Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:6](=[C:8]([CH:14]=[O:15])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:7]=1)#[N:2].C(O)(=[O:18])C.S(=O)(=O)(O)N.Cl([O-])=O.[Na+]>O>[C:1]([C:3]1[O:4][C:5]2[C:6](=[C:8]([C:14]([OH:18])=[O:15])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:7]=1)#[N:2]
Reactant: CC(=O)O
Reactant: COc1ccc(C=O)c2cc(C#N)oc12
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: COc1ccc(C(=O)O)c2cc(C#N)oc12

Procedure:
A mixture of Compound IIi (0.2 g) obtained in Reference Example 9, a 80% aqueous solution (2 ml) of acetic acid, sulfamic acid (0.145 g), and a 80% aqueous solution (0.084 g) of sodium chlorite was stirred at room temperature one night. The mixture was diluted with water, and then the precipitated solid was collected by filtration and dried to give Compound IIab (0.259 g, 83%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:32])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A suspension of 2-(7-fluoro-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (1.170 g, 3.75 mmol) and Lawesson's reagent (1.516 g, 3.75 mmol) in toluene (40 mL) was heated at reflux for 3 h then cooled to ambient temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column on silica gel (eluting with 0%˜10% EtOAc in petroleum ether) to give 2-(7-fluoro-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a light yellow solid (1.05 g, 85%). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (d, J=6.8 Hz, 1H), 7.43 (d, J=11.6 Hz, 1H), 6.16 (brs, 1H), 5.07 (s, 2H), 4.02-4.10 (q, J=7.2 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[Mg].Cl[CH:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]1=2>O1CCCC1.C1C=CC=CC=1.O>[CH:22]1[C:13]2[CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:12]=2[CH:25]=[CH:24][CH:23]=1
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
A Grignard solution prepared from 13.4 grams (0.1 mole) of 1-methyl-4-chloropiperidine, 2.43 grams (0.1 gram atom) of magnesium and 100 milliliters of tetrahydrofuran is added dropwise with stirring to a cooled solution of 17.0 grams (0.075 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 100 milliliters of tetrahydrofuran. After completion of the addition, stirring is continued for several hours at ambient temperature. The solvent is then vaporized under reduced pressure to obtain a residue which is dissolved in a biphasic mixture of benzene and water. The benzene solution is washed, dried filtered and the solvent vaporized as previously described to obtain the desired 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine, equational isomer as residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[OH-].[NH4+:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and aqueous ammonium hydroxide at about −5° C. to about −60° C. to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH2:6].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:4]([F:3])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(F)cc1Br

Procedure:
A solution of bromine (16.0 g; 0.10 mol) in glacial acetic acid (25 ml) is added dropwise to a solution of 2,4-difluoroaniline (12.9 g; 0.10 mol) in glacial acetic acid (75 ml) while maintaining the temperature of the reaction mixture below 25° C. The reaction mixture is stirred an additional 0.5 hour during which time a solution of sodium acetate (5.48 g; 0.137 mol) in water (100 ml) is added. The reaction mixture is then diluted with water (300 ml), the precipitated purple solid is filtered, washed with water (100 ml) and dried under vacuum.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=O)[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>CCO>[N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[N:2][OH:3])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc2ncccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a suspension of hydroxylamine hydrochloride in EtOH (150 mL) was added a suspension of NaOH (2.4 g, 59.7 mmol) in EtOH (25 mL). The reaction mixture was stirred at ambient temperature for 15 minutes. The precipitated sodium hydrochloride was filtered off. A solution of 1-quinolin-6-yl-ethanone (9.3 g, 54.25 mmol) in EtOH (150 mL) was added. The reaction solution was stirred for 16 hours at ambient temperature. EtOH was removed in vacuum to give 1-quinolin-6-yl-ethanone oxime (10.1 g, >99% yield).
Reaction SMILES: [N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C.CS(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>CC(C)=O>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: C1=CCN=c2ccccc2=C1
Reactant: CS(=O)(=O)OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CN1C=CC=Cc2ccccc21
Temperature: 25 °C
Yield: 119.5 %

Procedure:
To a solution of the 2H-benzazepine (80 mg, 0.26 mmol) from step J above in acetone (5 mL) were added triethylamine (0.06 mL, 0.43 mmol), N,N-diisopropylethylamine (0.025 mL, 0.26 mmol) and 2,2,2-trifluoroethyl methanesulfonate (60 mg, 0.26 mmol). The reaction solution was heated under reflux for 1 hour and then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by flash column chromatography (90:10 to 80:20 hexanes/ethyl acetate) to give the N-trifluoroethyl benzazepine (70 mg, 69%) as a white foam: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.72 (s, 1H), 6.67-6.50 (br, 2H), 4.29 (d, J=8.0 Hz, 1H), 4.19-4.07 (br, 1H), 3.90 (d, J=15.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.32-3.26 (br, 2H), 3.16-3.12 (m, 4H), 3.03-2.89 (m, 2H), 2.26-2.19 (m, 1H), 2.09-2.00 (m, 1H). To a solution of the N-trifluoroethyl benzazepine (65 mg, 0.17 mmol) in methanol (2 mL) were added maleic acid (19 mg, 0.17 mmol) and water (10 mL). The resultant solution was lypholized overnight to give 4-(5-phenyl-2-(2,2,2-trifluoroethyl)-2,3,4,5,-tetrahydro-1H-benzo[c]-azepin-8-yl)morpholine, maleate salt (84 mg, >99.0% AUC HPLC) as a light pink solid: 1H NMR (CD3OD, 500 MHz) δ 7.32 (t, J=7.5 Hz, 2H), 7.23 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.84 (d, J=2.5 Hz, 1H), 6.75 (d, J=6.5 Hz, 1H), 6.71-6.54 (br, 1H), 6.30 (s, 2H), 4.35 (d, J=7.5 Hz, 1H), 4.21-4.04 (br, 1H), 3.92 (d, J=15.0 Hz, 1H), 3.84 (t, J=5.0 Hz, 4H), 3.29-3.25 (m, 2H), 3.22-3.07 (m, 6H), 2.34-2.27 (m, 1H), 2.06 (d, J=13.5 Hz, 1H); ESI MS m/z 391 [M+H]+.
Reaction SMILES: BrC1C[C@@H](C)CO[C@@]21[C@@H](C)[C@@H]1[C@]3(C)[C@@H](C[C@@H]1O2)[C@H]1[C@@H]([C@]2(C)[C@@H](CC1)C[C@@H](O)CC2)[C@@H](O)[C@@H]3O.[Br:34][CH:35]1[CH2:71][C@@H:70]([CH3:72])[CH2:69][O:68][C@@:36]21[C@@H:40]([CH3:41])[C@@H:39]1[C@:42]3([CH3:67])[C@@H:55]([CH2:56][C@@H:38]1[O:37]2)[C@H:54]1[C@@H:45]([C@:46]2([CH3:58])[C@@H:51]([CH2:52][CH2:53]1)[CH2:50][C@@H:49]([OH:57])[CH2:48][CH2:47]2)[C@@H:44](O)[C@@H:43]3[O:60]C(=O)C(Cl)(Cl)Cl.[OH-].[Na+]>O.C(O)C>[Br:34][CH:35]1[CH2:71][C@@H:70]([CH3:72])[CH2:69][O:68][C@@:36]21[C@@H:40]([CH3:41])[C@@H:39]1[C@:42]3([CH3:67])[C@@H:55]([CH2:56][C@@H:38]1[O:37]2)[C@H:54]1[C@@H:45]([C@:46]2([CH3:58])[C@@H:51]([CH2:52][CH2:53]1)[CH2:50][C@@H:49]([OH:57])[CH2:48][CH2:47]2)[C@H:44]1[O:60][C@@H:43]31
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H]5O[C@H]5[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1

Procedure:
The following procedure is a variation of that described in Helv. Chim. Act., 1953, 36, 1241. (3β,5α,11α,12β,25R)-11,23-dibromospirostan-3,12-diol (18.08 g) was dissolved in pyridine (500 mL) at room temperature and treated with silver oxide (70.0 g). The resulting mixture was stirred in the dark for 71 hours. The mixture was filtered and the solid washed with ether and then chloroform. These washes were combined with the filtrate and concentrated. The resulting solid was purified by flash chromatography (1:1 hexane:ethyl acetate) to give 12.2 g of a 1:1 mixture of the title compound and (3β,5α,25R)-23-bromospirostan-3-ol-12-one. Further chromatography (7:3 hexane:ethyl acetate) provides pure title compound. (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11 -diol: Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α, 11β,12β,25R)-23-bromo-11,12-epoxyspirostan-3-ol was treated with trichloroacetic acid in toluene at room temperature for 3 days to give the title compound. (3β,5α, 11β,12α,25R)-23-bromo-spirostan-3,11,12-triol: Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11-diol was saponified with sodium hydroxide in water and ethanol to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: CC(=O)Nc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of N-(3,4-difluorophenyl)acetamide (48 g) in concentrated sulfuric acid (140 ml) was added dropwise concentrated nitric acid (d 1.42, 56 ml) at -1° to 3° C. during 50 minutes with stirring in an ice-salt bath. After stirring for 1.5 hours at 3° to 16° C., the reaction mixture was poured into ice water (560 ml). The resulting precipitate was collected by filtration, washed with chilled water sufficiently to give N-(4,5-difluoro-2-nitrophenyl)acetamide (55.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][N:31]=4)=[C:25]([CH:28]=3)[C:26]#[N:27])[NH:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Yield: 35.5 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.20 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (80 mg, 0.26 mmol, 1.3 eq) were heated at 130° C. (sealed bottle) in 500 μl of absolute ethanol for 24 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP—NH column and DCM/10% MEOH in DCM solvent system (gradient 10-80% of 10% MeOH in DCM in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with hexane to obtain 5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (36 mg, yield=32.4%, purity=92%) in form of tain coloured powder. MS: [M+H]+=508.40. 1H NMR (300 MHz; CDCl3) δ/ppm 2.64 (s, 3H), 2.94 (t, J=7.23 Hz, 2H), 3.53 (s, 2H), 3.57-3.66 (m, 2H), 7.14-7.23 (m, 2H), 7.51 (d, J=8.37 Hz, 2H), 7.55-7.64 (m, 2H), 7.96 (d, J=8.60 Hz, 1H), 8.34 (s, 1H), 8.50 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14]([CH3:30])=[N:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:38])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:38][CH2:30][C:14]1[C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][O:11][C:12]=2[C:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(CBr)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Ethyl 3-(4-methoxyphenyl)-4-methyl-7-(pivaloyloxy)isoxazolo[4,5-c]pyridine-6-carboxylate (58 mg, 0.14 mmol), NBS (28 mg, 0.15 mmol) and benzoyl peroxide (3.4 mg, 0.014 mmol) were added to 3 mL of carbon tetrachloride. The mixture was refluxed for 16 h. After the mixture was cooled to room temperature, another 1 equiv of NBS and 0.1 equiv of benzoyl peroxide were added, and the reaction mixture was refluxed for an additional 16 h. After the mixture was cooled, 20 mL of CH2Cl2 and 1 g of silica gel were added, and the solvent was removed in vacuo. The crude was purified by flash chromatography (0-30% EtOAc/hexanes) to give 34 mg of the title compound. MS: (+) m/z 491.28, 493.25 (M+1, 79Br/81Br).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15][CH:14]=1>ClCCl>[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N+:16]([O-:6])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1CCCC2
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c2c1CCCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred suspension of 3-chloroperoxybenzoic acid (34 g, 197 mmol) in dichloromethane (170 ml) at 0° was treated dropwise with 5,6,7,8-tetrahydro-4-methylquinoline (23.7 g, 161 mmol) in dichloromethane (30 ml), warmed to room temperature, washed with 1N-NaOH (3×200 ml), and extracted with dichloromethane (5×150 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (21 g) as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:10]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:13][C:12]([O:11][CH2:9][CH3:10])=[O:33])=[CH:3][CH:4]=1
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccncc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
A mixture of isonicotinaldehyde (25 g), ethyl(triphenylphosphoranylidene)acetate (82 g) and toluene (300 ml) is stirred for 3 hours at 100° C. After cooling, the crystals that precipitated are removed by filtration, and the filtrate is concentrated in vacuo. The residue is dissolved in a mixture of ethyl acetate and petroleum ether (1:1, 400 ml), and the resulting solution is extracted with 5% hydrochloric acid (500 ml). The aqueous layer is extracted with ethyl acetate (50 ml) and neutralized with potassium carbonate. After cooling, the resulting crystals are collected by filtration and dried to give ethyl 3-(4-pyridyl)acrylate (34 g) as colorless prisms, mp 64°-66° C.
Reaction SMILES: [C:1](=[NH:9])([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18]([N:9]=[C:1]([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCCC(=N)OCC
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=NC(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of 6.5 g (50.3 mmole) of ethyl valerimidate (free base) in 90 ml of dry CH2Cl2 was treated with 7.71 ml (5.60 g, 55.3 mole) of triethylamine. The resulting solution was stirred under N2 at -10° C. in an ice-salt bath as a solution of 4.81 ml (5.46 g, 50.3 mole) of ethyl chloroformate in 10 ml of CH2Cl2 was added dropwise over 25 minutes. Upon completion of the addition, the cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. Next, the solvent was removed by evaporation in vacuo. The residue was taken up in hexane and filtered to remove triethylamine hydrochloride. Concentration of the filtrate yielded 7.08 g (70%) of the product as a yellow oil, suitable for use in the next step without further purification. NMR indicated a mixture of syn and anti isomers. TLC (98:2 CH2Cl2 --MeOH) showed a close pair of spots, Rf 0.48, 0.52; mass spectrum (EI) m/e 201 (M+).
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1>>[CH3:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][C:22]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cc1coc2ccccc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)oc2ccccc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 3-methyl-benzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:21][OH:22])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])(=[O:11])=[O:10])[CH:7]=1.O.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:21][O:22][CH2:24][N:8]([S:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][CH3:20])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(Br)ccc1CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCOCC
Solvent: CCCCCCC
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 871 %

Procedure:
A mixture of N-(5-bromo-2-hydroxymethyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide (2.51 g, 6.17 mmol), toluene-4-sulfonic acid monohydrate (117 mg, 0.617 mmol), and formaldehyde diethyl acetal (15.5 mL) was heated under reflux at 100° C. for 16 h. After cooling, heptane was added to the suspension, which was stirred for 15 min. The precipitate was collected by filtration and dried to afford 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.25 g, 87%). Off-white solid, MS (ISP)=418.1 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+:11]([O-])([O:13]C(C)C)=[O:12].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:4][C:3]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: O=C(O)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
To a stirred suspension of salicylic acid (0.69 g, 5 mmol) in dichloromethane (10 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.69 mL) was then added dropwise to the mixture which was allowed to stir at room temperature for thirty minutes (became a yellow solution, followed by formation of a yellow precipitate) and then poured onto water (50 mL). The yellow precipitate was filtered off and then triturated with water (10 mL). The insoluble material was filtered off and dried to afford yellow crystals, (0.42 g, 46%) of m.p. 121–122° C. identified by NMR as the title compound (lit. m.p. 123° C., Merck Index No. 6553). The mother liqours were concentrated on a rotary evaporator (60° C., water aspirator pressure) and recrystallised from a dichloromethane/petroleum ether mixture to give yellow/orange crystals (0.35 g, 39%) of m.p. 226–228° C., identified by NMR as 2-hydroxy-5-nitrobenzoic acid (5-nitrosalicylic acid) (lit. m.p. 228–230° C., Merck Index No. 6554). (85% combined yield, Ortho:Para selectivity, 1.2:1)
Reaction SMILES: [Cl-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([C:39]([C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=O)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>C1COCC1>[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([C:39]([C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[CH2:2])=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(C(=O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc([N+](=O)[O-])cc1)c1ccnc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of methyltriphenylphosphonium chloride (0.54 g, 1.7 mmol) in THF (10 mL) at −78° C. was added n-butyllithium, 2.5 M in hexanes (0.80 ml, 2.0 mmol). After 20 min, a mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone (0.177 g, 0.57 mmol) in THF (5 mL) was slowly added. After 10 min, the mixture was allowed to warm to RT. The reaction was quenched with saturated aqueous NH4Cl. The mixture was diluted with EtOAc and washed with water and brine. After drying the organic fraction with Na2SO4, the solvent was removed in vacuo and the residue purified by silica gel chromatography using 40-100% hexanes:EtOAc to afford 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline as a yellow foam. MS: M+H+=307.1.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][CH2:18][C:12]3=[N:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1)#[N:2]>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[NH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:23][CH:24]=1)#[N:2]
Reactant: N#Cc1ccc(CN2C(=O)C3CCCC3=Nc3ccccc32)cc1
Solvent: CCOCC
Product: N#Cc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Yield: 65 %

Procedure:
Employing 9-(4-cyanobenzyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized by substantially the same procedure as in Reference Example 15. Yield 65%. m.p.224°-226° C. (decomp.) (diethyl ether).