Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([CH3:21])=[O:20]>C1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:18][C:19](=[O:20])[CH3:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Solvent: c1ccccc1
Product: CC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]-pyridine-3-carbaldehyde (0.50 g) and acetonylidenetriphenylphosphorane ##STR12## (0.82 g) in benzene (6 ml) was refluxed for 4 hours and then the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3-buten-2-one (trans isomer) (0.21 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[CH3:9]
Reactant: CCOC(=O)CO
Reactant: BrCCCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride in 40 mL DMF stirred at 0° C. was slowly added ethyl glycolate (5 g, 48 mmol). After 1 hour, 1,4-dibromobutane (8.6 mL, 72 mmol) was added, and the mixture was stirred for an additional 2 hours. The reaction was allowed to warm to room temperature for an additional 3 hours. A sodium bicarbonate solution was added, and the organic layer was dried over anhydrous sodium sulfate, concentrated and the residue was purified by chromatography to afford a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:14]2[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]12
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile (Ex. 19) and 220 mg of 60% sodium hydride dispersed in mineral oil in 50 ml of N,N-dimethylformamide was stirred at room temperature under nitrogen for 3 1/2 hours. Then one ml of iodomethane was added and the reaction mixture was stirred under nitrogen for 16 hours. The mixture was evaporated in vacuo and gave an oil. The oil crystallized upon trituration in n-hexane to give the product which was recrystallized from ethyl acetate:n-hexane (1:4) and this gave the desired product as yellow crystals, mp 120°-122° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[C:5]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]=12.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:4]1[S:3][C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[C:6]2[CH2:7][CH2:8][C:9](=[O:10])[C:5]=12
Reactant: OB(O)c1ccncc1
Reactant: O=C1CCc2c(Cl)sc(-c3ccccc3F)c21
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CCc2c(-c3ccncc3)sc(-c3ccccc3F)c21
Yield: 91.2 %

Procedure:
To a stirred solution of 1-chloro-3-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one (118 mg, 0.443 mmol) in DME (7.5 mL) was added 4-pyridineboronic acid (130 mg, 1.06 mmol), saturated aqueous NaHCO3 solution (2.5 mL) and bis(triphenylphosphine)palladium(II)chloride (100 mg, 0.14 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 20 hours. The whole was extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (1:1) to provide the title product (125 mg, 91% yield).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:11]([CH3:17])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>C1COCC1>[CH3:17][C:11]1[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(C)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 5.6 mL, 5.6 mmol) is added to a solution of 3-chloro-2,5-dimethylpyrazine (346 mg, 2.42 mmol) and Fe(acac)3 (43 mg, 0.12 mmol) in THF (10 mL) at −30° C. After stirring for 30 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (212 mg), one obtains 2,5-dimethyl-3-phenylpyrazine as a pale yellow syrup (287 mg, 64%). 1H NMR (300 MHz, CD2Cl2) δ 8.31 (s, 1H), 7.55–7.59 (m, 2H), 7.43–7.51 (m, 3H), 2.55 (s, 3H), 2.54 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ 152.7, 150.6, 148.4, 142.1, 139.5, 129.3, 128.7, 128.6, 22.7, 21.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[SH:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1>>[CH:10]1([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([S:23][C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)=[CH:3][N:4]=2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cn1ccnc1S
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: Cn1ccnc1Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercapto-1-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH3:11]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:11][N:3]1[C:4]([N+:8]([O-:10])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc(C)c([N+](=O)[O-])[nH]1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc(C)n(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58 %

Procedure:
2,4-dimethyl-5-nitroimidazole (7.0 g, 0.05 mole) and dimethylsulfate (7.0 ml, 0.074 mole) were heated at 100° C. for 1 hour 50 minutes. After cooling to room temperature, the reaction mixture was added to about 60 ml of water. Solid sodium bicarbonate was added until the solution is basic, and the mixture was then cooled on ice. The resulting crystals were filtered off and dried to give 6.2 g. This was recrystallized from water to give 4.5 g of 1,2,4-trimethyl-5-nitroimidazole.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)[CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1
Reactant: Cc1cccc(CCN2CCNCC2)n1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
4-(methylsulfonylamino) benzoic acid (2.16 g, 10.05 mmol) was added to a stirring solution of 1-hydroxybenzotriazole hydrate (1.36 g, 10.05 mmol) and dicyclohexylcarbodiimide (2.08 g, 10.05 mmol) in DMF (30 mL) at 25° C. under nitrogen. After 45 minutes, 1-[2-(6-methyl-2-pyridyl)ethyl]piperazine (2.27 g, 11.05 mmol) was added as a suspension in DMF (15 mL). The resulting mixture was stirred at room temperature overnight. The work-up was performed as disclosed in Example 5 to give 2.94 g (73%) of the title compound which was treated with ethanolic HCl to afford 2.15 g of product as a dihydrochloride: mp 165°-167° C.; 1H NMR (DMSO-d6): δ10.14 (s, 1H), 8.19 (m, 1H), 7.63 (m, 2H), 7.45 (d, J=8.72 Hz, 2H), 7.25 (d, J=8.71 Hz, 2H), 3.85-3.20 (m, 12H), 3.06 (s, 3H), 2.67 (s, 3H); IR (KBr): 3420, 3000, 2560, 1640 cm-1 ; MS (m/z) 403 (MH+, 25%) 217 (30), 91 (100).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu]I.CO.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cnc(N2CCCC2=O)cn1
Yield: 30.4 %

Procedure:
A mixture of 5-bromopyrazin-2-amine (5 g, 29 mmol), pyrrolidin-2-one (11 mL, 144 mmol), copper (I) iodide (1.1 g, 5.75 mmol), potassium carbonate (7.94 g, 57.5 mmol), and (1R,2R)-cyclohexane-1,2-diamine (1.38 mL, 11.49 mmol) was refluxed under nitrogen in dioxane (100 mL) for 18 h. After cooling, 200 mL ethyl acetate and 20 mL methanol were added to the reaction. This was filtered through celite, concentrated, and absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride). The purified product was recrystallized from ether/ethyl acetate to afford 1-(5-aminopyrazin-2-yl)pyrrolidin-2-one (1.57 g, 8.81 mmol, 30.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J=1.51 Hz), 7.69 (1H, d, J=1.51 Hz), 6.20 (2H, s), 3.84 (2H, t, J=7.05 Hz), 2.49 (2H, t, J=7.93 Hz), 2.04 (2H, dq, J=7.68, 7.51 Hz). MS (LC/MS) R.T.=0.48; [M+H]+=179.27.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([NH:35][CH2:34][CH2:32][OH:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: NCCO
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](NCCO)C3)ccc12

Procedure:
Prepared according to the method of example 33(b), using N-[6-Chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (0.225 g) and ethanolamine (2 mL) to afford the title compound (0.052 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(-n2ccnc2)ccc1C(=O)O
Temperature: 110 °C
Yield: 25.5 %

Procedure:
To a mixture of methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoate (Example 246, 50 mg, 0.13 mmol), imidazole (17.8 mg, 0.26 mmol), and potassium carbonate (90.6 mg, 0.66 mmol) was added DMF (1 mL). The mixture was then heated to 110° C. for 16 h. The reaction mixture was allowed to cool to rt. The solvent was removed under reduced pressure, and the crude was purified by HPLC purification using gradient elution from 10 to 80% acetonitrile in water to afford 13.8 mg (25%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 9.48 (t, 1H), 8.15 (d, 1H), 8.07 (t, 1H), 7.76 (t, 1H), 7.52 (d, 1H), 7.28-7.42 (m, 4H), 7.10 (dd, 1H), 6.48 (s, 1H), 2.06 (s, 3H), 1.35 (s, 9H). ES-MS m/z 416.2 (MH+); HPLC RT (min) 2.21.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:14][C:13]2([F:16])[F:15])=[O:11])=[CH:6][CH:5]=1.[Cl-].[NH4+].C(OCC)C>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:12]2[CH2:14][C:13]2([F:15])[F:16])[OH:11])=[CH:8][CH:9]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)C1CC1(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
336 mg (8.89 mmol) of sodium borohydride were added to 1.75 g (8.08 mmol) of the compound from Example 124A in 33 ml of ethanol and 9 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 1 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 1.44 g (82% of theory) of a mixture of the diastereomers of the title compound were obtained.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]2[NH:38][CH2:39][CH2:40][CH:27]12)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH:29]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]2[N:38]([C:6](=[O:8])[CH:2]([NH:1][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH:3]([CH3:4])[CH3:5])[CH2:39][CH2:40][CH:27]12)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccccc2)C2NCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution containing Cbz-Val-OH (233 mg, 0.92 mmol) and crude 13 (256 mg, 0.84 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (352 mg, 0.93 mmol) and DIPEA (125 mg, 1.01 mmol) were added and the reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (1:4) and washed successively with 1M HCl, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 410 mg (90%) of 14 as a white solid. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.31 (m, 9H), 6.96 (m, 1H), 5.79 (m, 1H). 5.07 (m, 2H), 4.91 (d, J=2.7 Hz, 1H), 4.51-4.43 (m, 2H), 4.35 (t, J=7.5 Hz, 1H), 4.07-3.99 (m, 2H), 3.90 (app d, J=26.4 Hz, 0.5H), 3.77 (app d, J=27.3 Hz, 0.5H), 3.31 (m, 2H), 2.49 (m, 0.5H), 2.35 (m, 0.5H), 1.92 (m, 1H), 1.51 (m, 9H), 0.95 (m, 6H) ppm.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:8]>>[CH3:8][C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:6])([CH3:6])[CH2:8]1
Reactant: C=C(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(C)CC(C)(c2ccccc2)c2ccccc21
Temperature: 145 °C
Yield: 75 %

Procedure:
To 6.0 kg. of 62% sulfuric acid at 50°C was added 1.0 kg. of α-methyl styrene over a 5 minute period. The mixture was refluxed (145°C) for 20 hours. After cooling, the lower acid phase was drawn off and discarded. The organic phase was washed with sulfuric acid several times and then with water several times. The product was recrystallized from methanol which afforded 750 g of white crystals with a melting point of 50.5°-52.0°C. The yield was 75%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O

Procedure:
When the above reaction was run using 15.6 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 10.2 g (55 mmol) of (R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 10.1 g (0.1 mol) triethylamine and 100 ml of acetonitrile, the yield of the title compound was 23.8 g.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:24][OH:25]
Reactant: NO
Reactant: CC1(COc2ccc(Cc3nnn[nH]3)cc2)CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(COc2ccc(Cc3nnn[nH]3)cc2)CCCCC1=NO
Yield: 56.7 %

Procedure:
2-Methyl-2-[[4-(1H-tetrazol-5-yl-methyl)phenoxy]-methyl]cyclohexanone (0.79 g, prepared in Example 3), hydroxylamine hydrochloride (0.22 g), sodium acetate (0.26 g) and ethanol (absolute, 20 ml) were combined and heated to reflux for 4 hours. The ethanol was removed in vacuo. The residue was partitioned between ethyl acetate and 10% HCl solution. The organic phase was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated on the rotary evaporator. The product was triturated with dichloromethane-diethyl ether mixture to afford 0.47 g of white solid, mp 153°-156° C. Analytical HPLC showed the product was 97.7% pure.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([OH:12])([CH2:10][CH3:11])[C:4]#[C:5][Si](C)(C)C.[H-].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:12][C:3]([CH2:10][CH3:11])([C:2]([F:14])([F:13])[F:1])[C:4]#[CH:5])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: CCC(O)(C#C[Si](C)(C)C)C(F)(F)F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a stirred solution of 3-(trifluoromethyl)-1-(trimethylsilyl)pent-1-yn-3-ol (10.5 g, 46.9 mmol) in DMF (140 mL), sodium hydride (60% in oil, 1.9 g, 46.9 mmol) was added portionwise. After 25 min stirring, a solution of 4-nitrobenzoyl chloride (8.7 g, 46.9 mmol) in 50 mL DMF was added slowly. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with pH 7 buffer 25% NH4OAc aq solution (500 mL) and the product was extracted with diethyl ether (4×), washed with water (3×) and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (Ethyl acetate/hexanes, 15:85). 1H NMR (400 MHz, acetone-d6): 8.45 (d, 2H), 8.27 (d, 2H), 3.69 (s, 1H), 2.60-2.40 (m, 2H), 1.16 (t, 3H).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[C:9]([O:13][C:14](=[O:37])[N:15]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[C:29]([CH3:36])[CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[C:9]([O:13][C:14](=[O:37])[N:15]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH3:36])[CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A solution of Na2S2O4 (3.00 g, 17.2 mmol) in water (20 mL) was added to a solution of (3-methyl-4-nitrophenyl)-(4-trifluoromethylbenzyl)-carbamic acid tert-butyl ester (1.41 g, 3.44 mmol) in tetrahydrofuran (20 mL), and the resulting mixture was stirred for 20 hours at +55° C. After cooling to room temperature, the water phase was saturated with potassium carbonate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate, solvents were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a white solid (1.09 g, 83%).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]4[C:25](=[O:26])[CH2:24][C@@H:23]([C:27]5[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=5)[O:22][C:20]=4[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].[H][H]>[OH-].[Na+].[Ni]>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]([C:25]([CH2:24][CH2:23][C:27]4[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=4)=[O:26])=[C:20]([OH:22])[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43]
Reactant: [H][H]
Reactant: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)cc3O2)cc1O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)cc2O)cc1O
Reaction time: 15 h
Yield: 94.7 %

Procedure:
18.9 g (0.030 mol) of neohesperidin are dissolved in 90 ml of 2-N sodium hydroxide and treated with 1.2 g of Raney-nickel. The mixture is hydrogenated for 15 hours under normal pressure. The hydrogen uptake corresponds to 30 mmol. The solution is filtered and adjusted to pH 6 with 36 ml of 5-N hydrochloric acid while cooling with ice and stirring. The clear yellow solution is left in a refrigerator for 48 hours and then filtered under suction. The white residue is washed with cold water and dried overnight in a high vacuum. There are obtained 17.4 g (95% yield) of neohesperidin dihydrochalcone of melting point 150°C.