Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]1[O:18][C@@H:16]1[CH3:17]>>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:15][C@H:16]([OH:18])[CH3:17])[CH:8]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](O)Cn1cc(N)cn1
Reaction time: 64 h

Procedure:
To a solution of 4-nitropyrazole (44.7 mg, 0.395 mmol, 1 equiv) in (R)-propylene oxide (1 mL) was added cesium carbonate (78 mg, 0.24 mmol, 0.61 equiv) at 24° C. After 64 h, the reaction mixture was partitioned between ethyl acetate (3 mL) and half-saturated aqueous sodium chloride solution (3 mL). The organic was separated, and the remaining aqueous phase was extracted with ethyl acetate (2×3 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in methanol (4 mL) and circulated through a H-Cube® continuous-flow hydrogenation reactor (ThalesNano) fitted with a palladium on carbon catalyst cartridge at 30° C. The resulting solution was concentrated in vacuo to provide product as a pink oil, which was used without further purification. 1H NMR (500 MHz, CDCl3), δ: 7.17 (s, 1H), 7.01 (s, 1H), 4.13 (m, 1H), 4.00 (dd, J=13.8, 2.7 Hz, 1H), 3.84 (dd, J=13.8, 7.9 Hz, 1H), 3.47 (s, 1H), 3.15 (br s, 2H), 1.18 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([NH:36][OH:35])=[O:34])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidinecarboxylic acid (402 mg, 0.79 mmol) in dimethylformamide (8 ml), 1-hydroxybenzotriazole (128 mg, 0.95 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml, 1.19 mmol), and hydroxylamine (0.242 ml, 3.95 mmol), 396 mg (96%) of the product was isolated as a solid. HR-MS: m/z Calculated for C23H26N2O8S2 523.1203; Found 523.1198.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[BH4-].[Na+]>CC#N.C1COCC1.C(O)(=O)C>[CH2:17]([NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: c1ccc(CNCCC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,3-diphenylpropylamine (1.01 g, 4.79 mmol), acetic acid (28 ml, 049 mmol), and benzaldehyde (490 μl, 4.80 mmol) in CH3CN (2 ml) was added sodium cyanoborohydride (4.80 ml of a 1 M solution in THF, 4.8 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 18 hrs. The solvent was evaporated in vacuo, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in MeOH (100 ml) and sodium borohydride (182 mg, 5.55 mmol) added and the reaction was stirred for 30 min. The solvent was evaporated and the residue treated with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was separated, washed with saturated brine, dried (Na2SO4) and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>ClCCl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Yield: 11.2 %

Procedure:
Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2×250 mL) and the combined aqueous layers were back extracted with DCM (2×25 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (15% diethyl ether in hexanes) to yield 216 mg (15%) of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole as a white solid. LC/MSD m/e: 276.0 (M+H); 1H NMR (400 MHz) (CDCl3) δ 8.15 (2H, d, J=8.0 Hz), 7.73 (2H. d, J=8.0 Hz), 4.59 (2H, s), 2.48 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:35][C@H:36]2[CH2:38][O:37]2)(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:35][C@H:36]4[CH2:38][O:37]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OC[C@H]1CO1
Temperature: 25 °C
Yield: 97 %

Procedure:
After dissolving 4-(4-aminophenoxy)-6-cyano-7-hydroxyquinoline (277 mg, 1.00 mmol) in dimethylformamide (3.0 ml), sodium hydride (40 mg, 1.00 mmol, 60% in oil) was added at room temperature and the mixture was stirred. There was then added (2R)-oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (228 mg, 1.00 mmol), and the mixture was heated and stirred at 60° C. for 5 hours. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (322 mg, 0.97 mmol, 97%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCOc1cccnc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCOc1cccnc1
Reaction time: 5 h

Procedure:
A mixture of 2-[(3-pyridinyl)oxy]ethanol (1.9 g), 1,6-dibromohexane (6 ml), tetra-n-butylammonium bisulphate (0.5 g) and 50% w/v sodium hydroxide (20 ml) was stirred vigorously for 5 h, diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil which was purified by FCC eluting with hexane→ethylacetate to give the title compound (2.3 g) as an oil. T.l.c. (System E 80:20:1) Rf 0.63
Reaction SMILES: [CH3:1][CH:2]([S-:4])[CH3:3].[Na+].[F:6][C:7]1[C:13](F)=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:8]=1[NH2:9]>CN(C=O)C.CCOC(C)=O>[F:6][C:7]1[C:13]([S:4][CH:2]([CH3:3])[CH3:1])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:8]=1[NH2:9]
Reactant: CC(C)[S-]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc([N+](=O)[O-])c(N)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
Sodium 2-propanethiolate (5.66 g) was added to a solution of 2,3-difluoro-6-nitroaniline (10.04 g) in DMF (200 ml). The mixture was stirred at ambient temperature for 16 hours and then diluted with EtOAc (300 ml) and washed with brine (500 ml). The washing was extracted with EtOAc (300 ml). The organic phases were combined, washed with brine (500 ml), dried and volatile material was removed by evaporation to give the title compound (14.1 g) as a solid. NMR: 1.30 (d, 6H), 3.70 (septet, 1H), 6.70 (dd, 1H), 7.26 (s, 2H), 7.80 (dd, 1H); m/z 229.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH2:10][N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7].Br[CH2:19][CH:20]([CH:37]([CH3:39])[CH3:38])[CH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][CH:28]=[C:29]2[O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][CH:23]=1>O1CCCC1>[CH2:6]([O:8][C:9]1[CH:10]([CH2:19][CH:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:28]=[CH:27][CH:26]=3)[CH:31]=2)[CH:37]([CH3:38])[CH3:39])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7]
Reactant: CCOC1=NCC(OCC)=NC1
Reactant: COCCOc1cccc2ccc(CC(CBr)C(C)C)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1=NC(CC(Cc2ccc3cccc(OCCOC)c3c2)C(C)C)C(OCC)=NC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3.03 ml of n-butyllithium (1.6M in hexane) are added dropwise at −40° C. to the suspension of 0.884 g of 3,6-diethoxy-2,5-dihydropyrazine in 12 ml of tetrahydrofuran. After 20 minutes, a solution of 1.265 g of 7-(2-bromomethyl-3-methylbutyl)-1-(2-methoxyethoxy)naphthalene in 5 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred further at −40″C. for 30 minutes, then warmed to −20° C. over 1 hour. After 18 hours, the reaction mixture is concentrated by evaporation—the residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×)—the combined organic phases are washed successively with water (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [OH:1][C:2]1[CH:3]([CH3:14])[NH:4][C:5]([CH3:13])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1>C(Cl)Cl.CCOC(C)=O.CCCC(C)C.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][C:3]=1[CH3:14]
Reactant: CCOC(=O)C1=C(C)NC(C)C(O)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: CCOC(=O)c1nc(O)c(C)nc1C
Temperature: 35 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
A solution of 2M Hydrochloric acid in 1,4-dioxane (1177 mL, 4709.97 mmol) was added to Intermediate 1-6 (745 g, 2354.99 mmol) and stirred at room temperature for 15 minutes then warmed to 40° C. for a further 40 minutes. Pyridine (6500 mL) was then slowly added and then the reaction was heated to 80° C. for 2 hours in the presence of air. The reaction was then allowed to cool to ambient temperature and evaporated to dryness to afford a viscous oil. This was suspended in DCM (2.5 L) and washed water (1.5 L). The DCM was then dried over MgSO4, filtered and concentrated to afford an orange semi-solid, which was triturated with 1:1 EtOAc/iso-hexane (250 mL) to afford ethyl 6-hydroxy-3,5-dimethyl-1,4-dihydropyrazine-2-carboxylate (127 g, 27.1%) as a cream solid. The mother liquors were then purified by flash silica chromatography (gradient from 20% ethyl acetate/iso-hexane to 80% ethyl acetate/iso-hexane). Fractions containing the desired product were concentrated and the residue was triturated with a small volume of 1:1 EtOAc/iso-hexane to afford the title compound (9.00 g, 1.948%). Manganese dioxide (150 g) was added to a suspension of ethyl 6-hydroxy-3,5-dimethyl-4,5-dihydropyrazine-2-carboxylate (121 g, 610.44 mmol) in DCM (1.8 L) at ambient temperature giving rise to a 2° C. exotherm. The reaction was stirred for 10 minutes then warmed to 35° C. for 1 hour. The reaction was incomplete so an additional 115 g of Manganese dioxide was added and the reaction stirred for 1 hour at 35° C. then stirred to cool to ambient temperature. The reaction was filtered through a short bed of silica and washed through with 2 L of 1:1 EtOAc/iso-hexane and finally 2×2 L EtOAc. The fractions were then combined and reduce in-vacuo to give an orange solid, which was slurried in 300 mL of 1:1 EtOAc/iso-hexane, filtered and washed with iso-hexane to afford the title compound (87 g, 72.6%) as an orange solid.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[N:10]=1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Reaction time: 0.83 h
Yield: 27.1 %

Procedure:
Phosphorus trichloride (210 mg.) was added to a solution of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate-1-oxide (syn-isomer: 570 mg.) in dry dimethylformamide (10 ml.) at -30° C., and stirred at -20° to -30° C. for 50 minutes. 10% Aqueous solution (50 ml.) of sodium chloride was added to the resultant solution, adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue (560 mg.) was purified with column chromatography on silica gel (20 g.) (eluent:ethyl acetate), and the resultant residue (180 mg.) was pulverized with n-hexane (10 ml.) and diethyl ether (5 ml.) to give n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)- 2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer: 150 mg.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1ccc(N2CCOCC2)cc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4-morpholin-4-yl-benzaldehyde (43 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][OH:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)C(C)C)(C)C.N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:16][CH:17]=[O:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)N(CCO)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N(CC=O)Cc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Acetic acid [benzyl-(2-hydroxyethyl)carbamoyl]methyl ester (1.28 g, 5.10 mmol) was weighed into a 200 mL round bottom flask and purged with nitrogen. Dichloromethane (50 mL) was added, and the reaction was cooled to −15° C. for 10 minutes. Dimethylsulfoxide (3.61 mL, 51.0 mmol), N,N-diisopropylethylamine (4.43 mL, 25.5 mmol), and pyridine.sulfur trioxide complex (4.06 g, 25.5 mmol) were then added sequentially at −15° C. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was complete by thin layer chromatography, and was diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was removed via filtration and solvent was removed in vacuo to give crude title compound as a yellow oil. The crude material was chromatographed on silica gel using 1:1 ethyl acetate:dichloromethane as the mobile phase. Fractions were combined and solvent was removed in vacuo to give pure title compound as a colorless oil (0.72 g, 57% yield). (m/z): [M+H]+ calcd for C13H15NO4 250.11. found 250.0.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:33]1([CH2:34][O:26][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:27])[CH2:31][CH2:32]1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1

Procedure:
A 0.15 quantity of the compound obtained in Example 327 and 0.18 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of ethanol, 0.15 g of (bromomethyl)cyclopropane was then added to the obtained solution, and the obtained mixture was heated and refluxed overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 42 mg of white powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [CH2:1]([N:8]([C@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[O:25][CH3:26])[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:1]([N:8]([C:9]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[C@H:19]1[CH2:24][CH2:23][N:22]([C:28]2[CH:29]=[C:30]([CH:36]=[C:37]([CH3:39])[CH:38]=2)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:21][C@H:20]1[O:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)cc(Br)c1
Reactant: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)cc(N2CC[C@H](N(Cc3ccccc3)C(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 58.1 %

Procedure:
The same operation as in Example (42a) was performed using benzyl benzyl[cis±)-3-methoxypiperidin-4-yl]carbamate obtained in Example (259c) (150 mg, 0.42 mmol), ethyl 3-bromo-5-methylbenzoate obtained in Example (259e) (103 mg, 0.42 mmol), palladium acetate (10 mg, 0.04 mmol), (±)-BINAP (53 mg, 0.08 mmol), cesium carbonate (303 mg, 0.93 mmol), 1,4-dioxane (6 mL) and DMF (1.5 mL), to obtain 126 mg of the title compound as a yellow oily substance (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([F:44])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([F:44])[CH:37]=1)[CH3:35])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: COc1ccc(C(C)=CBr)cc1F
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (75 mg, 0.34 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K3PO4 (145 mg, 0.68 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 40 mg of 6-chloro-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.60 (m, 2H), 7.42 (d, 1H), 7.25 (d, 2H), 7.18 (t, 1H), 7.10 (s, 1H), 4.10 (m, 2H), 3.90 (s, 3H), 3.50 (m, 2H), 2.95 (m, 2H), 2.78 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]O>>[NH:20]1[C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccccc1CCO
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: c1ccc2c(c1)CCN2
Temperature: 220 °C

Procedure:
In a stainless steel reactor equipped with distillation column, 5.0 g of a commercially available amorphous aluminium silicate (KETJEN® C-25-W) consisting of 14.7% by weight of AL2O3 and 82.5% by weight of SiO2, and having a BET inner surface area of 547 m2 /g and a pore volume of 0.61 cm3 /g, are suspended in 130 g (117 ml) of 2-(2'-aminohenyl)ethanol using a magnetic stirrer. The suspension is heated to 220° C. Then, at a constant reaction temperature of 220° C. and under an initial pressure of 0.5 bar, the resultant indoline/water mixture is distilled off through the packed column at an average rate of 60 g of indoline per hour. During this distillation, the volume in the reactor is kept constant with a level probe by the continuous addition of fresh 2-(2'-aminophenyl)ethanol. The reduction in the distillation rate caused by the formation of high-boiling by-products is compensated for by gradually lowering the pressure for maintaining the distillation rate over the duration of the experiment form 0.5 to 0.07 bar. After a reaction time of 150 hours, the addition of 2-(2'-aminophenyl)ethanol is discontinued and the indoline present in the reactor is distilled off under reduced pressure affording 9.0 kg of indoline in 99.5% purity as distillate. 55 g of high-boiling by-products of unknown constitution are obtained as distillation residue. The yield of indoline is 98-99% of theory.