Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1.[O:26]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27]1.[C:33]([BH3-])#[N:34].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+]>[O:26]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:24][C@H:21]2[CH2:20][CH2:19][C@H:18]([O:17][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[O:8][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:16][CH2:15]4)[CH2:23][CH2:22]2)[CH2:27]1.[O:26]1[CH2:30][CH2:29][CH:28]([CH2:31][N:34]([CH2:33][CH:28]2[CH2:29][CH2:30][O:26][CH2:27]2)[C@H:21]2[CH2:22][CH2:23][C@H:18]([O:17][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[O:8][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:16][CH2:15]4)[CH2:19][CH2:20]2)[CH2:27]1
Reactant: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](N)CC3)ccc2O1
Reactant: O=CC1CCOC1
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](N(CC4CCOC4)CC4CCOC4)CC3)ccc2O1
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](NCC4CCOC4)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 61 mg trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexylamine (0.18 mmol) in 3 ml methanol and 0.2 ml of acetic acid at room temperature 39 mg tetrahydrofuran-3-carboxaldehyde (0.20 mmol) in 3 ml of methanol were added, and 12 mg of sodium cyanoborohydride (0.89 mmol (0.20 mmol) were then added in one portion. Stirring at room temperature was continued for 16 h. The solution was diluted with aqueous saturated sodium hydrogencarbonate solution and the aqueous layer extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by RP-HPLC. 23 mg of (tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine and 19 mg of bis-(tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine were isolated.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O.O>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCO2
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.5 %

Procedure:
To a solution of 2,3-dihydrobenzofuran (15.0 g, 125 mmol) in tetrahydrofuran (300 mL) was added N-bromosuccinimide (24.5 g, 138 mmol) at 0° C. The reaction solution was stirred at room temperature for 50 minutes, then, water was added, the solution was extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (hexane), and the title compound (24.0 g, 97%) was obtained as a colorless oily substance.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH3:46][C:47]1[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>C1COCC1>[CH3:46][C:47]1[N:52]=[CH:51][C:50]([O:45][CH2:44][C@@H:40]2[CH2:41][CH2:42][CH2:43][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:49][CH:48]=1
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.60 mmol) in 40 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.60 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, Aldrich Chemical Co.) and 6-methyl-3-pyridinol (Aldrich Chemical Co., 1.60 g, 14.60 mmol) were added to the reaction vessel, and the mixture was stirred for 16 hours. Solvent was removed in vacuo, and the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was filtered and washed with hexane. The hexane was removed in vacuo. The residue was purified by silica gel flash chromatography using a gradient from 100% hexane to a 1:1 solution of ethyl acetatelh exane (100%Hex, 10% EtOAc/Hex, 20%EtOAc/Hex, 1:1EtOAc/Hex) to give 1.61 g (57% ) of the title compound as a pale yellow oil. TLC Rf=0.42 (1:1 EtOAc/Hex). MS (DCI/NH3) m/e: 293 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][C:22]([OH:24])=[O:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=3)[CH3:2].Br[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[O:27]1>C1COCC1>[O:29]=[C:28]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]([O:23][C:22](=[O:24])[CH2:21][C:3]2([CH2:1][CH3:2])[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH2:5][O:4]2)=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:18])([F:20])[F:19])[CH:11]=4)[O:27]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CCC1(CC(=O)O)OCCc2c1[nH]c1cc(OC(F)(F)F)ccc21
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC2OC(=O)c3ccccc32)OCCc2c1[nH]c1cc(OC(F)(F)F)ccc21
Yield: 74.6 %

Procedure:
A solution of 1-ethyl-1,3,4,9-tetrahydro-7-(trifluoromethoxy)pyrano[3,4-b]indole-1-acetic acid (0.650 g, 1.89 mmol, prepared according to the procedure of Example 1), 3-bromophthalid (0.402 g, 1.89 mmol) and TEA (0.382 g, 3.79 mmol) in dry THF (60 mL) was refluxed for 4 hours. The solvent was evaporated and the residue was partitioned between water and ether. The extracts were washed with 5% NaHCO3 and brine, dried (MgSO4) and evaporated to dryness. Flash chromatography of the residue (on silica Merck-60, eluant: CHCl3) provided 0.670 g (74.6%) of the pure product (as a mixture of diastereomers) which was recrystallized from ether-hexane, m.p. 150° C. (softening starts at 124° C.).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]12([C:23](=[O:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.CI>C1COCC1.CCCCCC>[C:13]12([C:23](=[O:32])[CH:24]([CH3:1])[CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: CC(C)NC(C)C
Reactant: O=C(CCc1cccnc1)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Cc1cccnc1)C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a stirred solution of diisopropylamine (0.42 ml, 3.0 mmol) in THF (10 ml) at 0° C. was added butyllithium (1.6M; 1.87 ml, 3.0 ml) in hexane followed after 5 minutes by a solution of 1-(1-adamantyl)-3-(3-pyridyl)propan-1-one in THF (8 ml). After stirring for a further 20 min at 0° C., methyl iodide (0.19 ml, 3.0 mmol) was added dropwise and the solution was allowed to attain room temperature. After 1 hr the mixture was partitioned between ether and water. The ether extracts were dried (Na2CO3) and concentrated. Chromatography on elution with petrol-ether-triethylamine 100:50:1 afforded the title compound (0.62g, 73%), which crystallised from pentane, m.p 69-70 C; IR νmax 1696 cm-1 ; 1H-NMR (CDCl3) δ1.06 (3H,d,J 6.7 Hz, CHCH3) 1.51-1.72 (12H, m, adamantyl CH2), 1.96 (3H, s, adamantyl CH), 2.57 and 2.92 (2H, m, CHCH2), 3.28 (1H, m, CHCH3), 7.18 (1H, m, Py 5-H), 7.43 (1H, m, Py 4-H), 8.43 (2H, m, Py 6-H and 2-H); MS m/z 283 (M+). Anal. Calcd: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.56; H, 8.95; N, 4.91%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH:24]([C:25](O)=[O:26])[CH:23]2[CH2:28][CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH:24]([C:25](=[O:26])[NH:1][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])[CH:23]2[CH2:28][CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To the solution of 2-amino-1-(4-bromo-phenyl)-ethanone (HCl salt, 1.0 g, 4 mmol) and 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (0.98 g, 4 mmol) in DMF (13 ml) was added HATU (1.64 g, 4.3 mmol), followed by slow addition of diisopropylethylamine (2.2 ml, 12.7 mmol). The mixture was stirred for 4 hours and was diluted with EtOAc. The organic phase was washed with 1 N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g). m/z: 460.9 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CN1CCCC1=O>O>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)NCCOCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-benzyloxyethylamine (50 g), ethyl 2-bromo-2-methylpropionate (97.5 g) and N-methyl-2-pyrrolidone (1 l) was heated at 100° C. for 7 h. The mixture was cooled to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic phases were washed with water (4×500 ml) and brine (2×500 ml), dried (Na2SO4) and the solvents were evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (ethyl acetat containing 4% triethylamine) gave ethyl 2-(2-benzyloxyethylamino)-2-methylpropionate as an oil: 30 g
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:9][OH:10])=[CH:5][CH:4]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27].O.CCOCC>N1C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[CH2:9][O:10][C:25](=[O:28])[CH2:26][CH3:27])=[CH:21][CH:22]=1
Reactant: OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reactant: CCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
2-(4-Trifluoromethyl-phenoxy)-2-(3-trifluoromethyl-phenyl)-ethanol, 125, (0.01 mol) was dissolved in pyridine (20 mL) and the solution was cooled to 0° C. Propionyl chloride (0.015 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was washed with dilute hydrochloric acid, dried and concentrated. The residue was chromatographed to afford the title compound 135.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].C1(C)C=CC(S(OC[CH:32]([F:34])[CH3:33])(=O)=O)=CC=1.[CH3:36]N(C=O)C>>[F:34][CH2:32][CH2:33][CH2:36][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCC(C)F)cc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCCF

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (6.4 g, 24.5 mmol), sodium hydride (55% content, 1.33 g, 30.6 mmol), 2-fluoropropyl p-toluenesulfonate (described in Costa, Brian de; Radesca, Lilian; Dominguez, Celia; Paolo, Lisa Di; Bowen, Wayne D.; J. Med. Chem.; 35; 12; 1992; 2221-2230, 7.1 g, 30.6 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 1.39 g of the title compound as a colorless oily substance (18%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])([C:14]#[N:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24]C(OC(Cl)=O)C>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:11]1([C:14]#[N:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[ClH:24]
Reactant: COc1ccccc1C1(C#N)CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1C1(C#N)CCNCC1
Product: Cl
Reaction time: 5 h

Procedure:
To a solution of 1-benzyl-4-(2-methoxy-phenyl)-piperidine-4-carbonitrile 7a (6.17 g, 0.02 mol) in CH2Cl2 (200 mL) was added dropwise chloroformic acid 1-chloroethyl ester (3.66 g, 0.03 mol). After stirred for 5 h the mixture was concentrated under reduced pressure and methanol (200 mL) was added. The mixture was then heated to reflux for 30 min. The solvent was removed under vacuum. Diethyl ether (100 mL) was added and the white precipitate was collected by filtration to afford 4-(2-methoxyphenyl)piperidine-4-carbonitrile 7b as HCl salt. 1H NMR (CDCl3) δ 9.5-9.1 (br, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 3.87 (s, 3H). 3.44 (d, J=13.2 Hz, 2H), 3.08 (m, 2H), 2.48 (m, 2H), 2.28 (m, 2H). MS (ESI) m/z (M+H+) 217.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13](=[O:15])[CH3:14].[CH2:16]=O.[ClH:18].[CH3:19][NH:20][CH3:21]>C(O)C>[OH2:2].[ClH:18].[CH3:19][N:20]([CH3:16])[CH2:21][CH2:14][C:13]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)=[O:15].[CH3:19][N:20]([CH2:16][CH2:14][C:13]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)=[O:15])[CH3:21].[ClH:18]
Reactant: CNC
Reactant: COc1ccc2c(c1)c(C(C)=O)cn2C
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(C(=O)CCN(C)C)cn2C
Product: O

Procedure:
A mixture of 1-(5-methoxy-1-methyl-1H-indol-3-yl)-1-ethanone (0.23 g), paraformaldehyde (0.07 g) and dimethylamine hydrochloride (0.2 g) in ethanol (20 ml) was heated at reflux for 24 h, cooled, and the solvent was evaporated in vacuo. The residue was partitioned between sodium carbonate (2N; 50 ml) and ethyl acetate (2×50 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil, which was purified by FCC eluting with System A to give the free base of the title compound as an oil. This was dissolved in absolute ethanol (5 ml) acidified with ethanolic hydrogen chloride, and the salt was precipitated by the addition of excess dry ether (100 ml). The salt was filtered off and dried in vacuo to give the title compound (0.1 g), m.p. 210°-211°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH:5]([O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[Cl:1])[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Yield: 80.7 %

Procedure:
199.5 g (0.71 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 500 ml of chloroform, and 114 g (0.71 mol) of bromine were added dropwise at 20° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, 200 ml of water were carefully added and the chloroform phase was washed several times with ice-water and dried over sodium sulphate. After distilling off the solvent in vacuo, 205.2 g (78% of theory) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone was obtained as an oil, which was further reacted directly. ##STR83##
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl 4-hydroxy-3-methoxybenzoate (15.00 g), potassium carbonate (11.63 g) and N,N-dimethylformamide (2.00 mL) was added 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (17.45 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave a pale-brown solid (25.45 g, yield 91%). melting point: 103-104° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([CH3:20])(=[O:18])=[O:19])=[N:13][N:14]2[CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1n[nH]c2cc(Br)ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(S(C)(=O)=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
Sodium tert-butoxide (0.057 g) was added to an ice-cold solution of 6-bromo-3-(methylsulfonyl)-1H-indazole (Intermediate 75) (0.14 g) in tetrahydrofuran (1.5 ml). 2-(Trimethylsilyl)ethoxymethyl chloride (0.11 ml) was then added and the mixture was warmed to room temp. over 1 h. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml) the solvent was evaporated and the aqueous residue was extracted with ethyl acetate. The organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound (0.67 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1>ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20](=[O:22])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]2=[O:1])=[N:34][CH:35]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) in dichloromethane (0.5 mL) at room temperature was added a solution of oxalyl chloride in dichloromethane (2.0 M, 0.102 mL, 0.203 mmol). The reaction was stirred for 1 hour and then concentrated under a stream of nitrogen. The resulting acid chloride was dissolved in dichloroethane (0.5 mL), and 5-chloropyridin-2-amine (0.024 g, 0.186 mmol) was added followed by N-methyl morpholine (0.028 mL, 0.254 mmol). The reaction was heated to 70° C. After stirring for 3 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the product was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). The product was contaminated with aminopyridine starting material. A second silica gel column chromatography (SF15-24, Analogix®) eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 30 minutes (flow=30 mL/minute) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.44-8.46 (br s, 1H), 8.22 (dd, J=2.5, 0.7 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.65 (ddd, J=8.8, 2.6, 0.5 Hz, 1H), 7.21-7.39 (m, 10H), 4.19 (s, 2H), 3.54 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CCOCC.O>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:9]([CH2:16][CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH3:15])=[O:32]
Reactant: CCc1cccc(CC)c1NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(CC)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-dioxolan-2-ylmethyl)-2,6-diethylaniline (7.7 grams), sodium bicarbonate (6.0 grams), dioxane (20 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. This mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.0 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from an ether-pentane mixture to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan- 2-ylmethyl)-2,6-diethylaniline having a melting point of 86° to 87°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10](=[O:13])[C:11]=2[CH3:12])=[CH:3][CH:2]=1.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccncc2)N=NC1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1[nH]nc(-c2ccncc2)c1C
Temperature: 2 °C

Procedure:
1.5 mg of 3-(4-pyridyl)-4-methyl-5-pyrazolone, 2.3 g of triphenylphosphine and 0.27 g of methanol were placed in 30 ml of tetrahydrofuran. The mixture was cooled on an ice bath to 2° C. and 1.6 g of ethyl azodicarboxylate dissolved in 9 ml of tetrahydrofuran was added dropwise.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1CCN2C(=NCCC2)CC1.[N+:24]([CH3:27])([O-:26])=[O:25]>C(#N)C>[CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]([CH2:27][N+:24]([O-:26])=[O:25])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=CCC(C)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(CC(C)CC)C[N+](=O)[O-]
Yield: 39.2 %

Procedure:
Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated to an oil. A solution of the oil in ether was washed with 1N HCl, brine and dried. It was evaporated to give a light oil which was chromatographed on silica gel, eluting with 5% to 10% ether in Pet. ether to give 13 (3.6 g, 42%).