Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[O:7]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O
Product: CNC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 110.1 %

Procedure:
2 cm3 of dichloromethane and then 11.5 mg of methyl isocyanate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 4 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 66 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid N-methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.75 (s, 3H), 2.85 (d, J=5 Hz, 3H), 3.19 (broad t, J=5.5 Hz, 4H), 3.52 (broad t, J=5.5 Hz, 4H), 3.80 (mt, 2H), 4.33 (mt, 2H), 4.45 (broad q, J=5 Hz, 1H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.98 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNC(=O)c1cccnc1
Solvent: CCO
Product: O=C(NCCNCc1ccccc1)c1cccnc1
Reaction time: 1 h

Procedure:
A solution of N-(2-aminoethyl)pyridine-3-carboxamide (26.5 g.) and benzaldehyde (16.35 ml.) in ethanol (220 ml.) was kept for 48 hours. A small quantity of solid was removed by filtration. Sodium borohydride (6.1 g.) was then added to the filtrate which was stirred for 1 hour. Glacial acetic acid was then added cautiously until the solution was neutral. The solution was diluted with water (100 ml.) and basified with 2M sodium hydroxide. The mixture was extracted with ethyl acetate (3×200 ml.) and the extracts washed with saturated brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on a column of Florisil (200 g.), eluting with ethyl acetate, to yield N-[2-(benzylamino)ethyl]pyridine-3-carboxamide (29.5 g.) as a pale brown oil.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>C1C=CC=CC=1.O=[Mn]=O>[CH:1]([C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]=[O:11])([CH3:3])[CH3:2]
Reactant: CCCOc1c(CO)cccc1C(C)C
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: CCCOc1c(C=O)cccc1C(C)C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
MnO2 (6.88 g, 79.2 mmol) was added to a stirring solution of (3-isopropyl-2-propoxyphenyl)methanol (2.75 g, 13.2 mmol) in benzene (130 mL) under N2. After stirring for 48 h, the solution was filtered over diatomaceous earth, the pad rinsed with CH2Cl2 (200 mL) and the solution concentrated to a yellow oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 100 to 98:2) gave the title compound (1.49 g, 54%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.67 (dd, J=7.6, 1.7 Hz, 1H), 7.59 (dd, J=7.6, 1.7 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 3.87 (t, J=6.4 Hz, 2H), 3.35-3.30 (m, 2H), 1.85-1.78 (m, 2H), 1.21 (t, J=6.9 Hz, 7H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:28])[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]2[C:19]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)ccnc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nccc(C)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].Cl.N1C=CC=CC=1.C[OH:23]>>[OH:23][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1c(O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 2,6-dinitrobenzonitrile (10.0 g, 52.3 mmol) in MeOH (215 mL), was added a solution of Na (1.32 g, 57.5 mmol) in MeOH (23.3 mL). The reaction was refluxed under N2 for 2.5 hours, cooled to rt and the precipitate was collected by filtration. The resulting residue was combined with pyridine hydrochloride (15.1 g, 130 mmol), and the solids were melted at 200° C. for 18 hours. Upon completion, the reaction was cooled to rt, washed with brine (1×300 mL) and extracted with EtOAc (2×500 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated to provide 2-hydroxy-6-nitrobenzonitrile (6.70 g, 87%). 1H NMR (400 MHz, MeOD) δ 7.35 (dd, J=8.3, 0.8 Hz, 1H), 7.67 (t, J=8.2 Hz, 1H), 7.77 (dd, J=8.2, 1.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CSCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCSCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, thiomorpholine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.60 minutes; C20H18C12N4O2S (449.36); mass spectrum: (M+H)+=449.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=2[CH3:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:34])C(=O)C1>C(#N)C>[Cl:34][C:15]1[C:14]([CH3:26])=[C:13]([C:9]2[C:10]([CH3:12])=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[N:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2c(C)cnn2COCC[Si](C)(C)C)c(C)cc1C
Solvent: CC#N
Product: COC(=O)c1cc(-c2c(C)c(Cl)nn2COCC[Si](C)(C)C)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of methyl 2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate (compound 250.3, 3.0 g, 8.02 mmol) in acetonitrile (20 mL) was added NCS (1.07 g, 8.02 mmol). The mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with saturated sodium thiosulfate (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified with by silica gel column chromatography (hexanes:EtOAc, 20:1) to yield the title compound as a colorless oil (2.0 g, 61%). m/z (ES+) 409 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[CH:16][S:17][C:18]=1[NH2:19])=[O:13])[CH3:10]>C(#N)C.CCOC(C)=O>[NH2:19][C:18]1[S:17][C:16]([Br:1])=[N:15][C:14]=1[C:12]([O:11][CH2:9][CH3:10])=[O:13]
Reactant: CCOC(=O)c1ncsc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Br)sc1N
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
N-Bromosuccinimide (0.54 g, 3.03 mmol) was added to a solution of 5-aminothiazole-4-carboxylic acid ethyl ester (0.44 g, 2.53 mmol) [prepared according to the procedure described by Golankiewicz et al. (Tetrahedron, 41 (24), 5989-5994 (1985))] in acetonitrile (10 mL), and the mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 5% K2CO3 aq. solution (25 mL) followed by brine (25mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluted with 15% EtOAc in hexane to give 0.37 g (58% yield) of the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:8]([O:44][CH3:45])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:43])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([CH:32]3[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+].[Cl-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:8]([O:44][CH3:45])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:43])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:30]([CH:32]3[CH2:35][NH:34][CH2:33]3)=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CN(C(=O)OC(C)(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CNC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
243 mg of tert-butyl 3-{4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carbonyl}-azetidine-1-carboxylate are dissolved in 3 ml dichloromethane, cooled to 0° C. and combined with 261 μl trifluoroacetic acid. The mixture is allowed to come up to ambient temperature and stirred for 12 hours. Then a further 1.5 ml of trifluoroacetic acid are added and the mixture is stirred for 2 hours. Then it is diluted with dichloromethane and adjusted to pH 9 with 1 N sodium hydroxide solution. Saturated sodium chloride solution and saturated potassium carbonate solution are added and the phases are separated. The aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried on magnesium sulphate and the solvents are eliminated in vacuo.
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:20][CH:21]([C:29]([F:32])([F:31])[F:30])[C:22]([F:28])([F:27])[S:23]([O-:26])(=[O:25])=[O:24].[C:33]1([S+:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:28][C:22]([F:27])([S:23]([O-:26])(=[O:24])=[O:25])[CH:21]([O:20][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH2:14]3)[CH2:8]1)[CH2:10]2)=[O:18])[C:29]([F:30])([F:32])[F:31].[C:46]1([S+:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])(C3)C2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 28.4 g (0.10 mole) of the resulting 3-methacryloyloxyadamantanecarbonyl chloride were added 44.9 g (0.09 mole) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 10.1 g (0.10 mole) of triethylamine and 2.2 g (0.02 mole) of N,N-dimethylaminopyridiene in 45 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 7 hours. Thereafter, 105 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 250 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. Diisopropyl ether was added to the residue, followed by decantation. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(3-methacryloyloxy-adamantane-1-carbonyloxy)-propane-1-sulfonate was obtained as brown oil (61.7 g, yield 92%). The compound has the following structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2)=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[CH3:15][C:14]1([CH3:16])[S:17][CH:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][CH2:7][CH2:6]3)[NH:12][C@H:13]1[C:18]([OH:20])=[O:19]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccc2c(c1)CCC2
Solvent: CO
Product: CC1(C)SC(c2ccc3c(c2)CCC3)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
1.44 g (10 mmoles) of 5-formylindane are portionwise added to a solution containing 1.5 g of D-penicillamine in 100 ml of methanol at room temperature while stirring. After 48 hours, the mixture is evaporated to dryness. The residue is dissolved in ether with boiling, treated with activated carbon and filtered. The crude product is precipitated by adding petroleum ether. The thus-obtained product is dissolved in hot ethanol, clarified with carbon, filtered, then water is added up to a beginning opalescence. On cooling, the title compound precipitates in a crystalline form in a yield of 1.57 g (57.1%), m.p. 140°-142° C., [α]D20 =+18° (c=0.551, dimethylsulphoxide).
Reaction SMILES: S(O)(C)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([S:15][CH2:16][C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>>[Cl:6][C:7]1[C:8]2[C:17]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][S:15][C:9]=2[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2cc(OC)cc(Cl)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To MsOH (5 mL) was added methyl 4-((3-chloro-5-methoxyphenyl)sulfanyl)-3-oxobutanoate (1.41 g) at 0° C. The mixture was stirred at the same temperature for 15 min. The mixture was poured into ice water and extracted with EtOAc. The organic layer was separated, washed successively with 0.1N NaOH and brine, dried over MgSO4 and concentrated in vacuo. The residue was subjected to silica gel column chromatography (EtOAc/hexane) to give methyl (4-chloro-6-methoxy-1-benzothiophen-3-yl)acetate as a crude product (1.280 g). The product was used to the next step without further purification. To a mixture of aluminum chloride (0.894 g) and toluene (30 mL) was added 1-dodecanethiol (5.32 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. A solution of methyl (4-chloro-6-methoxy-1-benzothiophen-3-yl)acetate obtained above (1.21 g) in toluene (15 mL) were added to the mixture at 0° C., and the mixture was stirred at room temperature for 40 h. The mixture was poured into water at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was diluted with MeOH (50 mL), and the mixture was treated with conc. H2SO4 (100 μL). The mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure. To the residue was added brine at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (0.558 g).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[C:12]1([CH:22]=[C:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCCC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCCC(=O)C(=Cc1cccc2ccccc12)C(=O)OCC

Procedure:
A solution of ethyl 3-ketohexanoate (6.6 g), 1-naphthaldehyde (7.34 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 mL) was heated under reflux for 3 hours and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. The title compound was obtained as a colorless amorphous solid from ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture), 3-amino-2-methylpyrazole and p-toluenesulfonic acid.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@H:4]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:3]1.[Br:25]N1C(=O)CCC1=O>O1CCOCC1>[Br:25][C:13]1[NH:12][C:11]2[C:17]3[C:14]=1[CH2:15][C@@H:16]1[C:6]([C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:5][C@H:4]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:3][N:2]1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: C1COCCO1
Product: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g 6-methyl-8α-pivaloylamino-9,10-didehydro-ergoline in 120 ml dioxane is treated with 960 mg N-bromosuccinimide and the resulting mixture stirred at room temperature overnight The reaction mixture is then evaporated and the residue partitioned between ethyl acetate and 2N Na2CO3. The organic layers are dried (Na2SO4), evaporated and chromatographed on 80 g silica gel using 98:2 CH2Cl2 /CH3OH. Crystallization from ether gives the title compound, m.p. 169°-171°.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O:18]C(=O)CCC)(=O)[CH2:14][CH2:15][CH3:16]>>[C:13]([NH2:1])(=[O:18])[CH2:14][CH2:15][CH3:16].[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC(=O)OC(=O)CCC
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCC(N)=O
Temperature: 100 °C

Procedure:
5 g of phenylalanine was added to 20 mL of butyric anhydride and the resulting mixture heated to about 100° C. for about 3 h. Excess butyric anhydride was then removed under reduced pressure to provide a solid residue that was recrystallized from ethanol to provide phenylalanine butyramide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.Br[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:12]2[C:13]([C:14]#[N:15])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1Br
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
4-methoxyphenylmagnesium bromide (280 g, 15% solution in tetrahydrofuran) is added dropwise over seven hours to a refluxing solution of 2-bromobenzonitrile (32 g), palladium (II) chloride (1.3 g) and triphenylphosphine (3.8 g) in tetrahydrofuran (210 ml). [HPLC: yield 94-95%]. After cooling to room temperature and the addition of water (50 ml), tetrahydrofuran is removed under vacuum. The residue is extracted with toluene (230 ml). Insoluble material is filtered off and the solvent distilled off. The crude product is recrystallised from ethanol to give 4'-methoxybiphenyl-2-carbonitrile as a solid, m.pt. 82-83° C. 1H NMR (CDCl3): 3.90(s,3H), 7.02(d,2H), 7.36-7.52(m,4H), 7.59-7.65(m,1H), 7.74(d,1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]([NH2:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>N1C=CC=CC=1>[CH3:16][O:17][CH2:18][C:19]([NH:14][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([NH:15][C:19](=[O:20])[CH2:18][O:17][CH3:16])[C:4]=1[Cl:3])[C:8]([O:10][CH3:11])=[O:9])=[O:20]
Reactant: COC(=O)c1cc(N)c(Cl)c(N)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C(=O)OC)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 4-chloro-3,5-diaminobenzoate dihydrochloride (1.1 g) in pyridine (20 ml) is added dropwise methoxyacetyl chloride (0.8 ml) at room temperature. The mixture is stirred at room temperature for 1.5 hour, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.1 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1B(O)O)[CH3:15].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:17]2[C:18]([CH2:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:14][CH3:15])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)cc1OC
Reactant: CCc1cccc(CC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-4-methoxy-nicotinic acid methyl ester (4.0 g, 19.8 mmol), 2,6-diethylphenyl boronic acid (7.0 g, 39.3 mmol), Na2CO3 (2M in H2O, 39 mL) and Pd(PPh3)4 (2.0 g, 1.7 mmol) in toluene (200 mL) is heated overnight at 80° C. under argon. On cooling, hexane (200 mL) is added and the organic layer separated. The organic layer is washed with 1N NaOH and water, dried (Na2SO4) and concentrated. The residue is purified by silica gel column (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester. 1H NMR (CDCl3) 8.99 (s, 1H), 7.30 (m, 1H), 7.15 (d, 2H), 6.89 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.34 (m, 4H), 1.06 (t, 6H).