Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])=[C:4]([CH:25]=[CH2:26])[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][C:27](=[O:29])[CH3:28])=[N:3][C:4]([CH:25]=[CH2:26])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(NC(C)=O)nc1C=C
Temperature: 60 °C
Yield: 25.5 %

Procedure:
Under an argon atmosphere, to a solution of 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (100 mg, 292 mmol) in anhydrous pyridine (20 mL) were successively added 4-(dimethylamino)pyridine (DMAP) (3.0 mg, 25 μmol) and acetyl chloride (65.0 μL, 911 μmol) at room temperature. The mixture was heated at 60° C. and stirred for an hour. After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give N-(3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazin-2-yl)acetamide (10) (89.5 mg, 232 μmol, 79.7%) as a yellow solid. TLC Rf=0.17 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.89 (s, 3H), 4.28 (s, 2H), 5.19 (dd, 1H, J=1.0, 10.8 Hz), 5.39 (dd, 1H, J=2.0, 10.8 Hz), 5.66 (dd, 1H, J=1.0, 17.2 Hz), 6.30 (dd, 1H, J=2.0, 17.2 Hz), 6.45 (dd, 1H, J=10.8, 17.2 Hz), 6.52 (dd, 1H, J=10.8, 17.2 Hz), 6.94 (dd, 1H, J=2.6, 8.4 Hz), 7.19-7.24 (m, 5H), 7.27-7.32 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12](OCC)(OCC)OCC.Cl(O)(=O)(=O)=O>CCOCC>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:11])[CH:10]=[CH:12][O:1]2)=[CH:4][CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: O=c1ccoc2cc(O)ccc12
Yield: 53.2 %

Procedure:
To a round bottomed flask, 0.26 mol of 2′,4′-dihydroxyacetophenone was added and mixed thoroughly with 232 mL of triethyl orthoformate. Then 26.4 mL of perchloric acid was dropped slowly into the resultant mixture. After 30 min reaction, 300 mL ether was added, and solids were precipitated. Following sucking filtration, the dried solids were transferred into a 1000 mL round bottomed flask, and refluxed for 2 hours after 250 mL hot water was added. Sucking filtration was conducted again, and then 22.69 g of 7-hydroxychromone was obtained by recrystallization with ethanol, with a yield of 53.2% and MS m/z (M)162.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:28])[C:11]2[O:17][C:16]3[C:18]([Cl:24])=[CH:19][C:20]([CH2:22][NH2:23])=[CH:21][C:15]=3[CH2:14][S:13](=[O:26])(=[O:25])[C:12]=2[CH:27]=1)=[O:7].[C:29](O)([C:31](F)(F)F)=O.[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:28])[C:11]2[O:17][C:16]3[C:18]([Cl:24])=[CH:19][C:20]([CH2:22][N:23]([CH2:1][CH3:2])[CH2:29][CH3:31])=[CH:21][C:15]=3[CH2:14][S:13](=[O:25])(=[O:26])[C:12]=2[CH:27]=1)=[O:7]
Reactant: CC=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(CN)cc(Cl)c1O2
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)Cc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetaldehyde (0.1 ml, 2.35 mmol) was added to a cooled solution of Example 198k (0.2 g, 0.47 mmol) in dry methanol (15 mL). Subsequently TFA (0.036 ml, 0.47 mmol) was added and the reaction mixture was stirred for 2 h. at 0° C. NaBH3CN (0.075 g, 1.17 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. It was treated with a 10% aqueous sodium bicarbonate solution (1 mL) and the solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.150 g, (76.53%); 1H NMR (DMSO-d6): δ 1.05 (t, 6H, 2CH3), 2.55 (q, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.55 (s, 2H, CH2), 4.00 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 7.39 (s, 1H, Ar), 7.50 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar); MS: m/e (ES+) 438 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=O)[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl-].[OH:46][NH3+:47].C(=O)([O-])O.[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[N:47][OH:46])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [NH3+]O
Reactant: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 97.6 %

Procedure:
To 2 mL of a methanol solution containing 84 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 40 mg of hydroxylammonium chloride was added, and stirred at room temperature for 9.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 84 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-(hydroxyimino)propyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.O>[O:29]=[C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
triphenylphosphine (30.0 g, 114.3 mmol) is added, at ambient temperature, to a solution of commercial ethyl 4-chloro-3-oxobutanoate (18.81 g, 114.3 mmol) in 200 mL of anhydrous THF. The reaction medium is taken to reflux for 18 h before being concentrated under vacuum. The oil obtained is taken up in distilled water then washed with ether. The aqueous phase is then basified by a saturated aqueous solution of NaHCO3 (up to pH 8). After extraction with AcOEt, the organic phases are combined, dried over MgSO4, filtered then concentrated under vacuum. Purification is carried out by recrystallization from ether in order to produce, after filtration and drying, compound 5′-2 (14.96 g, 38.0 mmol, 34%) in the form of a slightly yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:32].[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])(=[O:32])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCS(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (37.3 mg, 0.84 mmol) in methanol (4 mL) at 0° C. was added a solution of potassium permanganate (13.3 mg, 0.084 mmol) in water (2 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silica gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to give the residue. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfonyl-1H-pyrrolo[2,3-b]pyridine (8 mg, 21%): LC/MS m/e calcd for C23H28N2O4S2 [M+H]+ 461.62, observed 461.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.59 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.88-7.92 (m, J=8.3 Hz, 2H), 7.59-7.63 (m, J=8.3 Hz, 2H), 6.62 (s, 1H), 4.36 (t, J=8.0 Hz, 1H), 3.25 (q, J=7.4 Hz, 4H), 3.07-3.13 (m, 4H), 2.26-2.34 (m, 1H), 2.11-2.19 (m, 1H), 1.61-1.71 (m, 2H), 1.46-1.53 (m, 2H), 1.23 (t, J=7.3 Hz, 5H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:22]=1)=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[O:13][N:14]=2.[I:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[O:13][N:14]=[C:10]3[CH:9]=[CH:8][C:7]([C:28]([C:27]4[CH:34]=[CH:35][C:24]([I:23])=[CH:25][CH:26]=4)=[O:29])=[CH:22][C:11]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(I)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
BuLi 1.6M (0.106 mol) was added dropwise at −70° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.0816 mol), obtained in Example A1a, in THF (250 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. A solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.098 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour then brought to room temperature. The mixture was hydrolysed with water, extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (48 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 16.5 g (44%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-iodophenyl)-methanone, mp.196° C. (intermediate 35).
Reaction SMILES: Br[C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].Cl[Si:13]([CH3:16])([CH3:15])[CH3:14].CN(CCN(C)C)C>C1COCC1.[Zn]>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:8][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[CH2:9][CH2:10][CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CCCC1(Br)CCCCC1=O
Agent: CN(C)CCN(C)C
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC1=C(O[Si](C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
A solution of 2-bromo-2-propylcyclohexanone (6.21 g, 28.3 mmol) and chlorotrimethylsilane (9.35 mL, 8.0 g, 73.7 mmol) in 65 mL THF was added dropwise to a slurry of Zn (2.78 g, 42.5 mmol) and TMEDA (2.2 mL, 1.65 g, 14.2 mmol) in 35 mL THF cooled in an ice bath. The mixture was allowed to stir in the cold for an additional 1.5 hrs, then allowed to warm to room temp. The mixture was filtered to remove the insolubles. The solvent was evaporated under reduced pressure and the residue extracted with Et2O (200 mL in 2 portions). The combined ethereal extracts were evaporated under reduced pressure and the residue fractionated under reduced pressure. A fraction boiling at 92°-96° (13 torr) was collected to afford 4.79 g (80%) of trimethyl(2-propylcyclohex-1-enyloxy)silane. MS (EI) 212 M(+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][N:17]=5)[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ccc(N2CCC(O)CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylic acid (0.10 g, 0.45 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1 eq) and HATU (0.19 g, 0.49 mmol, 3 eq). The mixture was stirred at room temperature for 30 min then concentrated and purified by HPLC to afford (S)-6-(4-hydroxypiperidin-1-yl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)pyridazine-3-carboxamide (0.12 g, 0.29 mmol, 66%). 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1 H), 8.02 (d, J=9.8 Hz, 1 H), 7.94 (d, J=5.5 Hz, 1 H), 7.81 (s, 1 H), 7.5 (d, J=9.8 Hz, 1 H), 7.18 (d, J=5.8 Hz, 1 H), 4.98-4.80 (m, 1 H), 4.80-3.80 (br, 4 H), 4.20-4.10 (m, 2 H), 4.00-3.90 (m, 1 H), 3.55-3.45 (m, 2 H), 2.60-2.35 (m, 2 H), 2.05-1.95 (m, 2 H), 1.68-1.55 (m, 2 H); MS: (ES) m/z calculated for C20H24N8O2 [M+H]+ 409.2, found 409.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.260 g, 0.88 mmol) and Pd/C (0.026 g) in MeOH (4 mL). The reaction flask was evacuated and purged with hydrogen twice followed by stirring under a hydrogen atmosphere for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and concentrated to give the crude title compound as the major isomer (0.255 g, 97%; 1:3 a:β). Major isomer: 1H NMR (CDCl3) d 4.17-4.15 (m, 2H), 4.13-4.06 (m, 2H), 2.32-2.26 (m, 1H), 2.13 (d, J=7.0 Hz, 2H), 1.95-1.90 (m, 2H), 1.67-1.61 (m, 2H), 1.59-1.54 (m, 2H), 1.43 (s, 9H), 1.42-1.27 (m, 2), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) d 172.4, 153.3, 79.0, 60.2, 53.3, 41.3, 37.2, 28.4, 26.0, 14.2
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])(F)F)=O.ClC(=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)C=C.ClC(=C1CCN([C:28]([O:30][C:31](C)(C)[CH3:32])=[O:29])CC1)C=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:31]([O:30][C:28]([O:1][CH2:2][C:4](=[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[F:7])=[O:29])[CH3:32]
Reactant: C=CC(Cl)=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CC(Cl)=C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)OCC(F)=C1CCNCC1
Reaction time: 3 h

Procedure:
4-(1-Chloro-2-propenylidene)piperidine TFA salt (110; Scheme XXIX) To compound 109 (0.1415 g, 0.5489 mmol) in CH2Cl2 (5 mL) was added TFA (0.55 mL, 7.1 mmols) and the mixture stirred for 3 hrs whereupon all volatile materials were removed in vacuo. The crude title compound so obtained was used without further purification. MS 158 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23](O)=[O:24])[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]1([NH:37][C:23]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([C:12]([P:15](=[O:16])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:14])[F:13])=[C:2]([Br:1])[CH:3]=3)[N:8]=2)=[O:24])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCI (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:5]1[C:6]([O:8][CH2:11][CH3:12])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: CCI
Reactant: Nc1cc(O)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(N)c(F)cc1Br
Yield: 67.8 %

Procedure:
5-Amino-2-bromo-4-fluorophenol (10.30 g), ethyl iodide (9.36 g) and potassium carbonate (7.59 g) were suspended in acetonitrile (100 ml), and the mixture was heated under refluxing for about 6 hours. After the reaction, the precipitates were filtered, the solvent was distilled off, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v) to obtain the objective 4-bromo-5-ethoxy-2-fluoroaniline (7.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Yield: 126.6 %

Procedure:
Using a similar method to Example 371, and using (±)-6-[2-chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above) (0.198 g, 0.508 mmol), potassium carbonate (0.0337 g, 0.244 mmol), and 30% hydrogen peroxide solution (aq) (0.180 mL, 1.59 mmol) in dimethylsulfoxide (5.0 mL) provides 0.126 g (61%) of the title compound as a yellowish syrup: high resolution mass spectrum (electrospray): m/z calc for C23H23ClN3O2 408.1479, found 408.1449; 1H NMR (methanol-d4): 8.61 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.4, 8.8 Hz), 7.61 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J=2.0, 8.3 Hz), 7.35-7.29 (m, 4H), 7.27 (d, 1H, J=8.3 Hz), 7.24-7.18 (m, 1H), 7.11 (d, 1H, J=8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.2 Hz), 3.50-3.39 (m, 1H), 3.15 (dd, 1H, J=7.8, 9.3 Hz), 2.99-2.91 (m, 1H), 2.82 (td, 1H, J=6.3, 8.8 Hz), 2.60 (t, 1H, J=8.8 Hz), 2.45-2.34 (m, 1H), 2.03-1.92 (m, 1H).
Reaction SMILES: CC1(C)O[C@@H:5]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[C:15]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=3[N:10]=[CH:9]2)CO1.NC1C=C[C:35]([NH:38][C:39]2C3C(=O)NC=NC=3N(C)C(=O)C=2)=C(F)C=1.Br.BrCCN(C)C>>[CH3:35][N:38]([CH3:39])[CH2:5][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H]3COC(C)(C)O3)cnc21
Reactant: Cn1c(=O)cc(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc21
Agent: Br
Agent: CN(C)CCBr
Product: CN(C)CCn1cnc2c(c(Nc3ccc(I)cc3F)cc(=O)n2C)c1=O

Procedure:
The title compound was prepared following the same procedure for the synthesis of compound 5G using compound 5F and 2-bromo-N,N-dimethylethanamine hydrobromide as starting material. 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H) 7.68 (m, 2H) 7.33 (t, J=8.36 Hz, 1H) 5.78 (s, 1H) 4.51 (t, J=4.0 Hz, 2H) 3.69 (s, 3H) 3.66 (t, J=8.0 Hz, 2H) 3.09 (s, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([CH2:51][O:52][NH2:53])=[CH:49][CH:48]=1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([CH2:51][O:52][NH:53][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:18]([CH3:19])[CH3:20])=[CH:49][CH:48]=1
Reactant: COc1ccc(CON)cc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CONC(=O)[C@@H](C(C)C)N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (2.41 g, 5.82 mmol), 1-hydroxybenzotriazole (0.786 g, 5.82 mmol), 4-methyl-morpholine (1.9 mL, 17.46 mmol), and O-(4-methoxybenzyl)hydroxylamine (1.78 g, 11.63 mmol) (prepared according to Pol. J. Chem. 55, 1163-1167 (1981)) are dissolved in methylene chloride (55 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.45 g, 7.57 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate followed by 5% methanol/ethyl acetate) to give N-(4-methoxybenzyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide, m.p. 45°-53° C.
Reaction SMILES: [CH:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH3:7])=[O:5])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.N>CC(C)=O.O>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3](=[CH:1][O:2][CH3:19])[C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccccc1C(C=O)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCCCOc1ccccc1C(=COC)C(=O)OC
Reaction time: 2 h
Yield: 82.4 %

Procedure:
10 g of methyl α formyl-(2-butoxyphenyl)acetate are dissolved in 100 ml of acetone. 15 g of potassium carbonate are added, followed gradually with stirring by an equimolar amount of dimethyl sulfate. After 12 hours of refluxing, 50 ml of H2O are added, followed carefully by 30 ml of concentrated NH3 solution. After 2 hours of stirring, about 100 ml of solvent are drawn off, poured onto ice and extracted with dichloromethane. Drying of the organic phase leaves 8.7 g of oil.