Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)=[O:33])[CH:27]=1>C1COCC1>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)([OH:33])[CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:27]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: O=C(c1cccnc1)c1ccncn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cccnc1)(c1ccncn1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, diisopropylamine (0.079 mL, 0.56 mmol) was dissolved in THF (1 mL). The solution was cooled to 0° C. n-Butyl-lithium (2.5 M solution in hexanes, 0.215 mL, 0.54 mmol) was slowly added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (0.087 g, 0.51 mmol) in THF (1mL) was slowly added drop-wise. The reaction became dark red. After 10 min. a solution of pyridin-3-yl(pyrimidin-4-yl)methanone (0.099 g, 0.54 mmol, J. Heterocyclic Chem., 34, 17 (1997)) in THF (1 mL) was slowly added drop-wise. The reaction was stirred at 0° C. for 3 hr then removed from the ice bath. Sat. aq. NH4Cl (20 mL) was added and the reaction was stirred vigorously. The product was extracted with EtOAc (4×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford an oil which was purified by reverse phase HPLC (5-95% CH3CN/H2O+0.05% NH4OH). The fractions were combined and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (CDCl3) δ 9.01 (d, 1H, J=1.22 Hz), 8.85 (d, 1H, J=1.95 Hz), 8.70 (d, 1H, J=5.37 Hz), 8.58 (d, 1H, J=2.19 Hz), 8.42 (dd, 1H, J=1.46 Hz), 8.38-8.33 (m, 3H), 7.94-7.87 (m, 2H), 7.70-7.67 (m, 1H), 7.07 (dd, 1H, J=1.22 Hz), 7.19-7.14 (m, 1H), 7.13-7.08 (m, 2H), 5.98 (s, 1H), 5.12 (s, 1H). HRMS m/z (M+H) Calculated: 356.1506, found: 356.1519.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH2:15][CH3:16])[CH2:13]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:37]=[N+:38]=[N-:39].[O-]S([O-])(=O)=O.[Mg+2].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N-]=[N+]=[N-]>C(Cl)Cl.CCOC(C)=O.CCCCCC>[N:37]([CH2:13][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])([CH3:17])[CH2:15][CH3:16])=[N+:38]=[N-:39]
Reactant: CCC(C)(CO)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(C)(CN=[N+]=[N-])NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Benyloxycarbonylamino)-2-methyl-1-butanol (1.358 g, 5.722 mmol) and triphenylphosphine (1.800 g, 6.86 mmol) were dissolved in 10 mL CH2Cl2, and the resulting solution was cooled to 0° C. A solution of hydrazoic acid (prepared from sodium azide (1.30 g, 20.0 mmol), 0.533 mL concentrated sulfuric acid and 1.3 mL water) in 20 mL CH2Cl2 was passed through a plug of MgSO4, the filtrate was added to the above alcohol solution, then diisopropyl azodicarboxylate (1.35 mL, 1.40 g, 6.91 mmol) was added dropwise over 3 min. The reaction mixture was stirred at 0° C. for 1 h, then at room temperature for 5 h. The mixture was concentrated in vacuo, and the residue was applied to 300 g of silica gel in a fritted disc funnel and eluted with 3×500 mL of 10% EtOAc-hexane. The second fraction contained pure desired azide (0.822 g, 3.13 mmol, 55%) as a colorless oil: Rf 0.17 (10% EtOAc-hexane); 1H NMR (CDCl3) δ 1.33 (s, 6 H), 2.02 (bt, J=7.5 Hz, 2 H), 3.32 (bt, J=7.5 Hz, 2 H), 4.74 (br s, 1 H), 5.05 (s, 2 H), 7.3-7.4 (m, 5 H); MS m/e 263 ((M+H)+), 280 (M+NH4)+).
Reaction SMILES: Cl.[CH:2]1[C:13]2[C:12](=CCCN3CCCC(C(O)=O)C3)[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.ICI.C(=O)([O-])[O-:34].[K+].[K+]>CN(C)C=O>[CH2:2]1[C:13]2[CH2:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]1=[O:34]
Reactant: O=C(O)C1CCCN(CCC=C2c3ccccc3OCOc3ccccc32)C1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: O=C1C=CC2=C(C1)Cc1ccccc1OCO2
Temperature: 105 °C
Yield: 89.1 %

Procedure:
1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid hydrochloride ##STR4## 2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry dimethylformamide (180 ml). Dried, finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added, and the mixture was heated at 105 ° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-2-one as a solid (9.5 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[O:17])=[CH:11][C:10]=2[N+:23]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[NH2:23][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccco1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(NC(=O)c2ccco2)ccc1Sc1ccc(O)cc1
Yield: 90 %

Procedure:
The product from Example 255b was reduced with Fe and NH4Cl following the procedure from Example 9E to provide the title compound (980 mg, 90%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>O1CCOCC1.O>[N:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[N+:17]=[N-:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Yield: 94.7 %

Procedure:
To a solution of the compound prepared in Example 255 (0.500 g) in dioxane (31 mL) and water (3 mL) was treated with sodium azide (0.143 g) at room temperature. The mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate, dried and evaporated in vacuo to obtain the title compound (0.534 g) having the following physical data.
Reaction SMILES: COC1C=C([C@H]2OC(=O)N[C@@H]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)C=CC=1.Br[C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[F:58])#[CH:51]>>[F:58][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[C:50]#[C:51][C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Reactant: C#Cc1ccccc1F
Agent: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3F)n2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with optically-enriched (4R,5R)-4-(6-bromopyridin-2-yl)-5-(3-methoxyphenyl)oxazolidin-2-one and 1-ethynyl-2-fluorobenzene. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (dd, J=7.9, 7.6, 1H), 7.63 (ddd, J=7.6, 7.0, 1.2, 1H), 7.60 (d, J=7.6, 1H), 7.41 (m, 2H), 7.36 (dd, J=7.9, 7.9, 1H), 7.18 (m, 2H), 7.05 (m, 2H), 6.94 (m, 1H), 5.89 (bs, 1H), 5.62 (d, J=5.8, 1H), 4.98 (d, J=6.1, 1H), 3.86 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 163.1 (d, J=253), 162.1, 160.2, 158.9, 158.6, 143.6, 139.8, 137.7, 134.0, 131.2 (d, J=7.7), 130.2, 127.4, 124.2 (d, J=3.8), 120.1, 117.9, 115.8 (d, J=21), 114.9, 111.0, 93.1, 83.7, 83.5, 64.9, 55.5.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:11]=[O+][O-].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]([CH:9]=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=CC(C)CC(=O)OCC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 53.18 g of 3A in 400 ml of dry methylene chloride was cooled to -78° C. Ozone was passed through the cold solution for 3.5 hours, air was passed through the solution for 10 minutes, then the solution was allowed to warm. At -50° C., 41.63 g of triethylamine was added drop-by-drop slowly. A strongly exothermic reaction occurred immediately, and the mixture was maintained at 5°-10° C. over the period of addition of the amine (30 minutes). The mixture then was stirred at room temperature for 2 hours, the solvents were evaporated under reduced pressure, and the residue was vacuum-chromatographed on silica gel, ether being used as eluent. The solution thus obtained was dried (MgSO4) and the solvent was evaporated to give ethyl 3-methyl-4-oxobutanoate (3B), as a slightly unstable pale yellow oil.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1>C(Cl)Cl>[Br:5][C:6]1[S:10][C:9]([NH:11][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[N:8][CH:7]=1
Reactant: O=CC1CC1
Reactant: Nc1ncc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cnc(NCC2CC2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Add acetic acid (2 mL, 33.4 mmol) to a mixture of 5-bromo-thiazol-2-ylamine (1 g, 5.6 mmol), sodium triacetoxyborohydride (3.5 g, 16.7 mmol) and cyclopropane carboxaldehyde (820 mg, 11.7 mmol) at room temperature under a nitrogen atmosphere. Stir the resulting solution for 1.5 h at ambient temperature. Dilute the solution with DCM (50 mL) and wash with saturated aqueous NaHCO3 (80 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 7:3 gradient) to obtain the title compound (970 mg, 75%). MS (ES+) m/z: 233.1 (M+).
Reaction SMILES: [Li+].[BH4-].[N+:3]([C:6]1[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[N:20]=[C:21]([C:23](OCC)=[O:24])[CH:22]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[N+:3]([C:6]1[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[N:20]=[C:21]([CH2:23][OH:24])[CH:22]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)c1cc2n(n1)CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCn2nc(CO)cc2C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
LiBH4 (640 mg) and MeOH (1.2 mL) was added to the THF (267 mL) solution of 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylic acid 2-ethyl ester 5-(4-nitrobenzyl) ester (10 g) under a nitrogen atmosphere at room temperature and stirred for 3 h at 40° C. Additional LiBH4 (523 mg) and MeOH (1.0 mL) was added to the solution and stirred for 1 h at 40° C. and 1 h at 50° C. The mixture was acidified with 3 mol/L HCl to pH 2 and stirred for 1 h at room temperature, then solid K2CO3 was added to the solution to adjust pH to 8. The insoluble material was filtered off and the filtrate was extracted with AcOEt. The organic layer was dried (K2CO3), and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (CHCl3/MeOH=49/1-19/1) to afford titled compound as pale yellow crystals (8.44 g, 95%).
Reaction SMILES: II.[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:19]=[CH:18][C:12]([CH:13](O)[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[CH:8]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: O=C(O)C(O)c1ccc(-n2cc(Cl)cn2)cc1
Agent: II
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(-n2cc(Cl)cn2)cc1
Reaction time: 0.25 h

Procedure:
340 mg of red phosphorus and 110 mg of iodine are added to 10 ml of glacial acetic acid. After 15 minutes, 2.8 g (0.01 mole) of 4-(4-chloropyrazol-1-yl) mandelic acid are added; heating under reflux is effected for 4 hours, followed by cooling, filtration, pouring on to a sodium sulphite solution and extraction with ether. The ethereal solution is dried and concentrated. 4-(4-chloropyrazol-1-yl) phenylacetic acid (m.p. 176°-178° C.) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]([OH:22])[C:9]2=[O:23])=[O:5])[CH3:2].Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:22][C:10]1[C:9](=[O:23])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[O:12][C:11]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCCCBr
Reactant: CCOC(=O)c1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2oc(-c3ccccc3)c(OCCCCl)c(=O)c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
6-Ethoxycarbonyl-3-hydroxyflavone (3.2 mmol), 1-bromo-3-chloropropane (3.2 mmol) and potassium carbonate (3.2 mmol) were dissolved in 20 ml of DMF, followed by stirring at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, and an insoluble mater was removed. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (petroleum ether:ethyl acetate=2:1), whereby the title compound represented by the following formula was obtained as a colorless oil (yield: 38%). ##STR61##
Reaction SMILES: Cl.[C:2]1([C:8]2([CH:18]3[CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[NH:21]1[CH2:22][CH:18]([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH2:19][CH2:20]1
Reactant: c1ccc(C2(C3CCNC3)CCC3(CC2)OCCO3)cc1
Agent: Cl
Product: O=C1CCC(c2ccccc2)(C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
4-(8-Phenyl-1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine hydrochloride (5.8 g, 17.9 mmol) was dissolved in 7.5 N hydrochloric acid (16 ml) and the mixture was stirred at room temperature for 24 h. When the hydrolysis had ended, the reaction mixture was extracted with diethyl ether (2×50 ml), and the aqueous phase was rendered alkaline with 5 N sodium hydroxide solution, while cooling with ice, and extracted with methylene chloride (3×50 ml) and the extract was concentrated. It was possible to isolate the ketone Ket-8 as a yellow solid with a melting point of 75-79° C. and a yield of 96% (4.1 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](=O)[CH:26]([NH:30][C:31]([NH:33][C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH3:45])[CH:35]=2)=[O:32])[C:27]([NH2:29])=[O:28])=[CH:17]1>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>[C:27]([C:26]1[NH:30][C:31](=[O:32])[N:33]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH3:45])[CH:35]=2)[C:25]=1[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:17]=1)(=[O:28])[NH2:29]
Reactant: CCCn1cc(NC(=O)NC(C(N)=O)C(=O)c2cn(CCCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CO
Product: CCCn1cc(-n2c(-c3cn(CCCCN4C(=O)c5ccccc5C4=O)c4ccccc34)c(C(N)=O)[nH]c2=O)c2ccccc21
Yield: 89.9 %

Procedure:
A mixture of 0.06 g (0.1 mmol) of the compound of step d), 2 ml of methanol, and a catalytic amount of scandium trifluoromethanesulfonate was heated to 105° C. for 4 hours. The reaction mixture was allowed to cool, the solvent was evaporated, and the residual purified by chromatography on silica (CH2Cl2:MeOH 97:3) to give 54 mg (93%) of the sub-title amide.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:34])[CH2:14][C:15]#[C:16][C:17]1(O)[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[S:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[CH2:18]1>CC1C=CC=CC=1C>[CH3:12][N:13]([CH2:14][C:15]#[C:16][C:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[S:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[CH:18]=1)[CH3:34]
Reactant: CN(C)CC#CC1(O)Cc2ccccc2Sc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CN(C)CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
63 G. of p-toluenesulfonic acid and 1,800 ml. of o-xylene are heated to boiling and the water present is distilled. The solution is reacted with 90 g. of 10-[3-(dimethylamino)-1-propynyl]-8-chloro-10,11-dihydro-dibenzo[b,f]-thiepin-10-ol. The reaction mixture is maintained at the boiling temperature for 45 minutes, whereby the remaining water is distilled. The mixture is cooled and poured into 90 ml. of 2N aqueous sodium hydroxide. The aqueous phase is extracted with ether. The resulting organic phase is washed three times with water and subsequently extracted three times with aqueous methanesulfonic acid. The aqueous phase is washed with water and made alkaline with concentrated sodium hydroxide. The reaction mixture is then extracted with ether, and the ether extract washed with water, dried and evaporated, whereby there is obtained N,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine, which after recrystallization from hexane, has a melting point of 118°-120°. The maleate is precipitated from ethanol and melts at 178°-180°.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N+:18]([O-])=[CH:17][CH:16]=1>>[CH2:1]([C:8]1=[N:9][NH:10][C:11](=[O:13])/[C:12]/1=[C:17]1\[NH:18][C:19]2[C:24]([C:15]([Cl:14])=[CH:16]\1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Cc2ccccc2)=NN1
Reactant: [O-][n+]1ccc(Cl)c2ccccc21
Product: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1

Procedure:
The title compound was prepared from 3-benzyl-1H-pyrazol-5(4H)-one and 4-chloroquinoline N-oxide under conditions similar to those described in Example 60. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H) 7.23-7.32 (m, 5H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C19H14ClN3O 335.08. found 336.2 (M+H)+.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]([F:31])([F:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]([F:30])([F:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([O:20][CH3:1])=[O:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(N[C@@H](CC(F)(F)Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethylsilyl chloride (0.61 g, 5.61 mmol, 2 eq) was added dropwise to a solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoic acid (1.02 g, 2.81 mmol) in 40 ml of methanol. After the addition had ended, the mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the residue was used crude in the reaction which followed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C.CCOC(C)=O>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A mixture of (3S*,4S*)-1-benzyl-pyrrolidine-3,4-dicarboxylic acid monoethyl ester (10 g, 36.1 mmol), di-tert-butylcarbonate (7.9 g, 39.6 mmol) and Pd(OH)2/C 20% (1 g, 50% wet) in EtOH (200 mL) is stirred under hydrogen atmosphere for 5 h. The crude material is filtered over a pad of Celite and concentrated. 1H-NMR indicates that the title compound is obtained cleanly. TLC, Rf (AcOEt)=0.17. MS (LC-MS): 286.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[N:13]O)[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>>[NH2:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:10]([OH:12])[CH3:11]
Reactant: CC(O)C(=NO)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)C(N)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well stirred solution of 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one-oxime (5.8 g, 28.4 mmol), was added a 1.0 M solution of LiAlH4 in ether (90 mL, 90 mmol) dropwise at 0° C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 3.5 mL of water, 3.5 mL of 3N NaOH followed by 10.5 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et2O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO4, filtered and the solvent was removed in vacuo. 1-amino-1-(3,4-difluorophenyl)-propan-2-ol was obtained as a yellow glassy syrup (3.6 g, 66%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>C(O)C>[CH:6]1([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(O)CN
Reactant: O=C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CNC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-amino-2-propanol (1.0 mL, 13.31 mmol) in ethanol (15 mL) was added cyclohexanone (1.9 g, 19.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and then NaBH4 (0.725 g, 19.17 mmol) was added. The reaction mixture was stirred at rt for 15 minutes and then quenched with water. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated. The residue was dissolved in DCM, dried over Na2SO4, filtered and concentrated to provide 1-(cyclohexylamino)propan-2-ol. Yield: 2.6 g (crude). 1H NMR (DMSO-d6) δ 4.39-4.36 (m, 1 H), 3.61-3.57 (m, 1 H), 2.47-2.30 (m, 3 H), 1.78-1.75 (m, 2 H), 1.66-1.63 (m, 2 H), 1.55-1.52 (m, 1 H), 1.23-1.12 (m, 3 H), 1.03-0.89 (m, 5 H). 1-(cyclohexylamino)propan-2-ol may also be prepared by following procedure of Example 1.