Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:14].C([Li])CCC.Cl[C:21]1[C:26]([N:27]=[C:28]=[S:29])=[CH:25][CH:24]=[C:23]([Cl:30])[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CN(C=O)C>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[S:29][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([Cl:30])[N:22]=3)=[C:3]([F:14])[CH:4]=1
Reactant: S=C=Nc1ccc(Cl)nc1Cl
Reactant: Fc1cc(C2OCCCO2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Reaction time: 0.33 h

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)-1,3-dioxane (7.65 g, 29.3 mmol) in 75 mL THF under argon at −78° C. was added 1-butyllithium 2.5M in hexanes (12.9 mL, 32.2 mmol) in portions over ˜20 min. The reaction mixture was allowed to stir 20 min, and was yellow. A solution of 2,6-dichloro-3-isothiocyanatopyridine (6.01 g, 29.3 mmol) in 20 mL THF was added dropwise via cannula. The resulting dark brown solution was allowed to stir 15 min, then was quenched by addition of sat'd aq. NH4Cl. The reaction mixture was partitioned between sat'd aq. NH4Cl and Et2O. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give an orange solid. The solid was treated with sodium carbonate (4.66 g, 44.0 mmol) and approximately 15 mL DMF, and stirred under nitrogen at 90° C. The reaction was heated overnight, and in the morning was a solid mass. The reaction was diluted with water, stirred rapidly for several hours, and filtered, rinsing with water and MeOH. The resulting solid was dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine. MS (ESI) m/z: Calculated: 350.0; Observed: 350.9 (M++1).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)=[CH:6][CH:5]=1.[CH3:23]I>>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: Cc1nc(Nc2ccc(OC(F)F)cc2)c2ccccc2n1
Reactant: CI
Product: Cc1nc(N(C)c2ccc(OC(F)F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (710 mg, 2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol), by a procedure similar to Example 7 (40.8% yield). 1H NMR (CDCl3): 7.77 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H), 6.78 (d, J=0.6 Hz, 0.25H), 6.54 (d, J=0.9 Hz, 0.5H), 6.29 (d, J=0.9 Hz, 0.25H), 3.62 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[C:14]#[N:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:12]=1[N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([F:1])=[C:3]([S:25]([Cl:24])(=[O:27])=[O:26])[CH:4]=[CH:5][C:6]1=2)#[N:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c(F)cccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Cl)c2F
Temperature: 0 °C
Yield: 58 %

Procedure:
To a vial charged with 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.168 g, 0.521 mmol) was added DCM (2.085 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.139 ml, 2.085 mmol), faster than dropwise. After 30 mins the solution was added to ice water, and mixture was extracted 2× with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, then isocratic at 25%, 10% DCM throughout) providing product as a white foam, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.127 g, 0.302 mmol, 57.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-3.99 (m, 2 H) 4.52 (dd, J=5.14, 3.67 Hz, 2 H) 6.42 (dd, J=9.19, 1.66 Hz, 1 H) 7.34 (dd, J=9.19, 6.75 Hz, 1 H) 7.60 (d, J=8.51 Hz, 1 H) 7.95 (dd, J=8.56, 1.81 Hz, 1 H) 8.07 (d, J=2.15 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CO>[OH:17][C:18]1[CH:19]=[C:20]([NH:21][S:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)(=[O:15])=[O:14])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3,4,5-trimethoxybenzenesulfonyl chloride (500 mg, 1.88 mmol) in methanol (10 mL) was added 3-hydroxy4-methoxyaniline (523 mg, 3.76 mmol) at ambient temperature. After stirring for 1 h, the reaction mixture was concentrated and the crude residue was purified by chromatography over silica to afford 430 mg (62%) of product as fme white needles, m.p. 145-146° C. 1H—NMR (CDCl3): δ9.74 (1H, s), 9.15 (1H, s), 6.98 (2H, s), 6.78 (1H, d, J=8.8 Hz), 6.63 (1H, d, J=2.6 Hz), 6.50 (1H, dd, J=8.8, 2.6 Hz), 3.76 (6H, s), 3.70 (3H, s), 3.68 (3H, s). Anal. Calcd. for C16H19N1O7S: C, 52.03; H, 5.18; N, 3.79; S, 8.68. Found: C, 51.87; H, 5.28; N, 3.76; S, 8.77.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:20][C:18]1[CH:17]=[C:16]([CH3:21])[N:15]=[C:14]([NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=1
Reactant: Cc1cc(C)nc(NC2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)nc(NC2CCNC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.3 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH2:31](I)[CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:31][CH3:32])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.63 g) in N,N-dimethylformamide (15 ml) were added potassium hydroxide (0.16 g) and ethyl iodide (0.66 ml) and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 ml), and was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.39 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(OC)(=O)C(OC)=O>CN(C=O)C>[CH3:1][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: COC(=O)C(=O)OC
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Potassium tert-butoxide was added to a solution of the indole product of Example 61 (354 mg, 1.12 mmol) and dimethyl oxalate (145 mg, 1.23 mmol) in DMF (3 mL) and heated to reflux for 1 h. The mixture was cooled to room temperature and quenched with water (5 mL). After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 20 g, hexanes to 10% EtOAc/hexanes) provide the N-methyl indole product (163 mg, 44%) as a yellow powder: mp 120-124° C.; 1H NMR (500 MHz, CDCl3) δ 7.27-7.24 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 7.01 (d, J=10.4 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.96 (d, J=15.2 Hz, 1H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (s, 3H), 2.99 (dd, J=11.3, 5.2 Hz, 1H), 2.68 (dd, J=11.4, 6.5 Hz, 1H), 2.47 (s, 3H); IR (KBr) 3438, 2943, 2779, 1579, 1488, 1422, 1358, 1266, 1064 cm−1; ESI MS m/z=329 [C19H18ClFN2+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15]C(=O)CC.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:2]([C:3](=[CH2:4])[CH2:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[I:6])[CH3:1]
Reactant: [Li]CCCC
Reactant: CCC(=O)CCCc1ccccc1I
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(CC)CCCc1ccccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (21.76 g, 61 mmol) in dry ether (300 ml) was stirred at 0° C. under nitrogen. To this was added a 1.6M solution of butyl lithium (33.3 ml, 53.3 mmole) dropwise. Stirring at 0° C. was continued for 45 min then a solution of 6-(2-iodophenyl)-3-hexanone (Intermediate 10) (11.5 g, 38 mmol) in dry ether (40 ml) was added dropwise. Stirring at 0° C. was continued for 3 hours after which time aqueous ammonium chloride solution was added and the mixture was extracted with ether. The combined extracts were washed once with a mixture of ammonium chloride and sodium chloride solutions, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was slurried with cyclohexane to extract the crude product. Purification by SPE eluting with cyclohexane gave the title compound as a colourless liquid (6.8 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:32](=[O:33])[NH:31][C:26]3[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(Cl)c(Cl)c3)C2=O)cc1
Reaction time: 4 h

Procedure:
The stirred solution of 4.1 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 75 ml of warm benzene and 2.4 g of triethylamine is combined with the solution of 3.8 g of 3,4-dichlorophenylisocyanate in 50 ml of benzene. After standing at ambient temperature for 4 hours, the benzene is evaporated, the residue taken up in methanol and the solution poured into 100 ml of 0.3 N hydrochloric acid. The mixture is allowed to stand overnight at room temperature, the precipitate is collected, washed with water, dried, triturated with benzene-ethyl acetate and recrystallized from methanol to yield the 1-(p-methoxyphenyl)-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=OCH3, R'=3--Cl and R"=Cl, melting at 120°-125°, resolidifying and remelting at 228°-232° (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]#[N:16])[C:11]([I:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:26]=[C:27]([C:31]3[O:36]C(C)(C)[O:34][C:33](=O)[CH:32]=3)[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][N:22]=[CH:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]#[N:16])[C:11]([I:17])=[CH:10][C:9]=1[NH:18][C:33](=[O:34])[CH2:32][C:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:26]=1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC#N)c(I)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1cc(CC#N)c(I)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-cyanomethyl-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example J6) (363 mg, 0.973 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) (411 mg, 1.52 mmol) according to the general procedure M. Obtained as a yellow oil (523 mg).
Reaction SMILES: [F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([CH3:6])(O)[CH3:4].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([CH3:6])=[CH2:4]
Reactant: CCCCCCCCCCCCCCCCC(F)(F)C(C)(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(F)(F)CCCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A solution of 160 mg of 3,3-difluoro-2-methyl-2-nonadecanol in 2 ml of pyridine containing 50 ul of phosphorous oxychloride is heated at 90° C. then allowed to cool to 50° C. An additional 250 ul of phosphorous oxychloride is added followed by heating at 90° C. for 2 hours. After allowing to stand at ambient temperature for 18 hours, the volatiles are removed and the concentrate partitioned between hexanes and 10% hydrochloric acid. The organic layer is washed with water and 10% sodium bicarbonate then dried and evaporated to a residue which is purified by chromatography on silica gel using hexane to give 140 mg of the desired product as an oil.
Reaction SMILES: C([C:3]1[C:4]([C:10]([OH:12])=O)=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1)C>C(OCC)C>[Br:9][C:7]1[CH:8]=[CH:3][C:4]([C:10]2([OH:12])[CH2:7][CH2:8][CH2:3][CH2:4]2)=[N:5][CH:6]=1
Reactant: CCc1cc(Br)cnc1C(=O)O
Solvent: CCOCC
Product: OC1(c2ccc(Br)cn2)CCCC1

Procedure:
The title compound was prepared using ethyl-5-bromo-2-carboxypyridine, 1,4-bis (bromomagnesium) butane and diethyl ether as solvent, but otherwise followed the general procedure for Preparation 36. 13C NMR (100 MHz, CDCl3) d 164.1, 148.9, 139.5, 120.9, 118.8, 83.2, 42.7, 24.9; MS (AP/Cl) 242.1, 244.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)CC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)CC)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of [4-difluoromethoxy-3-(4-ethanesulfonylbenzyl)-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.080 g), methanol (2.0 mL), tetrahydrofuran (2.0 mL), water (2.0 mL) and lithium hydroxide (0.006 mg) was stirred at room temperature for 45 minutes. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water to afford title compound as an off-white solid, 0.025 g.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][C:18]([C:20]1[CH2:25][C@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([NH:34][C:35](=[O:37])[CH3:36])[C@H:22](O)[CH:21]=1)=[O:19])[CH3:16].CCN(CC)CC.CCCCCC.C(OCC)(=O)C>ClCCl>[C:35]([N:34]1[C@@H:22]2[C@H:23]1[C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[CH:21]2)(=[O:37])[CH3:36]
Reactant: CCOC(=O)C1=C[C@@H](O)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C1=C[C@H]2[C@@H]([C@@H](NC(=O)OC(C)(C)C)C1)N2C(C)=O
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a cooled (4° C.) solution of PhMe2P (71 mg; 0.52 mmol) in dichloromethane (1 mL) was added dropwise during 1 min DIAD (104 mg; 0.52 mmol). After additional 5 min of stirring a solution of alcohol 12 (84 mg; 0.24 mmol) and Et3N (7 μL; 0.05 mmol) in dichloromethane (1 mL) was added dropwise. After 10 min the reaction mixture was directly loaded on a silica column. Chromatography [hexane-ethyl acetate (3:1)→(2:1), 6 ml silica] afforded 53 mg (70%) of aziridine 13 as a colourless oil with trace amounts of 14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.Cl.C(O)CCCCCCC.[Sn]>O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CCCCCCCCO
Product: Nc1ccc(O)cc1F
Yield: 95.3 %

Procedure:
The 14 g (0.09 mol) of 3-fluoro-4-nitrophenol from above was combined with 55 mL (0.66 mol) of concentrated HCl, 55 mL of H2O, and 0.5 mL of octanol and stirred mechanically. To this mixture was added 33 g (0.28 mol) of mossy tin and the mixture was heated on a steam bath to initiate the reaction. After the reaction had subsided (8-10 minutes), 92 mL of concentrated HCl in 160 mL of water was added. The reaction was stirred on the steam bath for 1/2 hour and filtered hot. The filtrate was cooled and made basic with solid sodium bicarbonate. The resulting salts were filtered off and washed with ethyl acetate. The filtrate was extracted three times with ethyl acetate; all of the ethyl acetate extracts were combined, washed twice with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was stripped in vacuo and the resulting residue dissolved and stripped twice with toluene then ethanol then acetonitrile. The solid residue was triturated in hexane, filtered and washed to yield 10.9 g (96%) of 4-amino-3-fluorophenol, mp 138°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13].[CH2:20]([Mg]Br)[CH2:21][CH3:22].[Mg].C(Br)CC.[Cl-].[NH4+].[OH-].[Mg+2].[OH-]>CCOCC>[CH3:13][N:12]([CH3:14])[CH2:11][C:10]([C:6]1[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[F:1])[CH:9]=[CH:8][CH:7]=1)([OH:15])[CH2:20][CH2:21][CH3:22]
Reactant: CCC[Mg]Br
Reactant: CN(C)CC(=O)c1cccn1Cc1ccccc1F
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CCCBr
Solvent: CCOCC
Product: CCCC(O)(CN(C)C)c1cccn1Cc1ccccc1F
Temperature: 0 °C

Procedure:
A solution of 11.0 g of 1-(o-fluorobenzyl)-2-(dimethylaminoacetyl)pyrrole, free base of Example 3a, in ether is added dropwise to a stirring solution of n-propylmagnesium bromide which is prepared from 1.67 g of magnesium turnings and 8.4 g of n-propylbromide. The mixture is refluxed for 4 hours, allowed to cool, hydrolized with ice-water and treated with concentrated ammonium chloride solution to dissolve the magnesium hydroxide precipitate. The organic phase is separated and the aqueous phase extracted with ether and the organic phases are combined, washed with a 5% sodium bicarbonate solution and water and dried. Removal of the ether leaves a crude yellow oil which is distilled at 133°-137° C./0.08 mm gives a light yellow oil of 1-(dimethylamino)-2-[1-(o-fluorobenzyl)-2-pyrryl]-2-hydroxypentane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2ccc(Br)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To 200 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 0.5 mL of iodomethane, 200 mg of K2CO3 and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 185 mg (88% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.