-6-(phenylsulphanyl)-4-pyridinyl]-phenyl}-acetamide are dissolved in 120 ml of DMF under argon, after which 9.36 g (120 mmol) of sodium sulphide are added and the mixture is stirred at 80° C. for 2 hours. A solution of 20 ml of 1N aqueous HCl in 44 ml of water is then added dropwise at from 40 to 65° C., after which the crystals which have formed during this procedure are filtered off with suction and washed with water. The precipitate is suspended in 200 ml of methanol and stirred under reflux for 5 minutes. After cooling down to room temperature, the precipitate is filtered off with suction, washed with methanol and diethyl ether and dried in vacuo.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](O)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=1[O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14])[CH2:12][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1

Procedure:
In a manner similar to the method described in example 94b, cis-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (2.7 g, 12 mmol) was reacted with methyl 5-chloro-2-hydroxybenzoate (1.77 g, 9.5 mmol) and diisopropyl azodicarboxylate, triphenylphosphine in tetrahydrofuran to give trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 2.7 g, 71%).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].OB(O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:22]([C:18]1[CH:17]=[C:16]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of 4-bromopyridine hydrochloride (5.25 g) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 3M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80° C. for 1 hour and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1%-2% methanol in chloroform) to give 4-(3-nitrophenyl)pyridine (3.46 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.O.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH:11]([C:24]([CH3:26])=[CH2:25])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([CH:29]4[CH2:31][CH2:30]4)=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:27])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)C1CC1
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(C3CC3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Under nitrogen atmosphere, to a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester (0.050 g) prepared in Example 172b in toluene (5 mL) was added water (0.1 mL), cyclopropyl boronic acid (0.020 g, 0.23 mmol), K3PO4 (0.098 g, 0.46 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol). The mixture was irradiated at 130° C. by microwave for 0.5 h. Then cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 0.5 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with NaHCO3 aqueous solution, dried over MgSO4 and concentrated. The residue was purified with Prep.LC to give title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(C(C#N)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
33.6 g (0.21 mol) of α-hydroxyimino-4-methylbenzylcyanide and 31.9 g (0.31 mol) of triethylamine are dissolved in 425 ml of tetrahydrofuran and to this solution is then added dropwise a solution of 26.44 g (0.23 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. Subsequently, the reaction mixture is filtered and the filtrate is washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then distilled off on a rotary evaporator, giving a solid residue which is recrystallised from toluene. 37.3 g (75%) of α-(methylsulfonyloxyimino)-4-methylbenzylcyanide are obtained in the form of a colourless powder having an m.p. of 97.5-102.5° C. The 1H-NMR spectrum shows it to be a pure stereoisomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 74360080 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoate (910 mg, 2.0823 nmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10.4 ml) and 1,4-dioxane (25 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (655 mg, 1.5484 mmol, 74%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][S:35][C:31]=2[N:32]=[CH:33][N:34]=1>C(O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH:3]([NH:2][C:29]2[C:30]4[C:37]([CH3:38])=[CH:36][S:35][C:31]=4[N:32]=[CH:33][N:34]=2)[CH2:11]3)=[CH:19][CH:18]=1
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(Nc2ncnc4scc(C)c24)C3)cc1
Yield: 58.3 %

Procedure:
Using 2-amino-5-[(E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol), ethanol (0.6 ml), triethylamine (50 μl, 0.36 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (11 mg, 0.060 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (14 mg, 0.035 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:33][C:34]1([CH3:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16][N:37]3[CH2:38][CH2:39][C:34]([CH3:40])([CH3:33])[CH2:35][CH2:36]3)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(CC(=O)Nc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc2OC(F)(F)F)CC1

Procedure:
The title compound was prepared as described for example 1e using 100 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-2-chloro-acetamide (raw material, as described above) and 15 mg 4,4-dimethylpiperidine. Yield: 2.5 mg
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([O-:17])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO.C1COCC1.O>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([OH:17])=[O:16])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)[O-])S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (87 mg, 0.24 mmol, 1 eq) in MeOH/THF (2 mL:2 mL) was added LiOH (21.5 mg, 0.512 mmol, 2.1 eq) in H2O (1 mL). The mixture was allowed to stir at RT overnight. The mixture was washed with Et2O and the aqueous layer acidified with 1M HCl. The solid precipitate was filtered off to give (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (70 mg, 87%) which was used without further purification. LC-MS M+H+329.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[C:1]([N:15]1[CH2:16][CH2:17][CH:12]([Br:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: BrC1CCNCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Benzoyl chloride (1.41 g) was added to a solution of 4-bromopiperidine hydrobromide (2.45 g) in THF (30 ml) at 0° C., followed by triethylamine (2.2 g, 2.2 eq). The solution was stirred at room temperature for 1 h, and evaporated and. The residue was dissolved in dichloromethane (100 ml), washed with water, 1M HCl and saturated sodium bicarbonate, dried and evaporated to give the title compound as colourless oil (2.76 g, 100%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32](OC3C=CC([N+]([O-])=O)=CC=3)=[O:33])[N:26]=2)=[CH:21][CH:20]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:33])[N:26]=2)=[CH:21][CH:20]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)OCC
Reactant: CCCCCCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
0.27 mL (1.84 mmol) of n-heptylamine is added to a solution of 0.45 g (0.92 mmol) of ethyl (Z)-2-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)acrylate in 15 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.29 g (67%) of ethyl (Z)-2-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}acrylate in the form of a pale yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH2:24][C@H:25]([N:30]2[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[C:26]([O:28][CH3:29])=[O:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C:40]1([C:46]2[CH:51]=[C:50]([CH2:52]O)[CH:49]=[CH:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:39][S:36]([N:33]1[CH2:32][CH2:31][N:30]([C@@H:25]([CH2:24][NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:52][C:50]3[CH:49]=[CH:48][N:47]=[C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:51]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:26]([O:28][CH3:29])=[O:27])[CH2:35][CH2:34]1)(=[O:38])=[O:37]
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Reactant: OCc1ccnc(-c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccnc(-c3ccccc3)c2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
0.23 ml (1.4 mmol) of diethyl azodicarboxylate is added slowly to a solution of 400 mg (0.9 mmol) of methyl (S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate (prepared as described in example 5.1), 193 mg (1.0 mmol) of (2-phenylpyridin-4-yl)methanol and 373 mg (1.4 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at ambient temperature and then evaporated to dryness. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 318 mg (57%) of methyl (S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)-benzenesulfonylamino]propanoate are obtained in the form of a white powder.
Reaction SMILES: C(O[C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]([CH3:27])[CH:19]=1)[CH3:15])=[O:7])(C)(C)C.C(OC(=O)[NH:35][CH:36]1[CH2:40][C:39](=[O:41])[O:38][CH:37]1[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47]C=1)C=C.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:43]([O:42][CH:37]1[CH:36]([NH:35][C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]([CH3:27])[CH:19]=2)[CH3:15])=[O:7])[CH2:40][C:39](=[O:41])[O:38]1)[C:44]1[CH:45]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: COc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: COc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1C
Yield: 71 %

Procedure:
Prepared from 1-[2-(4-methoxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (40) according to the procedure used to prepare 98a to afford 406 mg (yield 71%) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.09 (d, 0.6H), 1.35 (m, 2.4H), 1.90-2.20 (m, 3H), 2.22-2.50 (m, 10H), 2.84-2.90 (m, H), 3.52-3.62 (m, 1.6H), 3.65-3.80 (m, 3.4H), 4.10-4.40 (m, H), 4.50-4.75 (m, 3H), 4.82-4.95 (m, 2H), 5.54 (d, 0.8H), 5.80 (d, 0.2H), 6.87 (d, H), 7.10-7.40 (m, 6H), 7.45 (s, 2H); retention time on analytical HPLC: 16.71 min1; LC-MS: m/z=538 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:24][CH2:25][CH3:26])[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1.Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:23])[N:2]([CH3:1])[CH2:24][CH2:25][CH3:26])=[CH:9][CH:8]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N(C)CCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCN(C)C(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 54.3 %

Procedure:
N-Methyl-N-propyl-4-tributylstannylbenzamide (2.36 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.02 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.15 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.72 g of the free compound of the title compound as a pale yellow powder.