Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[C:27]#[N:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:31]1[C:30]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1ccc(F)c(Br)c1
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: CCO
Product: C[C@H](Oc1ccc(-c2cc(C#N)ccc2F)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 88 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxyl]enzeneboronic acid (0.20 g, Example 33), 3-bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.22 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:23]2C([NH:26][C:27](=[O:28])[C:22]=12)=O.[C:32](=[O:35])([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH2:19][CH2:20][C:21]12[CH:31]=[CH:30][CH:29]=[CH:23][CH:22]1[C:27]([NH:26][C:32]2=[O:35])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCCOCCNCc1ccccc1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(=O)C2(CCN(CCOCCOCCO)Cc3ccccc3)C=CC=CC12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
2-[2-(2-Benzylaminoethoxy)ethoxy]ethanol 32 (4.786 g, 20 mmol) and 2-bromoethylphthalimide (5.59 mL, 22 mmol) were dissolved in absolute acetonitrile (100 mL). Potassium carbonate (6.91 g, 50 mmol) was added, and the suspension was heated at reflux with vigorous stirring under an argon atmosphere for 18 hours. The suspension was allowed to cool to room temperature, diluted with acetonitrile (100 mL) and filtered through a Celite™ pad. The acetonitrile was removed under reduced pressure and the residue was purified by flash chromatography using a 1:1 mixture of 40% acetone in hexanes and chloroform as the eluent. Fractions contained the desired product (Rf=0.35) were combined, solvent removed under reduced pressure, and the residue dried in vacuo to provide the title compound 33 (4.2 g, 51%). CIMS (MH+): 413. 1H-NMR (CDCl3): δ 7.82 (m, 2H, phthalimide), 7.70 (m, 2H, phthalimide), 7.21 (m, 5H, phenyl), 4.39 (s, 2H, CH2-Ph), 3.70-3.21 (m, 12 H, OCH2CH2O), 2.85 (q, 2H, J=6.1 Hz, phthalimido-ethylene), 2.79 (q, 2H, J=6.4 Hz, phthalimido-ethylene). 13C-NMR (CDCl3): δ 168.8, 139.8, 134.3, 132.8, 129.4, 128.7, 128.0, 127.6, 73.1, 71.0, 70.8, 62.3, 59.9, 53.7, 52.4, 48.2, 45.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=O)[CH2:2][CH2:3][CH3:4].[Cl-].[OH:20][NH3+:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=[N:21][OH:20])[CH2:2][CH2:3][CH3:4]
Reactant: [NH3+]O
Reactant: CCCCOc1ccc2c(c1)C(=O)CC(C)(C)O2
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc2c(c1)C(=NO)CC(C)(C)O2
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of 52.0 g (0.21 mol) of 6-butoxy-2,2-dimethylchroman-4-one in 420 ml of ethanol were added dropwise in 30 min to a solution of 43.7 g (0.628 mol) of hydroxylammonium chloride and 51.5 g (0.628 mol) of sodium acetate in 420 ml of water and the mixture was kept at 60° C. for 3 h. The oily product phase was separated off and the aqueous phase was extracted with methylene chloride. After drying the organic phases over magnesium sulfate and concentrating in vacuo, 55.5 g of 6-butoxy-2,2-dimethylchroman-4-one oxime were obtained, which it was possible to crystallize by stirring with PE.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:15][C:14]1=[CH:13][CH2:12][C@@H:11]1[C@@H:3]2[CH2:4][CH2:5][C@@:6]2([CH3:32])[C@H:10]1[CH2:9][CH2:8][C@@H:7]2[C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25].CCN(C(C)C)C(C)C.CCOC(C)=O.[O:48]1[C:52](=[O:53])[CH2:51][CH2:50][C:49]1=[O:54]>C1COCC1>[CH3:25][C@@H:24]([C@@H:7]1[C@:6]2([CH3:32])[C@H:10]([C@H:11]3[C@H:3]([CH2:4][CH2:5]2)[C@:2]2([CH3:1])[C:14]([CH2:15][C@@H:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:52](=[O:53])[CH2:51][CH2:50][C:49]([OH:54])=[O:48])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCNC(=O)CCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 114.9 %

Procedure:
In a 2 μL round-bottomed flask, 3-((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)propan-1-amine (21.15 g, 47.7 mmol, Eq: 1.00) and Huenig's base (12.3 g, 16.6 ml, 95.3 mmol, Eq: 2.00) were combined with AcOEt (845 ml) to give a colorless solution. Dihydrofuran-2,5-dione (4.77 g, 47.7 mmol, Eq: 1.00) in THF (42 ml) was added and the reaction mixture was stirred at ambient temperature over night=>white suspension. All volatiles were removed i. v., the residue dissolved in CH2Cl2, the organic layer washed with NH4Cl and brine, dried over Na2SO4, and evaporated to dryness. The crude product was dissolved in CH3CN/H2O and lyophilized to yield 29.8 g of the title compound as fluffy powder. MS (ISP): (M−H) 542.5.
Reaction SMILES: [CH3:1][C:2]1(C)[CH:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[N:17](OCCCC)=[O:18].[CH3:24][O-].[Na+].Cl>CO.CCOCC>[OH:18][N:17]1[C:2]([CH3:1])=[C:10]([CH2:11][C:12]([O:14][CH3:24])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15]
Reactant: CC1(C)C(=O)c2ccccc2C1CC(=O)O
Reactant: C[O-]
Reactant: CCCCON=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1c(C)n(O)c(=O)c2ccccc12

Procedure:
A clear yellow solution of methyl 2-methyl-1-oxo-3-indane acetic acid (0.844 g., 3.87 mmol) and n-butyl nitrite (1.1 ml., 9.7 mmol) [W. A. Noyes, Org. Syn., Col. Vol. II, 108 (1943)] in 7.6 ml methanol was stirred as a 5% solution of sodium methoxide in methanol. (1.2 ml., 2.6 mmol) was added. Addition of 25 ml. ether to this red-brown solution followed by 1 N hydrochloric acid to pH 3-4 precipitated the title compound which was washed with water and ether and dried: 0.40 g. (42%) mp 185°-190°.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7]Cl)[CH2:4][CH3:5])[CH3:2].[Na].[OH:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[O:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:17])[CH3:16]>CC(C)=O>[CH2:1]([N:3]([CH2:6][CH2:7][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[O:13][C:14](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15](=[O:17])[CH3:16])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)C(=Cc1ccccc1)Oc1ccccc1O
Agent: [Na]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccccc1OC(=Cc1ccccc1)C(C)=O

Procedure:
21 g of N,N-diethylaminoethyl chloride are added drop by drop to 35 g of the sodium salt of 3-o-hydroxyphenoxy-4-phenyl-3-butene-2-one suspended in 600 cc of anhydrous acetone. The mixture is heated under reflux for 4 hours, the sodium chloride is filtered off, and the filtrate is evaporated to dryness. The residue is dissolved in water and extracted a number of times with diethyl ether. The ether phase, after drying over Na2SO4, is evaporated to dryness and purified by distillation in a bulb apparatus. (B.P. 200°-210°/0.6 mm Hg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC)=[CH:6][CH:5]=1.[Cl-].[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1.O>N1C=CC=CC=1.O1CCCC1>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:19]=[C:28]([C:27]3[CH:31]=[CH:32][C:24]([C:23]([O:22][CH3:21])=[O:33])=[CH:25][CH:26]=3)[O:1][N:2]=2)=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(C(=N)NO)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(-c2noc(-c3ccc(C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a solution of N-Hydroxy-4-octyloxybenzamidine (1.89 g) in pyridine (10 ml) was added terephthalic acid monomethyl ester chloride (1.67 g) in tetrahydrofuran (15 ml) dropwise at 0° C. The mixture was stirred at room temperature for 15 minutes, and poured into water. The precipitate was collected by filtration, dried and dissolved in pyridine (10 ml). The solution was refluxed for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl, water and brine. The separated organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile and collected by filtration. The solid was dried to give Methyl 4-[3-(4-n-hexyloxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (2.27 g).
Reaction SMILES: S(=O)(O)[O-].[Br:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br-:5].[CH2:22]([CH:12]1[C:13]2[C:8](=[CH:7][C:6]([Br:5])=[CH:15][CH:14]=2)[CH2:9][CH2:10][C:11]1=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2CCC1Br
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC(=[N+]1CCCC1)C2Cc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of the bisulfite adduct of bromotetralone of formula A-1 wherein Rx is Br (250 g, 760 mmol) (commercially available) in saturated sodium bicarbonate (1.25 L) and ethyl acetate (2.5 L) was stirred vigorously overnight. Phases were separated and the organic phase was transferred to a new flask and toluene (1 L) was added. The solution was distilled under reduced pressure to a volume of about 500 mL. An additional 500 mL of toluene was added and distilled under reduced pressure to a volume of about 300 mL. The solution was cooled to room temperature and pyrrolidine (54.1 g, 760 mmol) was added. The reaction was heated to 150° C. under Dean-Stark conditions. After 2 hr, about 13 mL of water was collected and concentration of a small sample showed the reaction was complete by NMR. The toluene solution of pyrrolidine enamine was cooled to 90° C. and benzyl bromide (105 mL, 912 mmol) was added dropwise. After 30 min, solids began to granulate and the solution became very thick. An additional 500 mL of toluene was added to aid stirring and heating was continued at 90° C. for 2 h. The slurry was allowed to cool to room temperature and granulate overnight. The solids were filtered and washed with toluene (2×500 mL). After drying in a vacuum oven overnight (50° C.), the title product of this preparation as a brown solid was collected: 250 g (557 mmol), 73% yield; mp 203-205° C.; IR (film) ν 1654, 1596 cm−1; 1H NMR (CDCl3) δ 7.25 (s, 1H), 7.17-7.13 (m, 3H), 7.08 (dd, 1H, J=8.3, 1.7 Hz), 6.98-6.93 (m, 2H), 6.68 (d, 1H, J=8.3 Hz), 4.29 (dd, 1H, J=7.5, 7.5 Hz), 4.25-4.17 (m, 2H), 3.95-3.86 (m, 1H), 3.62-3.49 (m, 2H), 3.27 (dd, 1H, J=13.7, 6.6 Hz), 3.14-3.05 (m, 3H), 2.07-1.95 (m, 3H), 1.92-1.84 (m, 1H); 13C NMR (CDCl3) δ 189.2, 137.2, 136.1, 132.2, 131.2, 130.9, 130.6, 129.8, 129.2, 127.8, 122.1, 55.1, 55.2, 51.3, 39.3, 34.0, 25.6, 24.9, 24.2; Anal. calcd for C21H22BrN: C, 56.15; H, 5.16; N, 3.12. Found: C, 55.64; H, 5.22; N, 3.22.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:15]1[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]2[O:11][CH2:10][CH2:9][O:8][C:13]=2[CH:14]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Yield: 27 %

Procedure:
160 ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added. The mixture was agitated at 40°-45° C. and then cooled. The crystals were dried off, washed and dried. 34 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 246° C.; yield: 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1.O1CCCC1>[CH3:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(C)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4'-Amino-3'-methylacetophenone from Step VIII (3.0 g, 20 mmol) in 15 ml of dry pyridine at 5° C. is reacted with 3.0 g (26.2 mmol) of methanesulfonyl chloride in 5 ml of tetrahydrofuran. The reaction is stirred at 5° C. for 2 hrs, then at room temperature overnight. The reaction is diluted with ice-water. The solid is collected, washed with water, air dried and crystallized from methylene chloride-pet. ether to yield the title compound; m.p. 152°-153° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[S:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])[OH:32].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])(O)(=O)=O.[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:10](=[O:32])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (65 mg, 1.01 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (124 mg, 0.716 mmol) at 0° C. and the resulting mixture was stirred at room temperature for two hours. To reaction solution was added an aqueous sodium hydrogensulfate solution, the organic layer separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 50 mg (yield: 22%) of the title compound. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:26][NH2:27]>C(O)CC>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:5]3[CH:4]=[C:3]4[O:2][CH2:1][O:9][C:8]4=[CH:7][C:6]=3[CH2:10][C:11](=[O:12])[NH:27][N:26]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(OC)cc1)OCO2
Reactant: NN
Solvent: O
Solvent: CCCO
Product: COc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(4-methoxybenzoyl)phenylacetate (102 mg, 0.31 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in 1-propanol (8 mL), mp: 194°-196° C. 1H NMR (CDCl3) 8.48 (s, 1H), 7.55 (d, 2H, J=8.8), 6.94 (d, 2H, J=8.8), 6.83 (s, 1H), 6.66 (s, 1H), 6.03 (s, 2H), 3.86 (s, 3H), 3.44 (s, 2H). Anal. calcd. for C17H14N2O4 : C, 65.80; H, 4.55; N, 9.03. Found: C, 65.56; H, 4.57; N, 8.72.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>CO>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: ClCCCCCBr
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCCCCl)C(C)=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of methyl acetoacetate [VI-2] (127.7 g, 1.1 mol) and methanol (200 g) is heated to 30° C. Thereto is added dropwise 28.1% solution of sodium methoxide in methanol (192 g, 1.0 mol), and the mixture is stirred for 1 hour. Thereto is added 1-bromo-5-chloropentane [V-1] (155.5 g, 0.838 mol), and the mixture is reacted at 70° C. for 2 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and thereto is added toluene (500 g). The precipitated salt is removed by filtration. The toluene layer is washed with water and concentrated under reduced pressure to give methyl 7-chloro-2-(1-oxoethyl)heptanoate [II-2] (189.9 g, content; 88.7%, yield; 91.2%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]([C:9]#[CH:10])[CH3:8].O1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([Li])CCC.BrCC1CC1>CCOCC.O.CN(C)P(=O)(N(C)C)N(C)C>[CH:14]1([CH2:15][C:10]#[C:9][CH:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:8])[CH2:12][CH2:13]1
Reactant: C#CC(C)C1CCCCO1
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C#CCC1CC1)C1CCCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-tetrahydropyranyl-but-3-yne (1.14 parts) in 15 parts by volume of tetrahydrofuran are cooled to -20° C. and 4.63 parts by volume of 1.6N n-butyl lithium are added. The reaction mixture is allowed to warm to 0° C. and again cooled to -20° C. and then 1 part of bromomethylcyclopropane in 3 parts by volume of tetrahydrofuran are added. The reaction mixture is allowed to warm to room temperature and 15 parts by volume of hexamethylphosphoric triamide is added and the reaction is stirred over three hours. The reaction mixture is poured into ether/water and extracted several times with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed by evaporation at reduced pressure and the residual oil is chromotographed with 10% ethyl acetate/hexane to provide 5-cyclopropyl-2-tetrahydropyranyl-pent-3-yne. This material is dissolved in a solution of 25 parts by volume of tetrahydrofuran, 25 parts by volume methanol, and 25 parts by volume of 1N HCl and stirred at room temperature for 1 hour. The reaction mixture is poured into a mixture of ether and water. The aqueous layer is extracted with ethyl acetate and the extracts are combined and washed with water and saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate and chromatographed with 15% ethyl acetate/hexane to provide 5-cyclopropyl-pent-3-yne-2-ol. 1.5 parts of this alcohol is reacted with 3.25 parts of pyridinium chlorochromate in 35 parts by volume of methylene chloride. The reaction mixture is stirred for three hours at room temperature, 100 parts by volume of ether is added and the mixture is stirred for 1 hour then filtered through Florisil. The solvent is removed by evaporation at reduced pressure. The residue is dissolved in hexane and again filtered. The solvent is evaporated under reduced pressure to provide 5-cyclopropyl pent-3-yne-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1.[CH3:20][I:21]>C(O)C>[I-:21].[CH3:20][N+:3]1[CH:4]=[CH:5][S:1][C:2]=1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:19])=[CH:11][CH:12]=1
Reactant: CI
Reactant: CCOC(=O)C(C)c1ccc(Nc2nccs2)cc1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(Nc2scc[n+]2C)cc1
Product: [I-]
Yield: 84 %

Procedure:
A mixture of ethyl 2-[4-(N-thiazol-2-ylamino)phenyl]propionate (6.3g), methyl iodide (30 ml) and ethanol (30 ml) is heated at 50°-55° C for 20 hours under nitrogen atmosphere. After evaporation of ethanol and methyl iodide, the resultant residue is washed with ether and ethyl acetate successively to give 3-methyl-2-[4-(1-ethoxycarbonylethyl)anilino]thiazolium iodide (8.0 g). (Yield 84 %).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Cl.[CH:12]12[NH:20][CH:16]([CH2:17][CH2:18][CH2:19]1)[CH2:15][C:14](=O)[CH2:13]2.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:14]1[CH2:13][CH:12]3[NH:20][CH:16]([C:15]2=1)[CH2:17][CH2:18][CH2:19]3
Reactant: O=C1CC2CCCC(C1)N2
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Temperature: 80 °C

Procedure:
In a 100 mL round-bottom flask were combined p-tolylhydrazine hydrochloride (1.80 g, 11.4 mmol; Alfa Aesar), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (2.0 g, 11.4 mmol; Accela ChemBio), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.39-1.50 (m, 2H), 1.75 (d, J=14 Hz, 2H), 1.91-2.07 (m, 2H), 2.38 (s, 3H), 2.72 (d, J=17 Hz, 1H), 3.27-3.39 (m, 1H), 3.70 (t, J=5 Hz, 1H), 4.55 (t, J=3 Hz, 1H), 6.88 (dd, J=8, 1 Hz, 1H), 7.14 (s, 1H), 7.18 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:8][NH:7][CH2:6][CH:5]1[CH2:4][N:3]([C:9]1[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:22])[C:11]=3[CH:10]=1)[CH2:2]2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>>[CH3:27][N:7]1[CH2:8][CH:1]2[CH:5]([CH2:4][N:3]([C:9]3[CH:21]=[CH:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:22])[C:11]=4[CH:10]=3)[CH2:2]2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1c2ccccc2-c2ccc(N3CC4CNCC4C3)cc21
Agent: C=O
Agent: [Na+]
Product: CN1CC2CN(c3ccc4c(c3)C(=O)c3ccccc3-4)CC2C1
Reaction time: 3 h
Yield: 100 %

Procedure:
The product of Example 13B (130 mg, 0.46 mmol) was treated with aqueous formaldehyde (5 mL, 37%; EM Science) and NaBH(OAc)3 (163 mg, 0.77 mmol; Aldrich). After stirring for 3 h, the reaction was quenched with saturated NaHCO3 (5 mL) and diluted with CH2Cl2 (5 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure and purified via column chromatography (silica gel, 1:9:90 NH4OH/CH3OH/CH2Cl2) to give the title compound (>100%, impure). MS (DCl/NH3) m/z 305 (M+H)+.