Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[C:2](/[CH2:16][CH3:17])=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:42][C:43]([OH:47])(C)[C:44]#C>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[OH:47][C:43]([CH3:44])([CH3:42])[C:17]#[C:16]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)O
Reactant: CC/C(Cl)=C\CN(CC)Cc1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCN(C/C=C/C#CC(C)(C)O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
To 7.5 ml tetrahydrofuran were added 1.13 g (5 mmol) of (E)-N-(3-chloro-2-pentenyl)-N-ethyl-3-hydroxybenzylamine, 4.76 mg (0.25 mmol) of copper (I) iodide, 18.0 mg (0.1 mmol) of palladium chloride and 52.5 mg (0.2 mmol) of triphenylphosphine, and further, 0.99 ml (10 mmol) of n-butylamine and 0.58 ml (6 mmol) of 3-methyl-1-butyne-3-ol under ice cooling. The mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=3/2). The desired fractions were put together and concentrated under reduced pressure to obtain 1.07 g (yield: 78%) of the above identified compound as an oil.
Reaction SMILES: C(N)CCC.[CH3:6][C:7]1[CH:11]=[C:10]([CH2:12][O:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[O:9][N:8]=1.[ClH:25]>C(O)C.C(OCC)C>[ClH:25].[CH3:6][C:7]1[CH:11]=[C:10]([CH2:12][O:13][NH2:14])[O:9][N:8]=1
Reactant: Cc1cc(CON2C(=O)c3ccccc3C2=O)on1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCN
Product: Cc1cc(CON)on1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.04 g of butylamine were added to a solution of 7.21 g of N-(3-methylisoxazol-5-yl)methoxyphthalimide [prepared as described in step (i) above] in 80 ml of ethanol, and the mixture was stirred for 1 hour at 60° C. At the end of this time, the temperature of the reaction mixture was lowered to room temperature, and then the reaction mixture was diluted with 300 ml of diethyl ether and acidified by the addition of a 10% by volume methanolic solution of hydrogen chloride at 0° C. The resulting crystals were collected by filtration, to afford 3.22 g of the title compound, melting at 193°-198° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[NH2-].[Na+].ClC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)(Cl)Cl.O>O1CCCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.69 g) in anhydrous tetrahydrofuran was added sodium amide (0.20 g) at room temperature, and the resulting mixture was heated under reflux for 1.5 hours. After cooling, 2,2,2-trifluoroethyl trichloromethylsulfonate (0.666 g) in anhydrous tetrahydrofuran was added to the mixture under ice-cooling, and then the mixture was heated under reflux for 11.5 hours. After cooling, water (0.2 g) was added thereto and inorganic materials were eliminated by filtration. The filtrate was evaporated and chromatographed to afford 5-[4-(2,2,2-trifluoroethyl)morpholin-2-yl]methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 174°-177° C. (hydrochloride).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:16][C:11]=2[S:10][C:9]1=[N:22]C(=O)C(F)(F)F)(=O)=O.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CO.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:22]=[C:9]1[N:8]([CH2:7][CH2:6][N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])[CH2:37][CH2:38]2)[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:16][C:11]=2[S:10]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCCn1c(=NC(=O)C(F)(F)F)sc2cc(OC(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1N1CCN(CCn2c(=N)sc3cc(OC(F)(F)F)ccc32)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
Using the procedure described in Example 1, starting with 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (5.88 g) in toluene (200 cc) and 4-(2-methylphenyl)piperazine (6.87 g) and after 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure. To the residue thereby obtained, methanol (100 cc) and a 7% strength aqueous-alcoholic solution (20 cc) of potassium carbonate are added and the mixture is stirred for 2 hours at approximately 20° C. The alcohol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (70:30 by volume) as eluent, and then an ethyl acetate/cyclohexane mixture (50:50 by volume) as eluent. 2-Imino-3-{2-[4-(2-methylphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline (1.8 g), m.p. 135° C., is thereby obtained.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H].Cl>C(OCC)(=O)C.O.O1CCCC1.CO>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Agent: O=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.70 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9% conversion) and an enantiomeric purity of 99.8%. The crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of carcoal (Darko KB) at r.t. for 2 h. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) and allowed to cool to room temperature whereby crystallization started spontaneously. The formed crystals were filtered off, washed with 10 ml of isopropyl acetate and dried at 75° C./500 mbar for 4 h to yield 1.60 g (79%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white crystals with a chemical purity of 99.6% and an enantiomeric purity of 99.8% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.4 %

Procedure:
p-Methoxyaniline (0.045 g, 0.368 mmol), triethylamine (0.037 g, 0.368 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.062 g, 0.368 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.075 g, 0.184 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.040 g, 0.0780 mmol, 42%).
Reaction SMILES: [Cl-].Cl[C:3]1[NH:4]S[SH+:6][C:7]=1Cl.[CH3:9][O:10][C:11](=[O:16])/[CH:12]=[C:13](\[NH2:15])/[CH3:14].N1C=CC=CC=1>ClCCl>[C:3]([C:7]1[S:6][N:15]=[C:13]([CH3:14])[C:12]=1[C:11]([O:10][CH3:9])=[O:16])#[N:4]
Reactant: ClC1=C(Cl)[SH+]SN1
Reactant: COC(=O)/C=C(/C)N
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nsc1C#N
Yield: 15.6 %

Procedure:
4,5-Dichloro-[1,2,3]-dithiazol-1-ylium chloride (prepared according to Chem. Ber. (1985) 118, 1632) (8.34 g, 40 mmol) was dissolved in dichloromethane (30 ml) and methyl-3-aminocrotonate (4.6 g, 40 mmol) was added dropwise at room temperature. After stirring the solution for 1 hour at room temperature pyridine (6.47 ml, 80 mmol) was added slowly. The mixture was concentrated and purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as an orange solid (1.14 g, 15.6% yield). 1H-NMR (400 MHz, CDCl3): 2.88 (3H, s, Me), 4.0 (3H, s, Me).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClCCl>[C:2]1([NH:1][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 54.3 %

Procedure:
To a mixture of aniline (0.35 g, 3.75 mmol) and pyridine (1 ml) a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) (0.45 g, 1.82 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 40° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 6N HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the title compound (0.30 g, 54%). 1H NMR (DMSO-d6, HMDSO), δ: 6.60 (1H, d, J=16.0 Hz); 6.93-7.43 (5H, m); 7.60 (1H, d, J=16.0 Hz); 7.79 (2H, d, J=8.0 Hz); 7.87 (2H, d, J=8.0 Hz); 10.35 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:28])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=1[F:28])[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)OC(C)(C)C)c3)nc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1

Procedure:
A solution of tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-2-fluorophenyl)carbamate (0.65 g, 1.54 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with 0.1N aqueous sodium hydroxide solution (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.49 g, quantitatively) as a white amorphous.
Reaction SMILES: [Cl-].[Li+].O.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([N+:23]([O-:25])=[O:24])[CH:7]=1)#[N:5]>CS(C)=O>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([N+:23]([O-:25])=[O:24])[CH:7]=1)#[N:5]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91.1 %

Procedure:
Lithium chloride (10.7 g, 255 mmol) and water (2.3 g, 127 mmol) were added to a solution of diethyl (4-cyano-2-nitrophenyl)malonate (39 g, 127 mmol) in DMSO (700 ml) under argon and the solution was heated at 100° C. for 4 hours. The reaction mixture was allowed to cool and then poured slowly into stirred ice water (1000 ml). The resulting pale yellow precipitate was colllected by filtration, washed with water (100 ml×4) and dried under vacuum to give ethyl (4-cyano-2-nitrophenyl)acetate (27.1 g, 91%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16]>CO.[Pd]>[OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C=CCCCC1C2CCC(C2)C1CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCC1C2CCC(C2)C1CO
Yield: 91.1 %

Procedure:
28.7 g (0.11 mole) of methyl 6-(3-hydroxymethylbicyclo[2.2.1]hept-2-yl)-hex-2-enoate are hydrogenated in 450 ml of methanol, with the addition of 12 g of palladium-on-charcoal (5% strength), at 60° C. under a pressure of 30 bar for 11/2 hours. The catalyst is removed by filtration, the methanol is evaporated off in vacuo and the oil which remains is chromatographed on silica gel, using methylene chloride/methanol (99:1), to give 25.5 g (91% yield) of methyl 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hexanoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)=[CH:5][CH:4]=1.[C:29](O)(=[O:32])[CH:30]=[CH2:31]>>[O:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:8][CH:7]=4)[CH:15]=[CH:14][N:13]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: C=CC(=O)O
Reactant: NCc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Product: C=CC(=O)NCc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 27.3 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(4-(aminomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (70 mg, 0.18 mmol) and acrylic acid (19 mg, 0.27 mmol) furnished the product (22 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][CH3:11])[C:7]#[N:8].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)C>CN(C=O)C>[CH2:19]([O:18][C:16]([C:15]1[N:10]([CH3:11])[C:9]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[C:7]=1[NH2:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CNc1c(Cl)cncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1c(N)c2cncc(Cl)c2n1C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-Chloro-4-methylamino-nicotinonitrile (340 mg, 2.02 mmol) was dissolved in DMF (5 mL) and the solution cooled in an ice-bath. This solution was treated portionwise with sodium hydride (120 mg, 60% in oil, 3.03 mmol). The ice-bath was removed and stirring continued for 15 minutes at room temperature before treating the mixture with ethyl bromoacetate (508 mg, 3.03 mmol). The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was isolated, washed with water followed by brine then dried (MgSO4) and evaporated to give a solid. Trituration of the resultant solid with diethyl ether gave the title compound (308 mg, 60%) as a cream solid. 1H NMR (CDCl3) 8.90 (1H, s), 8.26 (1H, s), 8.26 (1H, s, br), 4.43 (2H, q, J=7.0 Hz), 4.28 (3H, s), 1.44 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14](OCC)=[O:15].O>CS(O)(=O)=O>[Cl:10][CH2:11][C:12]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:4][C:14](=[O:15])[CH:13]=1
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)CC(=O)CCl
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-methylresorcinol (1 g) in 10 mL of methyl sulfonic acid is introduced into a flask and then 1.3 equivalents (1.42 ml) of ethyl 4-chloroacetoacetate are added dropwise. After 1 night of stirring at room temperature, the mixture is cooled to 0° C. and then 50 mL of water are added. The residue is then filtered, dried and washed with diethyl ether in order to obtain 1.63 g (90%) of the compound 5.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[CH3:35][C:36]([O:39][C:40]([NH:42][C@H:43]([C:59](ON1C(=O)CCC1=O)=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:41])([CH3:38])[CH3:37].CN1CCOCC1>CN(C=O)C>[NH:42]([C:40]([O:39][C:36]([CH3:38])([CH3:37])[CH3:35])=[O:41])[C@H:43]([C:59]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CN)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of 583 mg of H-Gly-Asp(OBzl)-Val-OBzl (Example 15Bb) and 477.5 mg of Boc-Lys(Z)-O Su in 10 ml of DMF is adjusted to pH 8.5 with N-methylmorpholine. After stirring for 18 hours the mixture is concentrated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated NaHCO3 solution, 5% KHSO4 /10% K2SO4 solution and saturated NaCl solution, dried and filtered. The filtrate is concentrated and the residue is crystallized from ether. There are obtained 385 mg of Boc-Lys(Z)-Gly-Asp(OBzl)-Val-OBzl, m.p. 95°-101° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution (7 M) of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate in DMF at 0° C. was treated with NaH (1.2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated with benzyl bromide (1.2 eq.). The reaction mixture was stirred at RT for 90 min then poured into water and extracted with AcOEt. The combined organic phase was washed with water and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:8 AcOEt/petroleum ether) to afford the title compound (71%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26].O>CC#N>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cc1csc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (500 mg) and triethylamine (0.592 mL) in CH3CN (20 mL) was added Tf2O (0.417 mL). The mixture was stirred at 0° C. for 10 min. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (745 mg).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[C:15]1[N:16]=[C:17]([CH:33]2[O:37][CH2:36][CH2:35][O:34]2)[N:18]([CH2:22][C:23]2[C:31]([Cl:32])=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)[C:19]=1[CH:20]=[O:21]>CN(C)C=O>[Cl:32][C:31]1[C:23]([CH2:22][N:18]2[C:19]([CH:20]=[O:21])=[C:15]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=[C:17]2[CH:33]2[O:37][CH2:36][CH2:35][O:34]2)=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1
Reactant: CCOC(=O)CCCCCS
Reactant: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCSc1nc(C2OCCO2)n(Cc2cc3c(cc2Cl)OCO3)c1C=O
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
3.9 g of ethyl 6-mercaptohexanoate is dissolved in 200 ml of anhydrous dimethylformamide, 1.1 g of sodium hydride at 50% in oil is added and the reaction medium is left for 20 minutes at ambient temperature. Then 7.6 g of the product obtained in Stage 4 above is added, and the whole is left overnight at ambient temperature. The dimethyl-formamide is evaporated off under vacuum, the residue is taken up in 200 ml of saturated ammonium chloride and extraction is carried out with three times 200 ml of methylene chloride. The organic phases are dried, filtered and evaporated to dryness. The residue is impasted in isopropyl ether and filtered. In this way 5.8 g of expected product (solid) is obtained.