Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(O)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 34.7 %

Procedure:
The O-alkylation procedure described for 190 was employed. To a suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219) (0.500 g, 1.74 mmol), K2CO3 (0.257 g, 1.86 mmol), and acetone (75 mL) was added ethyl 2-bromo-2-methylpropanoate (0.33 mL, 2.3 mmol) at RT. The reaction mixture was refluxed for 48 h, and filtered. The filtrate was concentrated and purified to afford 0.272 g (40%) of compound 227 as a white foam. In addition, 0.200 g of unreacted SM was recovered. 1H NMR (300 MHz, CDCl3): δ 7.04 (d, J=1.8 Hz, 2H), 7.01 (d, J=1.8 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.77 (d, J=2.7 Hz, 2H), 6.74 (d, J=2.4 Hz, 2H), 4.75 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.96 (d, J=6.9 Hz, 4H), 1.60 (s, 6H), 1.29 (s, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.934 (s, 6H), 0.92 (s, 6H). LCMS (ESI): m/z 449 (M−H)−.
Reaction SMILES: [Br-].C(C(C)(C)CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[Na].[H-].[Na+].C(OC([N:40]1[CH2:44][C@H:43]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:42][C@H:41]1C=O)=O)(C)(C)C>CS(C)=O.O>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([S:46]([NH:45][CH:43]2[CH2:44][NH:40][CH2:41][CH2:42]2)(=[O:48])=[O:47])=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1C=O
Agent: CC(C)(CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(NC1CCNC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-carboxy-4-methylpentyl)triphenylphosphonium bromide (3.83 g) in dimethyl sulfoxide (21 ml) was added sodium methylsulfinylmethide [19.5 m mol, prepared from sodium hydride (468 mg) and dimethyl sulfoxide (17 ml)]and the solution was stirred at room temperature for 30 minutes. To the resulting solution was added (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-formylpyrrolidine (1.0 g) in dimethyl sulfoxide (3.0 ml) and the mixture was stirred at room temperature for 1 hour. After addition of water (50 ml), the solution was washed with ethyl acetate and the aqueous layer was adjusted to pH 1 with 1N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase was washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give (2S,4R)-1-t-butoxycarbonyl-2-[(E and Z)-5-carboxy-5-methyl-1-hexenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH3:12])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Yield: 46.4 %

Procedure:
A solution of N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)propanehydrazide (5.0 g, 14.02 mmol) and phosphoryl trichloride (100 mL, 1073 mmol) was stirred at 90° C. for 5 hrs. The reaction was cooled, stripped to dryness, and the resulting material was reconstituted in a mixture of EtOAc and saturated NaHCO3 (400 mL, 1:1)). The organic phase was isolated, washed with saturated NaHCO3 (1×100 mL), and dried over MgSO4. The organic phase was removed via rotary evaporation to provide the title compound, 6-bromo-3-(1-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine 48D (2.2 g, 6.50 mmol, 46.3% yield). This material was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J=7.07 Hz, 3 H) 5.27 (d, J=7.33 Hz, 1 H) 7.49 (dd, J=9.60, 1.77 Hz, 1 H) 7.78 (dd, J=9.85, 1.01 Hz, 1 H) 7.94 (s, 2 H) 8.79 (s, 1 H). ESI-MS:m/z 339.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:19][O:18][C:12]([CH:13]([CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:13]([C:12]([O:18][CH3:19])=[O:17])[C:14](=[O:15])[CH3:16])[C:14](=[O:15])[CH3:16])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)C(C(C)=O)C(c1cccc([N+](=O)[O-])c1)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
To a mixture of 72.1 g of zinc chloride in 200 ml of ethyl acetate was added dropwise a mixture of 40.0 g of m-nitrobenzaldehyde and 61.5 g of methyl acetoacetate at room temperature over 50 minutes. The mixture was stirred at room temperature for further 15 minutes, and further stirred while heating at 60°-65° C. for 6.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, then 800 ml of ether and 800 ml of water were added thereto, and the desired product was extracted with ether. The aqueous layer was extracted again with 300 ml of ether, which was combined with the first ether layer. The combined layer was washed with 200 ml of a 5% aqueous sodium bicarbonate solution, and then with 200 ml of saturated saline. This substance was dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain 92.7 g of crude crystals. The crystals were recrystallized from methanol to obtain 47.7 g (yield 49.3%) of 3,5-bis(methoxycarbonyl)-4-(3-nitrophenyl)-2,6-heptanedione.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=O)[NH:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:14]>>[CH2:1]([C:4]1[C:5]([Cl:14])=[N:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1c(C)nc[nH]c1=O
Product: CCCc1c(C)ncnc1Cl
Temperature: 85 °C

Procedure:
A mixture of 5-propyl-6-methyl-pyrimidin4-one (10 mmol) and POCl3 (25 ml) is heated at 85° C. for 4 hours. The solvent is removed in vacuo and EtOAc (30 ml) and water (30 ml) are added to the residue. NaHCO3 is carefully added until the pH of aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml), dried (Na2SO4), and evaporated. Flash column purification of the residue with 6:1 EtOAc:hexane provides the title product as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][O:20]4)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C@H:21]12[CH2:23][C@H:18]([N:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:16]4)[CH2:22]1)[CH2:19][O:20]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3C[C@@H]4C[C@H]3CO4)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1N1C[C@@H]3C[C@H]1CO3)CNC2

Procedure:
Prepared in analogy to Example A2(c) from (1S,4S)-5-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Orange oil. MS (m/e): 217.4 ([M+H]+, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[S:10][C:11]([C:14](OC)=[O:15])=[CH:12][N:13]=1)[CH3:8]>O1CCCC1>[CH2:7]([C:9]1[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=1)[CH3:8]
Reactant: CCc1ncc(C(=O)OC)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)s1
Yield: 94.2 %

Procedure:
2.4 g of mixed lithium aluminum hydride was added under nitrogen to a solution of 11.3 g of methyl 2-ethyl-thiazole-5-carboxylate in 100 ml of anhydrous tetrahydrofuran at 20 to 25° C and the mixture was refluxed for 1 1/2 hours. After cooling the mixture, excess lithium aluminum hydride was destroyed by the addition of ethyl acetate. The mixture was added to water and was vacuum filtered. The recovered precipitate was empasted with ethyl acetate and then with a methanol-methylene chlorine mixture. The filtrate was washed with water, dried and evaporated to dryness to obtan 9.5 g of an oil which was rectified under reduced pressure to obtain 8.9 g of 2-ethyl-thiazole-5-methanol with a boiling point of 78° C at 0.1 mm Hg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])C(O)=O>C(O)(=O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=[C:7]([O:6][CH3:5])[C:15]=1[O:16][CH3:17]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of nitric acid (20.0 mL) and acetic acid (40.0 mL) under 10° C. was added 3,4,5-trimethoxybenzoic acid (10.0 g, 47.0 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into ice-water. The resulting precipitate was collected by filtration and washed with water, which was then recrystallized from ethanol to afford the product 1,2,3-trimethoxy-5-nitrobenzene (6.64 g, yield 66.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C.[Cl-]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([F:18])([F:30])[F:31])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCC(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of optically active 1,1,1-trifluoro-2-decanol (0.96 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylane chloride (20 ml). The mixture was left to stand until it reached room temperature and allowed to react overnight. The mixture was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water in this order, and was dried over anhydrous magnesium sulfate. After the solution was distilled to remove the solvent, the crude product thus obtained was purified by toluene-silica-gel column chromatography and recrystallized from ethanol to obtain the titled compound (1.84 g).
Reaction SMILES: [CH3:1][NH:2]N.Cl.C[N:6](C)[CH:7]=[CH:8][C:9]([C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[O:21][CH3:22])=O.N.CN1C=CC=N1>CO>[CH3:22][O:21][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[CH:16][C:11]=1[C:9]1[N:2]([CH3:1])[N:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(C)=O)cc1C(=O)C=CN(C)C
Reactant: CNN
Agent: Cl
Agent: Cn1cccn1
Agent: N
Solvent: CO
Product: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Temperature: -15 °C
Yield: 80 %

Procedure:
Methylhydrazine (319.3 g) was added to methanol (13.931 L) stirred and chilled to −15° C. under nitrogen. Aqueous HCl (37 wt %, 1859.6 g) was then added at a rate sufficiently slow to enable the stirred solution to be maintained at −12 to −7° C. with reactor jacket cooling. As stirring under nitrogen was continued at −10° C., 3-dimethylamino-1-(2′-methoxy-5′-acetamidophenyl)prop-2-en-1-one (4, 1546.9 g) was added as a solid over ten minutes. The resulting homogenous dark brown solution was stirred under nitrogen first at 0° C. for 3 hours and then at 10° C. for 5.5 hours before 33% aqueous ammonia (1090 mL) was added at a rate sufficiently slow (25 minutes) to enable the stirred solution to be maintained at 8.6-15.2° C. with reactor jacket cooling. LC/MS analyses of the reaction mixture before aqueous ammonia treatment revealed 97.3% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 83.3:13.2 ratio) and, after aqueous ammonia treatment, 100% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 87.8:12.2 ratio). The aqueous ammonia addition raised the reaction mixture pH to 8. Methanol (ca. 12 L) was then distilled off the stirred reaction mixture at atmospheric pressure and internal temperatures rising to 74.4° C. Product crystallization, which started at the end of the distillation, was completed by cooling the reaction mixture to −2° C. and holding that temperature with stirring for 44 hours. LC/MS analysis of the crystallization mixture's liquid phase revealed 5 and its other N-methylpyrazole isomer in about 1:3 ratio. (Higher ratios of 5:other isomer in the liquid phase jeopardize product yield, and lower ratios jeopardize product purity. In either case, the crystallization can be repeated by heating the stirred mixture back to reflux at atmospheric pressure and, prior to recrystallization, either distilling off more methanol (if the ratio is high) or adding additional methanol (if the ratio is low).) The reaction mixture was filtered by suction, and the filtered solids were washed with 0° C. water (3 L, then 2×500 mL) and dried at 40° C., <1 mm HgA to provide 5 (1157.7 g, 80.0% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[CH3:18]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)CCNc1cccc2ccccc12
Solvent: C1CCOC1
Product: CCN(CC)CCN(C(=O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.0 g (33 mmol) of N,N-diethyl-N'-naphthalenyl-1,2-ethanediamine in 100 mL of tetrahydrofuran is treated with a solution of 6.8 g 4-fluorobenzoyl chloride in 50 mL of tetrahydrofuran and stirred at room temperature. After one hour, the solvent is evaporated on the rotary evaporator. The residue is dissolved in 200 mL of methylene chloride and washed with 200 mL of water and 4N sodium hydroxide to pH=14. The organic layer is dried over sodium sulfate, filtered and the solvent evaporated to provide the title compound.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.B(O)(O)O.C(N(CC)CC)C.[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27]OC(=O)C)[CH2:25][S:26][C@H:21]12>O>[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][S:1][C:2]3[S:3][C:4]([CH3:7])=[N:5][N:6]=3)[CH2:25][S:26][C@H:21]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: OB(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1

Procedure:
A suspension of 40 g (0.30 mole) of 2-mercapto-5-methyl-1,3,4-thiadiazole (TD) in 3.15 liters of water, with 30 g of boric acid and 30.4 ml (≃0.217 mole) of triethylamine was heated to 70/72° C. While the mixture was being vigorously stirred, at the same temperature, one 40 g shot (0.147 mole) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (92%) was added.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]2[NH:16][C:15](=O)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>CCOCC>[C:7]1([CH:13]2[CH2:14][CH2:15][NH:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CC(c2ccccc2)N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: c1ccc(C2CCN2)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Add lithium aluminum hydride (685 mg, 18.1 mmol) to anhydrous ether (20 mL), followed by 4-phenyl-2-azetidinone (760 mg, 5.2 mmol). Heat the mixture to reflux for 4 hr, cool to RT. Add 20% aqueous ammonium chloride solution to quench the reaction, filter through Celite®, concentrate and purify (silica gel chromatography, eluting with 10:90 2 M ammonia in methanol:DCM) to give the title compound as a colorless oil (380 mg, 55%).
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH2:7][S:8][CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:15][CH:9]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:6](=[O:5])[CH2:7][S:8]1
Reactant: COC(=O)CSC(C)CC(=O)OC
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C1C(=O)CSC1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a suspension of sodium methoxide (5.89 g, 109.2 mmol) in toluene (150 mL) was added methyl 3-(2-methoxy-2-oxoethylthio)butanoate (150 g, 72.8 mmol) dropwise. The resultant mixture was heated to reflux and stirred overnight. The resulting reaction mixture was cooled then poured into a mixture of 10.0 mL of acetic acid in 150.0 g of crushed ice. The solution was made basic (pH=8-9) by addition of saturated Na2CO3 and the resulting mixture extracted with ethyl acetate. The combined organic layers were then combined and washed with brine, dried over anhydrous Na2SO4, filtered, evaporated, and the residue purified by column chromatography (eluent: petroleum ether/ethyl acetate=20/1-5/1) to provide methyl 2-methyl-4-oxo-tetrahydrothiophene-3-carboxylate as a colorless oil (4.0 g, 32%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][CH2:8][NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6])[CH3:3].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH2:2]([O:4][C:5]([CH2:7][CH2:8][N:9]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:23](=[O:24])[CH2:22][Cl:21])=[O:6])[CH3:3]
Reactant: CCOC(=O)CCNC(C(=O)OCC)C(=O)OCC
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)CCN(C(=O)CCl)C(C(=O)OCC)C(=O)OCC
Reaction time: 5 h
Yield: 86 %

Procedure:
To a suspension of 14 g. (0.045 moles) of diethyl N-(2-ethoxycarbonylethyl)-amino-malonate hydrochloride prepared according to Example 1b) in 150 ml. of dry benzene 5.65 g. (4 ml., 0.05 moles) of chloroacetyl chloride are added with stirring. The mixture is boiled for 5 hours. The solution is evaporated in vacuo, the evaporation residue is triturated with 50 ml. of hexane, hexane is decanted and the same procedure is repeated two more times. The oily product is dried over sodium hydroxide in a vacuum desiccator. 13.6 g. (86%) of the named compound are obtained.
Reaction SMILES: S(O)(C(F)(F)F)(=O)=O.C1(OC)C=CC=CC=1.[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([N:43](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]>C(Cl)Cl>[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([NH2:43])=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2c2ccn3ncc(C(N)=O)c3c2)c1
Temperature: -20 °C

Procedure:
A flask was charged with TfOH (136.4 g, 909 mmol) and DCM (505 mL) and cooled to −20° C. Anisole (45 g, 416 mmol) was added followed by a solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (101 g, 166 mmol) in DCM (303 mL). The mixture was warmed to 20° C., and maintained for 15 hours. HPLC showed consumption of (I-53). The reaction was cooled to <0° C. and DCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10). The aqueous layer was separated and extracted with DCM (500 mL). The rag layer was filtered through Celite and the two layers were separated. The organic layers were combined and concentrated to dryness. The resulting solid was triturated with TBME (250 mL) at 20° C. to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). Melting point: 140° C. (dec.). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61-7.58 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.3, 23.8 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](Br)[CH3:18])=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 10 parts of α-bromo-α-methyl-p-tolyl 2-thienyl ketone and stirring at 60° C is continued for 4h. 30. The reaction mixture is poured onto water and the product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]2[CH2:7][CH2:8][O:9][C:10]3[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[N:13]=1)=[N+:2]=[N-:3].[CH3:19][CH:20]([CH3:23])[C:21]#[CH:22]>>[Br:18][C:16]1[CH:15]=[CH:14][C:11]2[C:12]3[N:13]=[C:4]([N:1]4[C:21]([CH:20]([CH3:23])[CH3:19])=[CH:22][N:3]=[N:2]4)[S:5][C:6]=3[CH2:7][CH2:8][O:9][C:10]=2[CH:17]=1
Reactant: C#CC(C)C
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 414, Step 3, 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methyl-1-butyne to afford the title compound as a beige solid. LCMS (Method A): RT=4.88 min, [M+H]+=391 and 393. 1H NMR (CDCl3): 8.12 (1 H, d, J=8.5 Hz), 7.59 (1 H, s), 7.30-7.25 (2 H, m), 4.41 (2 H, t, J=5.0 Hz), 3.98-3.90 (1 H, m), 3.36 (2 H, t, J=5.0 Hz), 1.44 (3 H, s), 1.42 (3 H, s).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:10](=O)[CH2:11][C:12](OCC)=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=[CH:11][C:12]1=[O:13]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=c1ccc2ccccc2o1

Procedure:
Scheme VIII describes the synthesis of 6-alkylaminocoumarins, as demonstrated by Structure 45, from phenol through a similar route as that described in Schemes I and II. A mixture of a phenol compound and a 3-ketoester such as ethyl 4,4,4-trifluoroacetoacetate are heated in refluxing toluene in the presence of TsOH to afford a coumarin compound e.g., Structure 43. Nitration of coumarin compounds (e.g., Structure 43) followed by hydrogenation give aminocoumarin compounds such as Structure 44. Sequential reductive alkylation provides dialkylamino-coumarin compounds as shown in Structure 45. Hydrogenation of a dialkylamino-coumarin compound (e.g., Structure 45) affords compounds Structure 46.