Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CON(C)[C:24]([C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH:36]([C:50]3[CH:58]=[CH:57][C:53]4[O:54][CH2:55][O:56][C:52]=4[CH:51]=3)[C:37]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])=[O:38])=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1)=[O:25]>O1CCCC1>[O:54]1[C:53]2[CH:57]=[CH:58][C:50]([CH:36]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([C:24](=[O:25])[CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:37]([NH:39][S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=3)(=[O:42])=[O:41])=[O:38])=[CH:51][C:52]=2[O:56][CH2:55]1
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(=O)Cc4ccccn4)ccc23)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (0.53 ml of 1.5M solution in cyclohexane) was added to a stirred solution of 2-methylpyridine (0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (3 ml) at −70° C. under a nitrogen atmosphere. After 20 minutes a solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (the compound of Example 103, 200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture at −70° C. The mixture was stirred at −70° C. for an additional 2 hours before being warmed to be 0° C. and then quenched with the addition of water (5 ml). The mixture was acidified with acetic acid, and extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (95 mg).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[CH3:22][C@:23]12[CH2:39][CH2:38][C@H:37]3[C@@H:28]([CH:29]=[CH:30][C:31]4[C@@H:36]3[CH2:35][CH2:34][C:33](=[O:40])[CH:32]=4)[C@@H:27]1[CH2:26][CH2:25][C:24]2=[O:41].C(O)(=O)C>O1CCCC1.[Cu]I>[CH3:16][Si:15]([CH3:17])([C:18]([CH3:21])([CH3:20])[CH3:19])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:29]1[CH2:30][C:31]2[C@H:36]([CH2:35][CH2:34][C:33](=[O:40])[CH:32]=2)[C@@H:37]2[C@@H:28]1[C@H:27]1[C@@:23]([CH2:39][CH2:38]2)([CH3:22])[C:24](=[O:41])[CH2:25][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 1 h
Yield: 172 %

Procedure:
7.4 g of magnesium filings is placed into 31 ml of tetrahydrofuran and combined within 1.5 hours with a solution of 113 g of 11-bromoundecyl-tert-butyldimethylsilyl ether in 310 ml of tetrahydrofuran. After one hour at a bath temperature of 100°, the mixture is diluted with 157 ml of tetrahydrofuran, cooled to -30°, mixed with 29.5 g of copper(I) iodide, stirred for 0.2 hour at -30°, a solution of 25 g of 4,6-estradiene-3,17-dione [Kalvoda, J., and Anner, G., Helv. Chim. Acta 50 : 269 (1967)]in 220 ml of tetrahdyrofuran is added dropwise, and the mixture is further stirred for 1.5 hours at -30°. Then, 18.7 ml of glacial acetic acid is added, the mixture is concentrated under vacuum, poured on water, suctioned off through "Celite", rinsed with ethyl acetate, extracted twice with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 88.6 g of 7α-[11-(dimethyl-tert-butyl-silyloxy)undecyl]-4-estrene-3,17-dione, [α]D =54.4°, as an oil, as well as 55.2 g of 7β-[11-(dimethyl-tert-butylsilyloxy)undecyl]-4-estrene-3,17-dione, mp 65°.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]([CH2:14][CH3:15])[C:3]1=[O:16].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:17][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)=[O:13])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH3:15])[C:3]1=[O:16]
Reactant: Nc1ccc(F)cc1
Reactant: CCN1C(=O)C(C)(C)c2ccc(C(=O)O)cc21
Product: CCN1C(=O)C(C)(C)c2ccc(C(=O)Nc3ccc(F)cc3)cc21
Yield: 58 %

Procedure:
By reaction of the 2,3-dihydro-3,3-dimethyl-1-ethyl-2-oxo-(1H)-indole-6-carboxylic acid prepared in Example 34b with 4-fluoroaniline analogously to Example 1c, there was obtained the title compound in a yield of 58% of theory; m.p. 179°-181° C., after recrystallisation from ethyl acetate.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C(=O)(O)[O-].[Na+]>COCCOC.O.C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=1
Reactant: Brc1ncccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncccn2)cc1
Yield: 84.4 %

Procedure:
A solution of 2-bromopyrimidine (1.00 g, 6.3 mmol) and tetrakistriphenylphosphine(0) palladium (0.218 g, 0.189 mmol) in ethylene glycol dimethyl ether (30 mL) was stirred at room temperature for 10 minutes. A solution of 4-formylbenzene boronic acid (1.14 g, 7.61 mmol) and sodium bicarbonate (1.58 g, 18.9 mmol) in 15 mL water was added and the reaction was heated at reflux for 18 h. The mixture was diluted with water and CH2Cl2. The layers were separated, and the aqueous solution was washed with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (10% to 30% hexanes in EtOAc) to afford the title compound (0.979 g). 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (s, 2H), 7.23 (s, 2H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH:9]1[C:18]2[C:13](=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1.CN(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[CH:9]1[C:18]2[C:13](=[C:14]([CH:19]([CH3:1])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccc2cnccc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (12.75 mL, 2M, 25.5 mmol) in THF (160 mL) at −78° C. under nitrogen was treated with ethyl 5-isoquinolinylacetate (5.00 g, 23.2 mmol) in THF (5 mL). After stirring for 30 minutes at −78° C., the mixture was treated with HMPA (5.2 mL) and methyl iodide (1.62 mL, 25.5 mmol). After stirring for 30 minutes at −78° C., the mixture was warmed to 0° C. over 1 hour and quenched by addition of saturated NH4Cl solution. The mixture was concentrated under reduced pressure to a volume of ˜10 mL, diluted with ethyl acetate (200 mL), washed with water (100 mL×5), washed with brine, dried with anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 230 (M+H)+; MS (ESI−) m/z 228 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C20H16F4N2O+1.25 HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22](=[O:25])[CH:21]=[C:20]2[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:16]([O:35][CH3:36])=[CH:17][CH:18]=2)[O:23][C:22](=[O:25])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CCCCCNC
Product: CCCCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylpentan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.61 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.23 (m, 4H), 0.83 (t, 3H); MS (ESI): 522.1.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:2]2.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][CH2:31][C:32]([N:2]1[C@H:3]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4][C@H:5]2[C@@H:1]1[CH2:8][CH2:7][CH2:6]2)=[O:33]
Reactant: O=C(O)CCCc1ccc2ccccc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccc2ccccc2c1
Temperature: -5 °C
Reaction time: 48 h

Procedure:
2 5 g of benzyl (lS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate and 2.2 g of 4-(2-naphthyl)butyric acid are dissolved in 40 ml of DMF and cooled to -5° C. 7.7 ml of triethylamine and then 10 ml of n-propylphosphonic anhydride (50 % strength solution in dichloromethane) were pipetted into this solution under a nitrogen atmosphere. This mixture was stirred at room temperature for 48 hours, to effect complete conversion. The solution was diluted with 100 ml of ethyl acetate and successively extracted two times each with saturated NaHCO3 solution, 10 % strength citric acid solution and saturated NaCl solution. After drying over MgSO4 and concentration of the organic phase, the crude product obtained was separated by column chromatography over silica gel (cyclohexane/ethyl acetate). This gave 2.52 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:21][CH2:22][O:23][CH3:24])[C@H:12]([O:17][CH2:18][O:19][CH3:20])[C@@H:13]([CH2:15][OH:16])[O:14][C@H:8]3[N:7]([CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:6]=2[CH:32]=1.O1CCC[CH2:34]1.CN(C)C=O.[H-].[Na+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:21][CH2:22][O:23][CH3:24])[C@H:12]([O:17][CH2:18][O:19][CH3:20])[C@@H:13]([CH2:15][O:16][CH3:34])[O:14][C@H:8]3[N:7]([CH2:25][CH2:26][N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[C:6]=2[CH:32]=1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](CO)O[C@H]21
Reactant: C1CCOC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](COC)O[C@H]21
Reaction time: 5 h

Procedure:
To the solution of 92 mg of the compound (25) obtained in Example 24 in 4.5 ml of a mixed solution of tetrahydrofuran-dimethylformamide (2:1), 30 mg of sodium hydride and 80 μl of methyl p-toluenesulfonate were added, and the mixture was stirred for five hours. After methanol was added to the solution, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride successively and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the title compound was obtained from the fraction of chloroformmethanol (19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][OH:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][O:14][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)c1cc(Cl)cnc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Cl)cnc1COc1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.9 %

Procedure:
To a mixture of ethyl 5-chloro-2-(hydroxymethyl)nicotinate (step 4, 340 mg, 1.59 mmol), 3-fluorophenol (325 mg, 2.90 mmol), and triphenylphosphine (761 mg, 2.9 mmol) in tetrahydrofuran (10 ml) was added 40% solution of diethylazodicarboxylate in toluene (506 mg, 2.9 mmol) and the reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water and the whole mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 300 mg (56%) of the title compound:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[N:7]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCOC(=O)Cn1ccc2cnc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1ccc2cnc(Cl)nc21
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a solution of ethyl 2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (1.25 g, 5.23 mmol) in EtOH/H2O (100 mL) was added NaOH (1.1 g, 26.15 mmol). The reaction mixture was stirred at room temperature until TLC showed completion. The reaction mixture was concentrated and the residue taken up in water (15 mL) and treated with 2M HCl until pH=3 then extracted with EA (2×25 ml). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated to yield the title product (600 mg, Yield 50%). The crude product was used in next step without further purification. LCMS (m/z): 212.0 (M+1).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.Cl.[NH2:13]O>C(O)C.O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:1])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide (70 mL of 50% w/w) was added to a solution of 4-fluorobenzaldehyde (140.5 g, 1.132 mol) and hydroxylamine hydrochloride (86.5 g, 1.25 mol) in ethanol (1 L) and water (2 L), and the reaction was stirred at room temperature for one hour and then adjusted to pH 14 with the addition of 50% w/w aqueous sodium hydroxide. The mixture was extracted with several portions of dichloromethane and then several portions of chloroform. The combined extracts were concentrated under reduced pressure approximately one liter, filtered through a layer of CELITE filter agent and sodium sulfate, and concentrated again under reduced pressure to yield 127 g of 4-fluorobenzaldehyde oxime as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:30]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)(=[O:32])=[O:31])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3)c3cc(Cl)ccc32)cc1OC
Reaction time: 0.5 h

Procedure:
66 mg of sodium hydride as an 80% dispersion in oil were added in portions to a solution of 490 mg of 5-chloro-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one in 5 ml of DMF and the reaction medium was stirred for 30 minutes. 520 mg of 3,4-dimethoxybenzenesulfonyl chloride were then introduced and the reaction medium was stirred overnight at room temperature. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product in the form of a white solid, which crystallized from absolute EtOH. m=0.71 g. M.p.=154° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1CN1CCNCC1.[Li]CCCC.[CH2:39]([O:41][CH:42]=[C:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:40]>C1COCC1.O>[CH2:52]([O:51][C:49](=[O:50])[CH:43]([CH:42]([O:41][CH2:39][CH3:40])[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:53]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Agent: [Li]CCCC
Agent: c1ccc(CN2CCNCC2)nc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(OCC)C(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from 1-Pyridin-2-ylmethyl-piperazine according to the literature: J. Med. Chem. (1993), 36, 2984) (2.00 g, 7.21 mmol) in THF (15 mL) was added n-BuLi (1.6 M in hexanes, 5.0 mL, 7.9 mmol) at −78° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to −78° C. and a solution of diethyl ethoxymethylenemalonate (1.72 g, 7.93 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over 1 hour and stirred at 0° C. for 1 hour. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 8:1 to 1; 1) to give 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 67%) as a mixture of diastereomers. Diastereomer 1: 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=4.4 Hz, 1H), 7.63 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.16 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 5H), 3.75 (q, J=7.2 Hz, 2H), 3.52 (d, J=4.4 Hz, 1H), 3.38 (m, 4H), 2.67 (m, 2H), 2.44 (m, 2H), 1.40 (s, 9H), 1.22 (m, 6H), 1.44 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.61 min. Diastereomer 2: 1H NMR (CDCl3, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 7.59 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.15 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.91 (m, 1H), 4.16 (m, 5H), 3.53 (m, 1H), 3.22 (m, 6H), 2.50 (m, 2H), 2.19 (m, 2H), 1.34 (s, 9H), 1.24 (m, 6H), 0.69 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.62 min.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6]CC)=[O:5].[CH2:18]([O:21]N)[CH:19]=[CH2:20]>>[Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:15])([CH3:16])[CH3:17])[C:3]=1[C:4]([NH:6][O:21][CH2:18][CH:19]=[CH2:20])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Reactant: C=CCON
Product: C=CCONC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Yield: 86 %

Procedure:
The acid prepared in Example 203 was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with aq O-allylhydroxylamine using General Method E1 to afford the title compound. Purification by recrystallization from ether/hexanes gave 0.68 g of the title compound as a white solid in 86% yield. m.p. 92°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 80.7 %

Procedure:
A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9d and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9e. MS m/z (M+H+) 258.1.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][C:8]=2[CH3:13])[N:3]=1.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[F:14][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([O:19][CH3:18])[C:2]([O:16][CH3:15])=[N:3]2)=[C:8]([CH3:13])[CH:7]=1
Reactant: C[O-]
Reactant: CO
Reactant: Cc1cc(F)cc2nc(Cl)c(Cl)nc12
Agent: [Na+]
Product: COc1nc2cc(F)cc(C)c2nc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
14 g (60.6 mmol) of 2,3-dichloro-7-fluoro-5-methylquinoxaline are introduced into 165 ml of methanol. An about 5.4M solution of sodium methanolate in methanol is added dropwise. The mixture is heated to reflux and stirred for 18 hours. The reaction mixture is cooled to 0° C., the suspension is filtered off on a suction filter and washed with cold methanol, and the filter material is dried in vacuo at 60° C. The crude product is recrystallized from hexane. The title compound is obtained as white crystals of m.p. 107-109° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[CH2:35][CH3:36])(=O)C>CN1CCCC1=O>[Br-:1].[Br-:1].[C:25]1([P+:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+:18]([C:36]2[CH:35]=[CH:30][CH:25]=[CH:26][CH:27]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(C)=O
Reactant: BrCCCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: [Br-]
Product: c1ccc([P+](CCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
28.61 Grams of 1,9-dibromononane and 52.46 g of triphenylphosphine were weighed out and placed in a 500-mL three-necked flask. These compounds were dissolved in 100 mL of N-methylpyrrolidone. This solution was stirred at 80° C. for 5 hours and the resultant reaction mixture was cooled to room temperature. Thereafter, the reaction mixture was poured into 500 mL of ethyl acetate kept being sufficiently stirred. The solid precipitated was collected by suction filtration and washed with 50 mL of ethyl acetate twice. The solid obtained was placed on a Petri dish and dried at room temperature under vacuum until the mass of the solid became constant. As a result, nonamethylenebis(triphenylphosphonium)dibromide was obtained as a white solid in an amount of 73 g (yield: 90%).