Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[N:5]=[C:4]([NH:12][C:13]2[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=C(S)[CH:26]=2)[N:21]=1>C(O)(C)(C)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:11]([S:8][C:6]3[N:5]=[C:4]([NH:12][C:13]4[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=4)[CH:3]=[C:2]([Cl:1])[N:7]=3)[CH:26]=2)[N:21]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: Cc1ccc2cc(S)ccc2n1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc4nc(C)ccc4c3)n2)[nH]n1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (2.02 g, 7.03 mmol) in tert-butanol (20 ml) was added 2-methylquinoline-6-thiol (1.23 g, 7.03 mmol). The mixture was heated to 70° C. for 4 hours, then cooled to ambient and diluted with ethyl acetate/saturated aqueous potassium carbonate. The mixture was filtered to remove unreacted starting material and the organic layer removed form the filtrate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 90 to 100% ethyl acetate/petrol. The title compound was further purified by trituration with dichloromethane. This gave the product as a white solid (514 mg, 19%); MS ES+383.25, ES−381.36.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>C1(C=CC(O)=CC=1)O>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Agent: Oc1ccc(O)cc1
Product: C=CC(C)(C)CC(=O)OCC
Yield: 75.1 %

Procedure:
A mixture of 12.9 g (0.15 mole) of 3-methyl-2-buten-1-ol, 48.6 g (0.3 mole) of ethyl orthoacetate and 0.5 g of hydroquinone was heated at 140° for 20 hours with stirring. Ethanol was removed by distillation during the heating. At the end of 20 hours, the mixture was distilled under reduced pressure to give, after removal of unreacted ethyl orthoacetate, 17.6 g (75% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 74°-78°/55 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][C:36]([C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1C(O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:42]([C:36]2[CH:35]=[C:34]3[C:39]([CH2:40][CH2:41][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33]3)=[CH:38][CH:37]=2)=[O:43])[C:10]2=[N:14][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N)C1
Agent: O=C(O)c1ccccn1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)C1

Procedure:
By analogy with the method described in example 1 (step 1.5), using 9-amino-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester in place of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) and 2-pyridine carboxylic acid, the compound, 0.286 g (80%), was obtained as a white powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH2:10]([N:12]([CH2:15]C)[CH2:13]C)C.COC(OC)N(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[N:7]=[C:3]([N:2]=[CH:10][N:12]([CH3:15])[CH3:13])[S:4][C:5]=1[CH3:9]
Reactant: Cc1nc(N)sc1C
Reactant: CCN(CC)CC
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(N=CN(C)C)sc1C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A suspension of 2-amino-4,5-dimethylthiazole hydrochloride (4.92 g, 30 mmol) (Formula A-1) in toluene (60 mL) was treated with triethylamine (4.5 mL, 35 mmol) and vigorously stirred for 30 minutes. The mixture was treated with dimethylformamide dimethyl acetal (7.3 mL, 60 mmol) and heated at reflux temperature for 2 hours. The solution was cooled, diluted with ethyl acetate, washed with saline, dried and evaporated. The residue was crystallized from hexane to provide pure N′-(4,5-Dimethyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula A-2) (4.31 g, 77%), m.p. 47-58°.
Reaction SMILES: [O:1](CCCCCCCC)P(OP([O-])([O-])=O)(=O)OCCCCCCCC.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[C:34]([OH:1])[C:33](=[CH:32][CH:31]=1)[OH:36])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCCCCCCCOP(=O)(OCCCCCCCC)OP(=O)([O-])[O-]
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 75 %

Procedure:
The procedure of Example 7 was repeated, except 0.2% by weight of dioctyl pyrophosphate was used in place of Na5R'5 (P3O10)2. Consequently, the conversion of para-tert.-butyl phenol was 7.2%, 4-tert.-butyl pyrocatechol was formed in a yield of 75% based on the converted butyl phenol and the conversion of peracetate was 99.0%.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][NH:54][CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]>CN(C=O)C>[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][N:54]([C:9](=[O:11])[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: O=C(O)COc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)COc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of phenoxy acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatograph to obtained the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH3:28][N:29]1C=CN=C1>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:29])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: Cn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.02 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-methyl-1H-imidazole (1.40 g, 0.017 mol, 99%) were added. The mixture was heated to between 160 and 165° C. for 6 h and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered and the collected solid was washed with water (3×10 mL) and xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.85 g).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH2:9][CH2:10]O)[CH3:8])[CH3:3].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1COCC1.CCCCCC>[I:36][CH2:10][CH2:9][C@@H:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: II
Reactant: CC(C)=CCC[C@H](C)CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CCC[C@H](C)CCI
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 3.12 g (20.0 mmol) of (S)-(-)-β-citronellol (purchased from Aldrich Chem. Co.) and 2.72 g (40.0 mmol) of imidazole in 50 mL of THF at 0° C. was treated with 5.0 g (19.5 mmol) of triphenylphosphine followed by 4.83 g (19.0 mmol) of I2 in 25 mL of THF dropwise over 20 minutes. The reaction mixture was stirred for 1.0 hour and was diluted with hexane. The organic mixture was washed with aqueous Na2SO3, brine, dried (Na2SO4) and evaporated to provide a crude white slurry. The slurry was purified by flash chromatography (300 g of silica gel) eluting with hexane to provide 4.00 g (79%) of title iodide as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]#[CH:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:18]#[CH:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (425.8 g) and K2CO3 (807.6 g) in acetone (2,960 ml) at reflux temper-ature of about 60° C. under a nitrogen atmosphere, was added dropwise 3-bromo-propyne (502.4 g) over a period of 2 hours. The reaction was heated at reflux for 3 more hours. After cooling to room temperature the reaction mixture was filtered and the excess of K2CO3 removed and washed several times with acetone. The filtrate was washed with saturated aqueous solution of NaHCO2 and NaCl. The aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to a volume of 1 liter. The solution was kept in the refrigerator overnight. The crystals were filtered out and washed with cold diethyl ether. The filtrate was kept in the refrigerator and some more crystals were formed and removed. This procedure was repeated 3 times resulting in 1,385.26 g of 4-(2-propynyloxy) benzaldehyde in 83% yield. The material was analysed by gas chromatography, and shown to be 99.9% pure. Infrared and mass spectroscopic analysis confirmed the structure.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].[Na+].[Cl-]>C(Cl)Cl>[Si:6]([O:5][CH2:4][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][Cl:28])([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)CCCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCCl)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
(S)-tert-butyl 1-amino-3-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (1 g, 3.29 mmol) was taken up in 10 mL of CH2Cl2 and cooled to 0° C. To this was added Et3N (0.731 g, 7.24 mmol), followed by 5-chloro-pentanoyl chloride (0.557 g, 3.62 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. Upon completion of the reaction, satd NaCl solution was added. The organic layer was extracted with EA, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(5-chloropentanamido)propan-2-ylcarbamate (1.2 g, 86%). 1H NMR (CDCl3, 300 MHz) δ 6.31 (s, 1H), 5.04 (d, 1H), 3.65 (m, 3H), 3.53 (m, 2H), 3.40 (m, 2H), 2.18 (t, 2H), 1.78 (m, 4H), 1.43 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=O)=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][NH2:22])([CH3:16])([CH3:15])[CH3:14].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH2:11][NH:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1cc(CC=O)ccc1F
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-5-(2-oxoethyl)benzonitrile (1.5 g, 9.2 mmol), tert-butyl(2-aminoethyl)carbamate (1.5 g, 9.2 mmol), NaCNBH3 (1.2 g, 18.4 mmol) and acetic acid (1.6 g, 27.6 mmol) in methanol (20 mL) was stirred at ambient temperature overnight. The solvents were evaporated, and the residue was basified with saturated NaHCO3 to pH=7-8, and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified with silica gel column chromatography to give tert-Butyl (2-{[2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]#[N:12].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:11]#[N:12])#[N:17]
Reactant: N#Cc1ccccc1F
Reactant: Cc1c(C#N)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C#N)n(-c2ccccc2C#N)c2ccccc12
Temperature: 60 °C
Yield: 94.7 %

Procedure:
A mixture of 3-methyl-1H-indole-2-carbonitrile (500 mg, 3.2 mmol), 2-fluorobenzonitrile (388 mg, 3.2 mmol) and Cs2CO3 (1.05 g, 3.2 mmol) in DMF (10 mL) was heated at 60° C. overnight. The mixture was poured into H2O and a precipitate formed. The solid was collected by filtration, washed with H2O and hexane, and dried under vacuum to give 1-(2-cyanophenyl)-3-methyl-1H-indole-2-carbonitrile (780 mg, 94.6%) as an off white solid that was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)CCCCCCCNc1cccc(Cl)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1

Procedure:
As described in example 3(b), the reaction is carried out with 10 g (35 mmol) of 8-(3-chlorophenylamino)-caprylic acid methyl ester, 6.2 g (35 mmol) of 2-chlorobenzoic acid chloride, 3.9 g (39 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:43]12[NH:49][CH:46]([CH2:47][CH2:48]1)[CH2:45][CH2:44]2>>[CH:46]12[N:49]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[C@@H:23]4[CH2:32][CH2:31][C:30]5[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=5[CH2:24]4)=[CH:40][CH:41]=3)[CH:43]([CH2:48][CH2:47]1)[CH2:44][CH2:45]2
Reactant: C1CC2CCC1N2
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Agent: Cl
Product: COc1cc(NCCCc2ccc(CCN3C4CCC3CC4)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 13.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=O)[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:2][O:3][N:4]=[C:10]([C:6]1[NH:5][CH:9]=[CH:8][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=O)c1ccc[nH]1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc[nH]1

Procedure:
97.5 g (1.2 eq) of methoxyamine hydrochloride are added to a solution of 148.8 g (0.97 mol) of methyl pyrrol-2-ylglyoxylate (prepared by a method similar to that described by B. Lindstrbm et al., Acta Chem. Scand. 27 (1973), 7) in 1 l of methanol, and the solution is refluxed for 2.5 hours. After evaporation in a rotary evaporator, the residue is taken up in ethyl acetate and the solution is washed with water, dried and evaporated down. 81 g (46%) of the pyrrole remained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].Cl.CCOCC>CO>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Reaction time: 96 h

Procedure:
To 4-methoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0° C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL). The solution was at room temperature for 4 days. 1N HCl was added to the solution followed by ether. The two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4). Upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 [M+H, 100%]. Anal. Calcd for C14H17N1O4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:12]=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>N1C=CC=CC=1.[Cu](Br)Br>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Reactant: Oc1ccccc1
Agent: Br[Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Reaction time: 20 h
Yield: 64 %

Procedure:
A 60% dispersion of sodium hydride (0.86 g, 22 mmol) was added to a mixture of copper bromide (2.6 g, 17.9 mmol) and phenol (1.7 g, 17.9 mmol) in pyridine (300 mL). After the effervescence subsided, the mixture was heated to reflux for 30 minutes. 3-Iodo-4-nitroanisole (5.0 g, 17.9 mmol) was added and stirring proceeded under nitrogen for 20 hours. The mixture was cooled and the reaction was quenched with saturated ammonium chloride (1 mL). The mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (250 mL) and washed with dilute aqueous HCl (2×200 mL), saturated sodium carbonate (2×200 mL) and water (200 mL), and was evaporated in vacuo. The residue was purified by ISCO silica gel flash chromatography in hexanes-ethyl acetate gradient, eluting 2.8 g of the product at 7:3 hexanes-ethyl acetate, in 64% yield; 1H NMR (CDCl3) δ 3.78 (s, 3H), 6.43 (d, J=2.3 Hz, 1H), 6.68 (dd, J=9.2, J=2.3 Hz, 1H), 7.03-7.07 (m, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.37-7.41 (m, 2H), 8.07 (d, J=9.2 Hz, 1H).
Reaction SMILES: C([Li])CCC.[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])Cl>CCCCCC.O=O.O>[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:7]1[CH:6]=[CH:10][CH:9]=[CH:8]1
Reactant: C1=CCC=C1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)Cl
Agent: O=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
8.5 ml (21 mmol) of a 2.5M solution of butyllithium in hexane were added dropwise to 1.4 g (21 mmol) of cyclopentadiene in 45 ml of O2 -free and H2O-free THF at 0° C. under argon and the mixture was stirred for a further 2 hours at room temperature. This solution was subsequently added at room temperature to a solution of 7.9 g (21 mmol) of 2 in 100 ml of O2 -free and H2O-free THF over a period of 2 hours and the mixture was stirred for a further 1 hour at room temperature. 50 ml of H2O were added, the phases were separated and the aqueous phase was further extracted twice with 30 ml of Et2O each time. The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo. After chromatography on 200 g of silica gel (hexane/methylene chloride 20:1), 4.4 g (51%) of 3 were obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:46](=[O:68])[C@@H:47]([NH:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=2)[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:48]([C@H:47]([N:55]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:46]([N:43]1[CH2:42][CH2:41][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:45][CH2:44]1)=[O:68])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CCCCOc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
In an inert atmosphere, trans-4-(trifluoromethyl)cinnamic acid (28 mg, 0.13 mmol) was dissolved in DCM (0.5 mL) followed by the addition of 1-chloro-N,N,2-trimethylpropenylamine (19.4 mg, 0.145 mmol). The mixture was stirred at rt for 30 min followed by the addition of DIPEA (34 mg, 0.26 mmol) and 1-(4-benzyl-piperazin-1-yl)-2-(4-butoxy-benzylamino)-(S)-3-phenyl-propan-1-one (63 mg, 0.13 mmol). Stirring was continued for 30 min. The mixture was concentrated in vacuo and the residue was directly purified by prep. HPLC to give 51 mg (57%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-butoxy-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=684.49.