Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.[Cl-].C(=O)([O-])[O-:15].[K+].[K+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)=[N:4][CH:3]=1
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(Br)cc2[nH]1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a mixture of 3-bromo-1,5-naphthyridine-5-oxide (C-3) (70.0 g, 311 mmol, 1.0 eq) and 4-toluolsulfonyl chloride (71.16 g, 373 mmol, 1.2 eq) in CHCl3 (1200 mL) was added a solution of potassium carbonate (146 g, 1056 mmol, 3.4 eq) in H2O (500 mL) at RT. The resulting mixture was stirred overnight and diluted with H2O (500 mL). The solid was collected by filtration, washed with water, dried in vacuo to afford the desired product 7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (28.8 g, 41.2% yield). 1H NMR (300 MHz, DMSO-d6) δ: 11.90 (bs, 1H), 8.51 (s, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 6.74 (d, J=9.6 Hz, 1H); ESI-MS m/z: 225.1 [M+H]+.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[CH2:13][C@H:14]([NH3+:27])[C@@H:15]([OH:26])[CH2:16][C@H:17]([C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:31]1[C:41]2[CH:40]=[C:39]([C:42](O)=[O:43])[C:38]3[CH:45]=[CH:46][CH:47]=[CH:48][C:37]=3[O:36][C:35]=2[CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[CH2:13][C@H:14]([NH:27][C:42]([C:39]1[C:38]2[CH:45]=[CH:46][CH:47]=[CH:48][C:37]=2[O:36][C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:41]=2[CH:40]=1)=[O:43])[C@@H:15]([OH:26])[CH2:16][C@H:17]([C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]([NH3+])Cc1cccc(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1cccc(OCc2ccccc2)c1)NC(=O)C1=Cc2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
(1S*,2S*,4R*)-1-(3-Benzyloxy-benzyl)-4-butylcarbamoyl-2-hydroxy-pentyl-ammonium chloride (210 mg, 0.48 mmol), Dibenzo[b,f]oxepine-10-carboxylic acid (138 mg, 0.58 mmol, 1.2 eq), EDCl (139 mg, 0.72 mmol, 1.5 eq), HOBt (78 mg, 0.58 mmol, 1.2 eq) and triethylamine (0.20 ml, 1.4 mmol, 3 eq) are dissolved in DCM (12 ml) and stirred at rt for 3 days. EtOAc is added. After washing with 0.5 N HCl, brine, bicarbonate and brine again, drying over magnesium sulfate, the solvent is evaporated and the residue recrystallized from DCM/ether/hexane with a drop of methanol to give a white solid (240 mg).
Reaction SMILES: [NH2:1][C:2]([NH:4][C@H:5]([C:17]([OH:19])=O)[CH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:16])=[O:3].ClC1C=CC=C([N+]([O-])=O)C=1CCl.Cl>O>[Cl:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[CH2:6][CH:5]1[NH:4][C:2](=[O:3])[NH:1][C:17]1=[O:19]
Reactant: NC(=O)N[C@@H](Cc1c(Cl)cccc1[N+](=O)[O-])C(=O)O
Agent: Cl
Agent: O=[N+]([O-])c1cccc(Cl)c1CCl
Solvent: O
Product: O=C1NC(=O)C(Cc2c(Cl)cccc2[N+](=O)[O-])N1
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
A mixture of DL-N-(aminocarbonyl)-2-chloro-6-nitrophenylalanine (6.15 g, 21 mmol) prepared from 2-chloro-6-nitrobenzyl chloride according to steps 1, 2 and 3 above, concentrated hydrochloric acid (70 mL) and water (70 mL) was heated on a steam bath. After 45 minutes, the mixture was cooled, filtered and the solid washed with water and dried in air to give 5-[(2-chloro-6-nitrophenyl)methyl]-2,4imidazolidinedione (4.90 g, 85%), which was used without further purification. An analytical sample was prepared by dissolving a sample of the crude material (0.6 g) in boiling ethanol (30 mL) and adding ether to precipitate pure material (0.48 g). m.p. 210°-212° C. (dec). Spectral data were in accord with the assigned structure.
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH:17]1([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][NH2:30])[CH:23]=2)[CH2:19][CH2:18]1.C(O[CH:35]=[C:36]([C:39]#[N:40])[C:37]#[N:38])C>CCO>[NH2:40][C:39]1[N:29]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=2[CH3:28])[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:31])[N:30]=[CH:35][C:36]=1[C:37]#[N:38]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: CCOC=C(C#N)C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C#N)c1N
Temperature: 65 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
DIPEA (3.4 g, 26.5 mmol) was added to the solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (8.45 g, 26.5 mmol) and 2-ethoxymethylene malononitrile (3.2 g, 26.5 mmol) in EtOH (100 mL) and stirred at 65° C. for 3 h. The solvent was removed the residue was suspended in EtOAc (˜100 mL), and water was added to this suspension. The solid product was filtered. The filtrate was washed by water, brine, dried over Na2SO4, concentrated, and purified by column chromatography on silica gel eluted with EtOAc. The product, combined from filtration and chromatography, was obtained as a beige solid (7.1 g, 96%).
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[N:16]=[C:15](O)[C:14]([CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]([CH3:29])=[CH2:28])=[C:21]([O:30][CH3:31])[CH:20]=2)=[C:13]([NH2:32])[N:12]=1.P(Cl)(Cl)(Cl)=O>>[NH2:10][C:11]1[N:12]=[C:13]([NH2:32])[C:14]([CH2:18][C:19]2[CH:20]=[C:21]([O:30][CH3:31])[C:22]([C:27]([CH3:29])=[CH2:28])=[C:23]([O:25][CH3:26])[CH:24]=2)=[CH:15][N:16]=1
Reactant: C=C(C)c1c(OC)cc(Cc2c(N)nc(N)nc2O)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reaction time: 4 h

Procedure:
0.65 G. of dimethylaniline was added dropwise while stirring to a suspension of 0.8 g. of 2,6-diamino-5-(3,5-dimethoxy-4-isopropenylbenzyl)-4-pyrimidinol in 6.5 g. of phosphorus oxychloride. The mixture was boiled for 4 hours while stirring and then about half of the phosphorus oxychloride was distilled under reduced pressure. About 10 g. of ice were added to the residue. The suspension was left to stand at room temperature for 2 days, adjusted to pH 10 with concentrated ammonia solution and the precipitate was filtered under suction 2 hours later. The precipitate was freed from dimethylaniline by steam distillation. After cooling the aqueous suspension, the resulting crude 2,6-diamino-4-chloro-5-(3,5-dimethoxy-4-isopropenylbenzyl)-pyrimidine was chromatographed on silica gel with benzene/methanol (9:1, v/v) and, after evaporation of the solvents, recrystallized from methanol. Yield: 0.27 g. (32%); melting point 199°-200° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[F:37])[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:38])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[O:29][C:20]1[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]2[N:24]=[C:16]([C:12]3[CH:11]=[C:10]([CH3:38])[C:9]([O:8][CH2:7][C:6]([OH:39])=[O:5])=[C:14]([CH3:15])[CH:13]=3)[O:17][C:18]=2[N:19]=1
Reactant: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 114.8 %

Procedure:
69 mg of {4-[5-(2,5-difluoro-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid tert-butyl ester were dissolved in 1.6 ml of dichloromethane and treated with 0.8 ml of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 71 mg of the title compound were obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:18])(=O)=O.C(O)=O>O>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOCCBr)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer, 168 g.), sulfuryl chloride (87.3 g.) and formic acid (168 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (1 l.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7].Cl>ClCCCl>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:6](=[O:7])[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13]2
Reactant: COC(=O)C(Cc1cccc(Cl)c1)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Under nitrogen atmosphere, 9.0 g of anhydrous aluminum chloride and 151.3 g of 1,2-dichloroethane were stirred to yield a suspension, and the suspension was cooled to 0° C. A mixture of 7.98 g of methyl 2-chloroformyl-3-(3-chlorophenyl)-propionate prepared in Referential Example 1 and 151.3 g of 1,2-dichloroethane was added dropwise to the suspension while maintaining the temperature at 5° C. or below, followed by stirring under the same condition for 2 hours. The reaction mixture was added dropwise to 53.6 g of 1.7 percent by weight hydrochloric acid cooled to 5° C. or below, followed by stirring under the same condition for 1 hour. After separating the mixture into a 1,2-dichloroethane layer and an aqueous layer, the product in the aqueous layer was extracted with 15.1 g of 1,2-dichloroethane. This procedure was repeated a total of two times. The resulting 1,2-dichloroethane layers obtained by these procedures were collected and were washed with 33.0 g of water, followed by removal of 1,2-dichloroethane under reduced pressure. The concentrated residue was purified by silica gel column chromatography [mobile phase: hexane/ethyl acetate=4/1 (by volume)] to yield 5.21 g of methyl 5-chloro-1-oxo-2,3-dihydroindene-2-carboxylate as a beige solid in a yield of 70% on the basis of 3-(3-chlorophenyl)-2-methoxycarbonylpropionic acid.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1ccccc1
Reactant: [H][H]
Product: c1ccc(C2CCCCC2)cc1

Procedure:
reacting benzene and hydrogen with a catalyst under hydroalkylation conditions to produce cyclohexylbenzene;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.I[CH3:10]>>[CH3:10][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: CI
Product: Cn1cc(Br)cc1C=O
Yield: 50 %

Procedure:
In a similar manner to Example 10(b), by reaction of 4 g (23 mmol) of 4-bromo-2-pyrrolecarboxaldehyde with 1.7 ml (27.6 ml) of iodomethane, 2.3 g (50%) of the expected product are obtained, with a melting point of 123-4° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CCCCCCCCCCCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([N:10]([C:6]6[CH:5]=[C:4]7[C:9](=[CH:8][CH:7]=6)[CH2:1][CH2:2][CH2:3]7)[C:11]6[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=6)=[CH:33][CH:32]=5)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(Nc2ccc3c(c2)CCC3)cc1
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Product: Cc1ccc(N(c2ccc(-c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc6c(c5)CCC6)cc4)cc3)cc2)c2ccc3c(c2)CCC3)cc1
Temperature: 205 °C
Reaction time: 30 h
Yield: 75.8 %

Procedure:
Indane-5-yl-p-tolylamine (18.1 g (0.081 mol)), 18.9 g (0.039 mol) of 4,4″-diiodo-p-terphenyl, 7.2 g (0.052 mol) of anhydrous potassium carbonate, 0.76 g (0.012 mol) of copper powder and 30 ml of n-dodecane were mixed, and heated up to 200 to 210° C. while introducing nitrogen gas, followed by stirring for 30 hours. After the termination of the reaction, the reaction product was extracted with 400 ml of toluene, and insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluent: toluene:hexane=1:4) to obtain 19.9 g of N,N′-bisindane-5-yl-N,N′-di-p-tolyl-4,4″-diamino-p-terphenyl (compound No. 1) (yield: 75.7%, melting point: 207.4 to 208.1° C.).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO.Cl>[CH2:1]([O:17][CH2:18][C@H:19]([OH:20])[CH2:23][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC[C@H](O)CO
Yield: 73.2 %

Procedure:
A stirred mixture of 28 g of (S)-4-[(hexadecyloxy)methyl]-2,2-dimethyl-1,3-dioxolane in 190 ml of methyl alcohol and 21 ml of 1N hydrochloric acid is refluxed for 2 hours followed by cooling in an ice bath. The resulting solid is filtered and washed with cold acetone. The solid is crystallized from acetone to give 18.2 g of crystals which liquified at ambient temperature. The resulting oil is purified by chromatography on silica gel using 1:1 ethyl acetate:hexanes. Fractions containing product are combined and evaporated to a material which is stirred with acetone at -20° C. to give 4.1 g of crystalline solid, m.p. 65°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[F:25][CH:26]([F:29])[CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:28][CH2:27][CH:26]([F:29])[F:25])=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCC(F)F
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)NCC(F)F

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 2,2-di-fluoro-ethylamine (28.5 mg, 0.35 mmol). The title compound was obtained as a solid (84.0 mg, 62% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.24 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 8.36 (1H, m), 5.98 (1H, m), 3.85 (2H, m), 3.50 (2H, m). MS m/z: 469.05, 471.06 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([OH:23])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Yield: 1246.1 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (6.06 g, 19.2 mmoles) was dissolved in acetone (150 mL), and benzyl bromide (2.60 mL, 21.9 mmoles) and anhydrous potassium carbonate (13.28 g, 96.1 mmoles) were added. The mixture was stirred and heated at reflux for 22 hours. The mixture was concentrated to remove most of the acetone, and ethyl acetate (100 mL) was added. Aqueous hydrochloric acid (1N, 200 mL) was added slowly, swirling frequently to dissolve the solid carbonate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50mL). The ethyl acetate solutions were combined and washed with water (100 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to about 50 mL. This solution was heated to boiling, and hexanes (150 mL) were added. The solution was cooled in ice, and crystals slowly formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford6.97 g (89% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (m.p. 106°-107° C., open capillary, uncorrected).
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH2:43][CH3:44])[CH:35]=2)[OH:33])=[CH:28][C:27]=1[N+:45]([O-:47])=[O:46].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH2:43][CH3:44])[CH:35]=2)=[O:33])=[CH:28][C:27]=1[N+:45]([O-:47])=[O:46]
Reactant: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: c1cc[nH+]cc1
Product: CCOc1cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Yield: 88.5 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (3.9 g, 11.6 mmol) and pyridinium chlorochromate (3.7 g, 17.4 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to afford (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone (3.4 g, 89%) as an orange solid: 1H NMR (CDCl3) δ 8.28 (d, J=2 Hz, 1H), 8.06-8.02 (dd, J=3, 8.7 Hz, 1H), 7.41 (d, J=1 Hz, 1H), 7.31-7.26 (dd, J=2, 8.4 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.21-4.12 (q, J=7 Hz, 2H), 4.05 (s, 3H), 3.96 (s, 3H), 1.50 (t, J=6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([Cl:44])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)O)cc4)cc3C2)c1Cc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)Cl)cc4)cc3C2)c1Cc1ccc(F)cc1

Procedure:
To a solution of 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.50 g, 1.07 mmol) and DMF (20 μL) in chloroform (15 mL) was added drop wise oxalyl chloride (0.35 mL, 4.0 mmol). The reaction mixture was refluxed for 15 min, and then concentrated to give 4-(4-{5-[(4-fluorophenyl)-methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoyl chloride as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH2:38]([N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[S:43]Cl)[CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:43][N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:19])[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CCCCN(CCCC)SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) (0.4 g, 0.96 mmol) in 8 ml methylene chloride cooled to 0° C. was added triethylamine (0.15 g) and dibutylaminosulfenylchloride (0.2 g). The reaction mixture was, warmed to room temperature and stirred for one hour. The mixture was subjected to silica gel column chromatography using hexane-ether (6:1) as the eluent. The title compound was obtained (0.24 g) in high purity.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=O)[CH:15]=1)=[CH:12][CH:11]=[C:10]([N+:17]([O-])=O)[C:9]=2[CH3:20])=[O:5])[CH3:2]>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH3:20])[C:10]([NH2:17])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc([N+](=O)[O-])c(C)c2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccc(N)c(C)c2O1
Reaction time: 48 h
Yield: 68.4 %

Procedure:
A mixture of 8-methyl-7-nitro-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (42.2 g, 0.152 mol) and palladium on carbon (4.7 g) in glacial acetic acid was hydrogenated at 50 psi for 48 hours. The catalyst was filtered through Celite® and the solvent removed under high vacuum. The crude product was chromatographed (25% ethyl acetate in hexanes) to afford 24.5 g (0.104 mol, 68.4%) of 7-amino-8-methyl-chroman-2-carboxylic acid ethyl ester as an orange oil which solidified upon standing: mp 82°-85°C.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9](O)([CH3:11])[CH3:10]>C1COCC1>[CH3:11][C:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])=[CH2:10]
Reactant: Cc1cc(C)c(C(C)(C)O)c(C)c1
Solvent: C1CCOC1
Product: C=C(C)c1c(C)cc(C)cc1C
Yield: 44.6 %

Procedure:
The same experiment as in Example 4 was carried out, except for using 50 ml of THF instead of 50 ml of CPME. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 44.6% and 33.1%, respectively.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:21][CH2:20][C:19]([N:17]1[CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14][CH2:15][CH2:16]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)COC(C)=O)CCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)CO)CCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydro-2H-pyridin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 72, Step 6, 238 mg) and anhydrous potassium carbonate (151 mg) in methanol (27 mL) is stirred under N2 at ambient temperature for 2 hrs and is then neutralized with hydrochloric acid (1 M) and concentrated under reduced pressure. The residue is then diluted with methylene chloride (100 mL) and saline (50 mL) and the resultant insoluble product is removed by filtration and dried under reduced pressure. The layers in the filtrate are separated and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give additional quantities of the title compound, mp 171—173° C.