Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][CH2:34][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,3-dibromopropane (2.85 ml) were added to dimethylformamide (5 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a white solid. Yield: 1.0 g (50%).
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[OH-].[Na+].[Na+].[CH3:35][S:36]([O-:38])=[O:37]>[Cu]I.CS(C)=O>[CH3:35][S:36]([C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1)(=[O:38])=[O:37]
Reactant: CS(=O)[O-]
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(I)ccc12)C(C)(C)C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(S(C)(=O)=O)ccc12)C(C)(C)C
Temperature: 95 °C
Reaction time: 24 h

Procedure:
9-Iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (130 mg, 0.31 mmol), copper(I) iodide (5.9 mg, 0.031 mmol), L-proline (7.1 mg, 0.062 mmol), sodium hydroxide (2.5 mg, 0.062 mmol), and methanesulfinic acid sodium salt (41 mg, 0.40 mmol) were combined in a vial. DMSO (2.0 ml) was added, and the resulting suspension was purged with argon (subsurface bubbling) for 5 min. The reaction mixture was stirred at 95° C. for 24 h. The crude material was precipitated out of solution by adding 2 mL of MeOH, followed by 1.5 mL of water. The solids were collected by vacuum filtration, and purified by preparative reverse phase HPLC, eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient, to afford 9-(methylsulfonyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6) δ 11.33 (br s, 1H), 10.45 (s, 1H), 8.74 (d, 1H), 8.01 (dd, 1H), 7.59 (br d, 1H), 7.36 (d, 1H), 6.36 (d, 1H), 4.71 (pentet, 1H), 3.25 (s, 3H), 1.17 (d, 3H), 0.93 (s, 9H). LRMS (ESI) calc'd for (C19H23N3O3S) [M+H]+, 374.1; found 374.1.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[NH:6]1)=[O:4]>CS(C)=O>[C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)CCC(=O)O)c2c(Cl)cc(Cl)cc2N1
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21

Procedure:
This compound was prepared by the method given for Example 36, step b, using trans-2-methoxycarbonyl-5,7-dichloro-4(2-carboxyethyl)carbonylamino-1,2,3,4-tetrahydroquinoline in place of trans-2-methoxycarbonyl-5,7-dichloro-4-butylcarbonylamino-1,2,3,4-tetrahydroquinoline to give the title compound as colourless crystals, m.p. 221°-223° C. δ DMSO, 360 MHz) 1.59 (1H, ddd, J=13.2, 12.9 and 3.8 Hz, CHACHBHCCHD), 2.15 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 2.31 (2H, t, J=6.7 Hz, COCHE2CHF2CO), 2.41-2.45 (2H, m, COCHE2CHF2), 3.83 (1H, dd, J=12.5 and 2.6 Hz, CHACHBHCCHD), 5.01 (1H, m, CHACHBHCCHD), 6.64 (1H, d, J=2.0 Hz, 6-H or 8 -H), 6.75 (1H, br s, ArNHCH), 6.87 (1H, d, J=2.0 Hz, 6-H or 8-H), 8.16 (1H, d, J=7.2 Hz, NHCO); m/e 342 (M-H2O), 198 (100% M-NHCO(CH2)2CO2H, CO2H,H); Found C, 46.59; H, 4.02; N, 7.57; C14H14Cl2N2O5 requires C, 46.56; H, 3.91; N, 7.76%.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=2)[N:4]=[CH:3]1.N1C=CC=CC=1.[C:26]1(=[O:41])[N:30]([CH2:31][CH2:32][C:33](Cl)=O)[C:29](=[O:36])[C:28]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:27]12.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([N:4]2[CH:3]=[N:2][N:1]=[C:33]2[CH2:32][CH2:31][N:30]2[C:29](=[O:36])[C:28]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:27]3[C:26]2=[O:41])=[C:10]([CH:9]=1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline (2.74 g. 0.01 mole) in dry tetrahydrofuran (150 ml.) is cooled in an ice bath, under nitrogen, and treated with dry pyridine (1.77 ml., 0.022 mole). This mixture is then treated dropwise, during 1 hour with a solution of β-phthalimidopropionyl chloride (5.23 g., 0.022 mole) in tetrahydrofuran (25 ml.). The mixture is kept in the ice bath for 1 hour and at ambient temperature for 4 hours. It is then poured into cold, dilute aqueous sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is mixed with toluene (165 ml.), treated with trifluoroacetic acid (0.732 ml.) and warmed, under nitrogen at 100°-110° C. for 1.5 hours. The mixture is concentrated in vacuo and the residue mixed with cold water and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (300 g) with 1.5% methanol-98.5% chloroform. The product thus obtained is crystallized to give 5-chloro-2-[3-(2-phthalimidoethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: N#N.CC1[N:5]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:27][CH2:26]4)=[CH:19][CH:18]=3)[N:11]=2)C(C)=CC=1.Cl.NO.[2H]C(Cl)(Cl)Cl.CO[2H]>CCOCC.C(O)C.O>[CH2:31]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:12]3[N:11]=[C:10]([NH2:5])[CH:15]=[C:14]([CH3:16])[CH:13]=3)=[CH:18][CH:19]=2)[CH2:30][CH2:29]1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(-c2ccc(CCN3CCN(CCc4ccccc4)CC3)cc2)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: N#N
Agent: NO
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1cc(N)nc(-c2ccc(CCN3CCN(CCc4ccccc4)CC3)cc2)c1

Procedure:
6-(4-(2-(Phenethylpiperazin-4-yl)ethyl)phenyl)-4-methyl-pyridinyl-2-amine: To a 100 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 165 mg (0.345 mmol) 2-(2, 5-dimethylpyrrol-1-yl)-4-methyl-6-(4-(2-(phenethylpiperazin-4-yl)ethyl)phenyl)-pyridine, 120 mg (1.726 mmol) hydroxylamine hydrochloride, 1 mL water, and 5 mL ethanol. The reaction was refluxed 14 hr, cooled, evaporated, and taken up in ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford an oil, which was converted to the hydrochloride salt using 1 N HCl in ether to give 18 mg (10%), mp 242-250° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([O:11]C)=[O:10])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2sc3c(c2c(-c2ccc(C(F)(F)F)cc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 56.3 %

Procedure:
1 M Aqueous sodium hydroxide solution (1.6 mL, 1.6 mmol) was added to a solution of (S)-methyl 2-(tert-butoxy)-2-(2-methyl-4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (75 mg, 0.15 mmol) in 1:1 tetrahydrofuran/industrial methylated spirit (4 mL) at room temperature. The resulting mixture was heated at 60° C. 1.5 h. The resulting solution was concentrated in vacuo and the residue was dissolved in water (10 mL). The aqueous solution was adjusted to pH 4 by the addition of 2 M aqueous hydrochloric acid solution and the resulting suspension was extracted with dichloromethane (20 mL). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product as a pale yellow solid. This was purified by flash column chromatography on silica eluting with methanol in dichloromethane (5%) to give the title compound (40.3 mg, 56%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ=1.01 (s, 9H), 1.89-1.30 (m, 6H), 2.71 (s, 3H), 2.90-2.75 (m, 2H), 5.02 (s, 1H), 7.48-7.34 (m, 1H), 7.90-7.64 (m, 3H). LCMS (run time=5 minutes, basic): Rt=3.30 minutes; m/z 478.01 [M+H+].
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:37](=[O:39])[C:36]2[CH:40]=[C:41]([CH:42]3[CH2:43][CH2:44]3)[C:33]([O:32][C@@H:26]3[CH2:27][C@H:28]4[CH2:31][C@@H:25]3[CH2:30][CH2:29]4)=[CH:34][C:35]=2[F:45])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 79 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with azetidine-1-sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.11 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz, 1H), 4.82-4.73 (m, 1H), 4.00 (t, J=7.6 Hz, 4H), 2.60-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.18-2.05 (m, 3H), 2.04-1.93 (m, 1H), 1.91-1.80 (m, 1H), 1.61-1.49 (m, 1H), 1.46-1.17 (m, 4H), 0.98-0.81 (m, 3H), 0.68-0.60 (m, 2H); MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[C@H:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:23]1([S:20]([N@@:19]2[CH2:17][CH:16]2[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:29])(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H](CO)NS(=O)(=O)c3ccccc3)CC2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@]3S(=O)(=O)c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, N-{(R)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide was reacted with triphenylphosphine and diethylazodicarboxylate to give ((R)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:19][C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: N#CC=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccc2)C(c2ccccc2)C1
Reaction time: 0.08 h

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 40.0 ml. of phenylhydrazine is added followed in 5 minutes by 48.0 ml. of cinnamonitrile. The reaction mixture is refluxed for 3 hours with exothermic crystallization of a product. The product is collected by filtration and washed with water. The material is recrystallized from absolute ethanol to give 56.0 g. of the desired product as a solid, m.p. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)OC(C)(C)C)=[C:4]([CH3:16])[CH:3]=1.[CH:17]([Li])([CH2:19][CH3:20])[CH3:18].CON(C)C(=O)C(C)CC.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:16]2
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Reactant: [Li]C(C)CC
Agent: CCC(C)C(=O)N(C)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)c1cc2cc(Cl)ccc2[nH]1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (4-chloro-2-methylphenyl)carbamate (338 mg) in tetrahydrofuran (6 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 2.69 mL) at −70° C. under an argon atmosphere. The mixture was warmed to −40° C. and then stirred for 10 minutes. Then a solution of N-methoxy-N,2-dimethylbutanamide (203 mg) in tetrahydrofuran (0.5 mL) was added dropwise, and the mixture was stirred at −40° C. for 40 minutes. The mixture was stirred at room temperature for additional 2 hours. 1 mol/L Hydrochloric acid (2.8 mL) was added to the reaction mixture under cooling with ice, and this resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (446 mg) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.8 mL) was added and this resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane, washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (173 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([O:24]CC)=O.O.[NH2:31][NH2:32]>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([NH:31][NH2:32])=[O:24]
Reactant: CCOC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Reactant: NN
Solvent: CCOCCO
Solvent: O
Product: NNC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Temperature: 115 °C
Yield: 31.2 %

Procedure:
A solution of Example 26 (200 mg, 0.49 mmol) in 2-ethoxyethanol (3 ml) was treated with hydrazine hydrate (0.10 ml, 2.04 mmol) and heated at 115° C. overnight. The reaction mixture was concentrated in vacuo. Purification by chromatography (10%-50% EtOAc in DCM, silica) gave the title compound (60 mg, 31%). δH (d3-MeOD) 7.81 (1H, d, J 9.6 Hz), 7.55-7.41 (3H, m), 7.34-7.31 (2H, m), 7.21-7.13 (2H, m), 7.06 (1H, s), 6.99-6.95 (1H, m), 6.42 (1H, d, J 9.6 Hz), 6.17 (1H, s), 5.76 (2H, s). LCMS (ES+) RT 2.78 minutes, 393 [35Cl]:395 [37Cl] 3:1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[C:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(=O)c1cc2c(cc1F)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(C(C)=O)cc21
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a mixture of 6-acetyl-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (12 g, 57.4 mmol) and K2CO3 (11.89 g, 86 mmol) in acetone (120 mL) was added ethyl 2-bromopropanoate (23.6 mL, 172 mmol) and the mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give ethyl 2-(6-acetyl-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate as a gray solid (13.2 g, 74.4%). 1H-NMR (CDCl3, 400 MHz): δ 7.40 (d, J=6.4 Hz, 1H), 6.80 (d, J=10.8 Hz, 1H), 5.24 (q, J=11.2 Hz, 1H), 4.66 (q, J=15.2 Hz, 2H), 4.23 (m, 2H), 2.60 (d, J=5.2 Hz, 3H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N:7]#[C:8][C:9]#N.Cl>>[CH3:1][N:2]1[C:6]([CH2:9][C:8]#[N:7])=[CH:5][CH:4]=[CH:3]1
Reactant: Cn1cccc1
Reactant: N#CC#N
Agent: Cl
Product: Cn1cccc1CC#N
Temperature: 25 °C
Yield: 14.3 %

Procedure:
N-methylpyrrole (4 g, 0.049 mole) is dissolved in 40 ml of dry (ethanol-free) chloroform in a dry, 200 ml, 3-necked round-bottomed flask and flushed with a stream of dry nitrogen. The temperature of the solution is lowered to 0° C and cyanogen (3.25 g, 0.063 mole) is added. Hydrogen chloride (dried through sulfuric acid) is introduced in a slow steady stream with mechanical stirring at 0° C for 4 hrs at which time all the N-methylpyrrole has been consumed. The hydrogen chloride flow is stopped; the chloroform is evaporated to 1/2 its volume at reduced pressure and room temperature; and the temperature is then lowered to -40° C. Dry pyridine (25 ml) is added dropwise with rapid stirring. The rest of the chloroform is evaporated at reduced pressure and then 25 mls of additional pyridine is added. The reaction mixture is allowed to warm to room temperature and hydrogen sulfide is introduced in a slow stream for 20 minutes. Chloroform (200 ml) is added and the reaction solution is washed with 35% aqueous potassium carbonate solution, followed by a 3N hydrochloric acid wash which is backwashed with chloroform. The combined chloroform extracts are washed with 5% aqueous sodium bicarbonate solution and dried over anhydrous MgSO4 powder. The mixture is filtered and the filtrate evaporated in vacuo to a brown oil. The oil is distilled under high vacuum to give 840 mg of N-methylpyrrole-2-acetonitrile, bp 61°-65° C at 0.04 Torr.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][O:36][CH3:37]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH2:34][CH2:35][O:36][CH3:37])[CH2:27][O:26][C:25]5=[O:31])=[CH:22][CH:23]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Reactant: COCCBr
Product: COCCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 43.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (655 mg) described in Example 299 and 1-bromo-2-methoxyethane (250 mg), the title compound (323 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[NH4+]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)C(Br)CC
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To 500mL of dry N,N-dimethylformamide was added 159 g (0.250 mol) sodium diatrizoate and 54.5 g (0.280 mol) of ethyl 2-bromobutyrate. The mixture was heated on a steam bath for 20 h, cooled to room temperature and poured into 3L of dilute ammonium hydroxide. The solid was filtered, washing with water, and air-dried. The solid was further purified by crystallization from 50% aqueous ethanol (after treatment with decolorizing carbon) affording two crops which were dried at 100° C. overnight to afford 121 g (66%) of a white powder, m.p. 288°-290 ° C. (dec.). Analysis for C17H19I3N2O6 : Calculated/Found: C,28.05/28.36/H,2.63/2.55;I,52.3/52.3
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1C(F)(F)F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and phenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.1, 29.5, 42.8, 60.2, 125.1, 126.6, 127.2, 127.4, 129.2, 130.8, 132.5, 137.1, 138.3 and 144.0.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:22])(=O)=O.[OH-].[K+]>CC(C)=O>[CH3:22][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccccc1)c1cccc2cc[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1ccc2cccc(C(=O)c3ccccc3)c21

Procedure:
A mixture of 8.57 g. (38.8 mmoles) of 7-benzoylindole, 5.38 g. (42.7 mmoles) of dimethyl sulfate and 5.12 g. of 85% potassium hydroxide in 40 ml. of acetone was heated to reflux for 75 minutes. The mixture was poured into 500 ml. of water and extracted with methylene chloride. The organic phase was separated, dried and concentrated. The residue was chromatographed on silica gel using methylene chloride-hexane as the eluant. The fractions containing the product were combined and concentrated to dryness, 6.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([O:34][CH3:35])(=[O:33])[C@H:30]([CH3:32])O.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C@H:30]([CH3:32])[C:29]([O:34][CH3:35])=[O:33])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)[C@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1ccc(Cl)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-chlorophenol (10.0 g, 69 mmol), triphenylphosphine (1.3 eq, 22 g), (S)-methyl lactate (1.3 eq, 9.4 mL) in DCM (230 mL) at 0° C. was added DEAD (1.2 eq, 13 mL) over 1 min. Reaction warmed to rt overnight. The mixture was then filtered through a pad of silica gel and concentrated. The residue was purified via flash chromatography eluting with 10% EtOAc/hexanes to provide the product as a colorless oil.