Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCOc1ccccc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCOc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.25 g--see Preparation 8), 2-phenoxyethyl bromide (0.18 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.18 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)=[N:16][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:21]1[CH2:22][CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:17][N:16]=2)[CH2:19][CH2:20]1)=[O:4]
Reactant: C1=C(c2ccc(-c3ncccn3)cn2)CCNC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Added chloroacetyl chloride (0.35 g, 4.39 mmol) in MeCl2 (15 ml) to a solution of 5-Pyrimidin-2-yl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl (3Q) (0.4 g, 1.68 mmol) and triethylamine (0.4 g, 2.87 mmol) in MeCl2 (10 ml) at 0° C., then stirred 2 hours at 0° C. Added saturated NaHCO3 solution and stirred an additional hour at 0° C. MeCl2 (100 ml) was added, organic layer separated, dried over Na2SO4, filtered and solvent evaporated yielding 4Q as a pale yellow solid (0.53 g, 100%) ESMS (MH 315).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22]>Cl.C(Cl)Cl>[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: Cc1cccc(O)c1C
Reactant: c1ccc(CN2CC3OC3C2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)c1C

Procedure:
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-epoxypyrrolidine, 18.3 g. (0.15 mole) of 2,3-dimethylphenol and 2 drops of concentrated hydrochloric acid was heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture was dissolved in methylene chloride and washed with four 100-ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate-potassium hydroxide and concentrated to give 28.6 g. of dark oil as residue. This oil was chromatographed or 600 g. of silica gel and the product was eluted with an acetone-benzene solution. The appropriate fractions were concentrated to give an oil which crystallized upon standing. This solid was recrystallized from ligroin to give 9.1 g. (31%) of white solid, m.p. 100°-4° C.
Reaction SMILES: [C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11](Cl)[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15].O>>[C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11]([NH2:15])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)c1cc2cc(Cl)ncc2[nH]1
Solvent: O
Product: CC(C)(C)c1cc2cc(N)ncc2[nH]1
Temperature: 200 °C
Yield: 27 %

Procedure:
To a solution of 2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (5.0 g, 24 mmol) in NH3.H2O (400 mL) was added CuSO4.5H2O (595 mg, 2.39 mmol). The mixture was heated at 200° C. (3 MPa pressure) for 24 h. After cooling, the mixture was extracted with CH2Cl2 (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to obtain 2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (1.2 g, 27%). 1H NMR (400 MHz, DMSO) δ 10.66 (br s, 1H), 8.02 (s, 1H), 6.39 (s, 1H), 5.86 (d, J=1.2 Hz, 1H), 4.85 (br s, 2H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([SH:15])=[C:10]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[S:26](Br)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[C:10]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH:9]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CCOC(=O)c1cc2cc(S)c(C(C)(C)C)cc2[nH]1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(SS(=O)(=O)c3ccc(C)cc3)c(C(C)(C)C)cc2[nH]1

Procedure:
The title compound was prepared according to General Method 15 using (6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic acid ethyl ester (prepared in Example AAA), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[C:20]1(=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=[O:30])[CH2:22][O:21]1.N1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11](/[CH:14]=[C:22]3\[O:21][C:20](=[O:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]\3=[O:30])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1COC(=O)c2ccccc21
Reactant: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCN1
Product: O=C1O/C(=C\[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the resulting stirred mixture from stage 1, at ambient temperature under argon, was added acetic acid (250 mL), 1H-2-benzopyran-1,4(3H)-dione (compound of formula (III)) (32.4 g, 200 mmol) and morpholine (17.5 mL, 200 mmol). The reaction mixture was heated to 40° C. for 4 hours then allowed to cool to ambient temperature and stir overnight. Water (250 mL) was added and the slurry stirred for 15 minutes at ambient temperature then filtered. The filter cake was washed twice with tert-butyl methyl ether (2×125 mL) and dried to give the title compound as a yellow solid (62.4 g). The material obtained was spectroscopically identical to that obtained in Stage 2, Example 3.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:6][CH:7]=1)[NH2:16]
Reactant: Cc1nccn1-c1ccc(Cl)nn1
Reactant: NN
Solvent: O
Product: Cc1nccn1-c1ccc(NN)nn1

Procedure:
6.7 g (35 millimoles) of 3-chloro-6-(2-methyl-imidazol-1-yl)-pyridazine are taken up in 30 ml of hydrazine hydrate and the mixture is heated for 5-10 hours at 100°-130° C. under nitrogen as a protective gas; the reaction mixture becomes homogeneous in the course of the first few hours. When the mixture has cooled, the crude product which has precipitated is filtered off. It is also possible to pour the reaction mixture into ice water and extract the mixture repeatedly with methylene chloride. Continuous extraction by means of a rotary perforator, using methylene chloride or chloroform as the extraction solvents, has also proved an advantageous method. Yet a further possibility is to distil off the hydrazine hydrate under reduced pressure.
Reaction SMILES: B.CSC.[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH:24]C2C=CC=CC=2OC)=O)[CH2:18][CH2:17]1>O1CCCC1>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH:22]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:5][CH3:6])[NH2:24])[CH2:20][CH2:21]1
Reactant: COc1ccccc1NC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccccc1C(N)C1CCN(CC2COc3ccccc3O2)CC1
Temperature: 95 °C
Yield: 189.8 %

Procedure:
Borane-dimethyl sulphide complex (1M solution in dimethyl sulphide; 0.5 ml) was added dropwise under nitrogen to a solution of 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide (0.35 g) in dry tetrahydrofuran (25 ml) and then the mixture was heated under reflux for 2 hours. The reaction was cooled and the solvents removed in vacuo. The residue was diluted cautiously with dilute hydrochloric acid (1M; 70 ml) and heated at 95° C. for 1.5 hours. The aqueous mixture was cooled and basified by the addition of aqueous sodium hydroxide solution (2.5M), there the product was extracted into dichloromethane. The organic extract was washed with water, then dried over magnesium sulphate, filtered, and the solvent removed in vacuo to yield 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl]-N-(2-methoxyphenyl) methylamine (0.32 g). The procedure was repeated using 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide (1.37 g, prepared in a similar manner to that described above). The products of the two reactions were combined and dissolved in ether. Hydrogen chloride was bubbled through the solution and the resulting solid precipitate collected by filtration (1.2 g). The solid was dissolved in saturated aqueous sodium hydrogen carbonate solution (100 ml) and the resulting oil extracted into ethyl acetate (100 ml). An excess of a saturated solution of oxalic acid in ethyl acetate was added and the solid precipitate was collected by filtration and dried in vacuo at 50° C. to yield 1-[1-(1,4-benzodioxan-2-ylmethyl) piperid-4-yl]-N-(2-methoxyphenyl)methylamine mono-oxalate (0.78 g), m.p. 215°-218° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[N:25]([CH3:27])[CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[N:25]([CH3:26])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N(C)C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](N(C)C)C2)nc1C
Yield: 90.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(dimethylamino)-piperidine-1-carboxylate obtained in Example (200d) (104 mg, 0.260 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (71.6 mg, 0.286 mmol) and sodium carbonate (551 mg, 5.20 mmol), to obtain 110 mg of the title compound (90%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[O:9]1CC[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C>O>[C:10]([NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3][O:2][CH3:1])(=[O:9])[CH3:11]
Reactant: COCC(N)C(=O)O
Reactant: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COCC(NC(C)=O)C(=O)O
Yield: 90 %

Procedure:
Into a vessel, equipped with a mechanical stirrer, was added O-methyl-D,L-serine (1.0 eq.) at 20° C. Tetrahydrofuran (6 volumes) and water (0.65 volume) were added. Acetic anhydride (1.2 eq.) was added dropwise over 5 minutes. The white suspension was stirred mechanically until complete conversion was observed by HPLC monitoring (approximately 16 h), by which time the reaction mixture had become homogeneous. The tetrahydrofuran and water were removed azeotropically. Toluene was added in order to effect complete removal of water and acetic acid (KF and GC control). The wet solid was dried at 40° C. under vacuum overnight. The title compound (90% yield) was obtained as a white solid with a chemical purity of >98% as measured by HPLC.
Reaction SMILES: CCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].O.CC[O:15][C:16]([CH:18]1[C:20]([CH3:22])([CH3:21])[CH:19]1[CH:23]=[C:24]([CH3:26])[CH3:25])=[O:17]>>[CH3:25][C:24]([CH3:26])=[CH:23][C@H:19]1[C:20]([CH3:21])([CH3:22])[C@@H:18]1[C:16]([OH:17])=[O:15]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCCC
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
In a 100 ml flask, 2.0 g of an ethyl chrysanthemate having the optical isomer ratio of 3.6% of (-)-cis, 19.1% of (+)-cis, 10.5% of (-)-trans and 66.9% of (+)-trans forms by weight, was dissolved into 18.0 g of n-heptane under nitrogen. To the solution was added 0.7 g of aluminum chloride, and the mixture was stirred at a temperature of 70° C. for 3 hours. Thereafter, water was added to the reaction mixture to decompose the aluminum chloride. The organic layer separated was evaporated to remove the solvent, and the residue was mixed with 6.1 g of an aqueous 10% sodium hydroxide solution and stirred at a temperature of 100° C. for 2.5 hours to effect the hydrolysis. The reaction mixture was extracted with toluene to separate the neutral substance. The aqueous layer was acidified with a diluted sulfuric acid and then extracted with toluene. The toluene layer was washed with water, dried and evaporated to remove the solvent. Distillation in vacuo yielded 1.32 g of a trans-chrysanthemic acid boiling at 110° to 116° C./2 mmHg. Its analysis by gas-chromatography showed the optical isomer ratio of 0.9% of (-)-cis, 6.3% of (+)-cis, 12.4% of (-)-trans and 80.4% of (+)-trans forms by weight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O1CCCC1.CO.[Li+].[OH-]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a chilled (0° C.) solution of ethyl 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate (0.95 g, 2.39 mmoles) in 20 mL of 1:1 (v/v) mixture of tetrahydrofuran and methanol was added an aqueous solution of LiOH (4.0 mL, 3 Molar) in one single portion. The reaction mixture was stirred at 0° C. for 15 minutes followed by warming up to ambient temperature. Saponification was allowed to proceed at room temperature for four hours forming a very pale clear solution. The crude reaction mixture was diluted with 12 mL of 2M H2SO4 and the product was extracted into diethyl ether (40 mL×2). The organic layers were combined, dried over MgSO4, concentrated under reduced pressure and then vigorously dried under high vacuum (0.01 mmHg) at room temperature for 24 hours to yield the title compound. The propenoic acid was then utilized in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[OH:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:10][CH3:11])[CH:5]=1)[O:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27]
Reactant: COc1cc(I)cc(OC)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
In a sealed tube purged with nitrogen, 1-iodo-3,5-dimethoxybenzene (36) (0.78 g, 3.0 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (0.65 g, 2.68 mmol), Cs2CO3 (1.3 g, 4.0 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.12 g, 0.50 mmol), CuI (0.05 g, 0.3 mmol), diglyme (2 mL) and toluene (10 mL) were added. The reaction mixture was stirred at 120° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (300 mL) and washed with water (100 mL). The organic layer was dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 2:1) gave (1S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (37) (0.71 g, 70%) as a colourless oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[O:23]([CH2:30][C:31]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:33][C:31](=[O:32])[CH2:30][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)COc1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)COc3ccccc3)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.7 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at room temperature with 4.7 g of phenoxyacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-7-oxo-6-(2-oxo-3-phenoxypropylidene)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a yellow oil [Rf: 0.44; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.21 (9H); 1.51 (3H); 1.56 (3H); 4.58 (1H); 5.66 (2H); 5.83 (2H); 6.05 (1H); 6.8-7.45 (6H)].
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>CN(C=O)C.O>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 29a from Example 8 (0.7 g, 2.1 mmol), 2-(tributylstannyl)thiophene (1.59 g, 4.3 mmol) and tris(triphenylphosphine)palladium dichloride (50 mg) in DMF (5 ml) is heated to 80° C. over night. The cooled reaction mixture is diluted with 4 volumes of water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 0.56 g (80%). Mp 184-185° C.
Reaction SMILES: [CH2:1](N(CC)C1C=CC=CC=1)C.[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#C)=[CH:17][C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:18]2[O:19][C:20]([CH3:21])=[CH:1][C:17]=2[C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1
Reactant: C#CCOc1cc(-c2cn(C)c(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(-c3cn(C)c(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1
Temperature: 190 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To 50 ml of N,N-diethylaniline, 0.64 g (1.8 mmol) of 5-(4-chloro-2-fluoro-5-propargyloxyphenyl)-1-methyl-2-trifluoromethyl-4(1H)-pyridone and 0.56 g (3.7 mmol) of cesium fluoride were added, and the mixture was stirred at from 180 to 200° C. for 2.5 hours This reaction solution was poured into water and extracted with ethyl acetate. After washing with concentrated hydrochloric acid, water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 75%) of the desired product. Melting point: 208-211° C. 1H-NMR (400 MHz, CDCl3) δ value: 2.46(3H,s), 3.80(3H,s), 6.31(1H,s), 7.01(1H,s), 7.07(1H,d), 7.57(1H,d)ppm.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:20][N:21](C(OC(C)(C)C)=O)[CH3:22])[CH2:10][N:11](C(OC(C)(C)C)=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C.N.CO>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:20][NH:21][CH3:22])[CH2:10][NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(CN(C)C(=O)OC(C)(C)C)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCC(CNC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 2-benzyloxy-N,N′-bis(t-butoxycarbonyl)-N,N′-dimethyl-1,3-propanediamine (73.0 mg, 0.17 mmol) in methylene chloride (2.0 mL) was added a 4.0 M solution of hydrogen chloride in ethyl acetate (1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, ethanol (5.0 mL) was added to the residue, and the resulting mixture was concentrated under reduced pressure. An approx. 10% solution of ammonia in methanol (2.0 mL, approx. 12 mmol) was added to the residue, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield the title compound as a colorless oil (35.0 mg, yield: 98%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=5)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[CH3:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH3:32])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(Cc2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Reactant: Cc1ccccc1C[Zn+]
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: Cc1ccccc1Cc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methylbenzyl)pyridin-2-yl)cyclopropanecarboxamide (VRT-810361) was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(4-methoxybenzyl)pyridin-2-yl)cyclopropanecarboxamide by reacting (2-methylbenzyl)zinc(II) chloride with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.