Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37]1([C:40]([F:43])([F:42])[F:41])[CH2:39][CH2:38]1)=[N:32][N:31]=[CH:30]2>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37]1([C:40]([F:43])([F:42])[F:41])[CH2:39][CH2:38]1)=[N:32][N:31]=[CH:30]2
Reactant: FC(F)(F)C1(c2nncc3cc(Cl)ccc23)CC1
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(C3(C(F)(F)F)CC3)nncc2c1

Procedure:
The title compound was prepared according to a procedure analogous to that described in Example 225, using 4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 6-chloro-1-(1-(trifluoromethyl)cyclopropyl)phthalazine as the starting materials. MS (ESI, pos. ion) m/z: 452.2 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)Cl.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>>[F:39][C:38]([F:41])([F:40])[C:36]([O-:42])=[O:37].[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[O:37])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(Nc1ccc(OC(C)=O)cc1)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc(NC(=O)c2ccc(N3CC[NH2+]CC3)cc2)cc1
Product: O=C([O-])C(F)(F)F
Yield: 95 %

Procedure:
tert-butyl 4-[4-(1-{[4-(acetyloxy)phenyl]amino}vinyl)phenyl]piperazine-1-carboxylate (0.1 M) in a solution of DCM/TFA (2/3) was stirred at RT for 30 min. The organic solvent was evaporated in vacuo and the crude residue was scratched with Et2O. The resultant white solid precipitate was filtered off to afford the title compound (95%); MS (ES+) m/z 339 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].N1C=CC=CC=1.Cl>C(Cl)Cl.CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]2[CH:13]=[N:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=c1cc(SCc2ccc(Cl)cc2)cn[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-n2ncc(SCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O

Procedure:
A solution of 5-(4-chlorobenzylthio)pyridazin-3(2H)-one Part A (21 mg, 0.083 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (39.9 mg, 0.17 mmol), pyridine (0.067 mL, 0.83 mmol) and Cu(OAc)2 (45.3 mg, 0.25 mmol) in CH2Cl2 (13.0 mL) and MeOH (2.0 mL) was stirred at RT open to air for 4 hours. The mixture was poured into 1.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) giving the title compound 5-(4-chlorobenzylthio)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one F-1 (23 mg, 61% yield) as white solid. LC/MS 447 (M+H)+, tR 4.14 min (method 3); 1H NMR (500 MHz, Chloroform-D) δ ppm 7.65 (1H, d, J=2.20 Hz), 7.35 (4H, s), 7.07-7.13 (2H, m), 6.96 (1H, d, J=8.80 Hz), 6.66 (1H, d, J=2.20 Hz), 4.15 (2H, s), 3.81-3.91 (5H, m), 1.35 (6H, s).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:30]([O-])=O.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:1]2[C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[CH2:4][CH2:5][CH2:6][CH2:7]2)(=[O:28])=[O:27])=[CH:22][C:21]=1[NH2:30]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: c1ccc2c(c1)CCCCN2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-benzo[B]azepine (0.37 g), triethylamine (0.35 mL) and 4-dimethylaminopyridine (26 mg) in methylene chloride (8 mL) was added 4-fluoro-3-nitrobenzenesulfonyl chloride (0.5 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7 mL). To the solution were added methanol (7 mL) and nickel(II) bromide (23 mg). To the mixture was added sodium borohydride (0.24 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.26 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25](Br)=[N:24][C:23]3[C:18]2=[N:19][C:20]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:21][C:22]=3[NH2:27])[CH:11]=1)(=[O:8])[O:5]CC)[CH3:2].C([O-])(=[S:35])C.[K+]>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]([SH:35])=[N:24][C:23]3[C:18]2=[N:19][C:20]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:21][C:22]=3[NH2:27])[CH:11]=1)(=[O:8])[OH:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1)OCC
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(O)Cc1cccc(Cn2c(S)nc3c(N)nc(OCCOC)nc32)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of (3-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phosphonic acid diethyl ester (50) (180 mg, 0.34 mmol) in DMF (2 ml) was added potassium thioacetate (778 mg, 6.8 mmol). The reaction mixture stirred at 100° C. for 24 h. After cooling to rt, the reaction mixture was filtered and purified by reversed phase prep-HPLC using a linear gradient of acetronitrile in water from 5% to 95%. 1H NMR (DMSO, 300 MHz): (1.08 (t, 3H), (3.00 (d, 2H), (3.25 (s, 3H), (3.58 (t, 2H), (3.77-3.84 (m, 2H), (4.29 (t, 2H), (5.23 (s, 2H), (6.87 (bs, 2H), (7.16-7.28 (m, 4H); 31P NMR (DMSO, 300 MHz): (23.20; MS: 454.1 (M+H)+, 452.0 (M−1).
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1[F:20].[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:4]1[C:3]([F:20])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1c(F)c(F)c2c(c1F)C(=O)c1ccccc1C2=O
Reaction time: 4 h
Yield: 69.8 %

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of o-anisidine were charged in a 50 cc, four necked flask and then the reaction was carried out at 50° C. for about 4 hours. After completion of reaction, o-anisidine was distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 1.91 g of 2-(o-methoxyanilino)-1,3,4-trifluoroanthraquinone (Dye 6') (yield 69.8 mol %) and 0.85 g of 2,3,-bis(o-methoxyanilino-1,4-difluoroanthraquinone (Dye 19') (yield 24.5 mol %). The physical properties of Dye 6' and analytical values defining the compound are tabulated in Table 23 and the physical properties of Dye 19' and analytical values defining the compound are tabulated in Table 24.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CS(C)=O.CCOC(C)=O>[F:27][C:28]1([F:34])[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC(F)(F)CC3)n2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of triazine A1 (270 mg, 0.9 mmol) in DMSO (0.9 mL) were added K2CO3 (370 mg, 2.7 mmol) and 4,4-difluoropiperidine hydrochloride (140 mg, 0.9 mmol). The mixture was stirred for 2 hours at 80° C. After cooling to room temperature it was diluted with EtOAc and extracted with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was stirred with DCM to give the solid title compound B2 which was isolated by filtration and dried in vacuo (white powder, 110 mg, 32%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.90-2.15 (m, 4H), 3.81-3.98 (m, 4H), 4.21 (s, 2H), 6.88 (s, 2H), 6.98-7.04 (m, 1H), 7.21-7.34 (m, 1H), 7.44-7.60 (m, 1H), 7.78-7.90 (m, 1H), 8.25 (s, 1H), 9.77 (s, 1H). MS (ES) C15H18F2N6O2S requires: 384. found: 385 (M+H)+.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C)[CH:13]=1)[C:6]([O:8]C)=O.COC(=O)C1C(=CC(N(C)C2C=CC=CC=2)=C([NH:44]C2C=CC=CC=2)C=1)C(OC)=O>>[CH3:29][N:22]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:44][C:3](=[O:30])[C:4]2=[CH:13][C:12]=1[NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1) in 5 ml of acetonitrile is heated at 80° C. for 16 hours with 0.93 ml (15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube. The reaction mixture is concentrated to dryness by evaporation, the residue is twice digested in dichloromethane and filtered, and the filtrate is concentrated by evaporation. Repeated chromatography on silica gel with hexane/ethyl acetate yields the title compounds in the form of slightly yellowish powders. (A): FAB-MS: 405 [M+ +H]; (B): FAB-MS: 391 [M+ +H].
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(CNc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.4 g, 6.8 mmol) was added to a DCE solution (10 mL) of 2-bromo-4-(trifluoromethyl)benzaldehyde (860 mg, 3.4 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (761 mg, 3.7 mmol), and AcOH (0.78 mL, 13.6 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[N:3]=1.[CH:25]([O:28][C:29]1[CH:35]=[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]([CH3:43])=[CH:32][C:30]=1[NH2:31])([CH3:27])[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:25]([O:28][C:29]1[CH:35]=[C:34]([CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]([CH3:43])=[CH:32][C:30]=1[NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[N:3]=1)([CH3:27])[CH3:26]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2ncn(C)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(ncn3C)n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-7-methyl-7H-purin-6-amine (1 equivalent) in isopropanol, was added 2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline (1 equivalent) and 4-methylbenzenesulfonic acid (1 equivalent). The suspension was stirred at 150° C. for 3 hours, cooled to room temperature and the solvent evaporated. The residue was purified using a preparative HPLC to afford the desired product as a gummy solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](O)(=[O:12])[CH3:11].C(OC(=O)C)(=O)C>O>[CH3:9][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:10]([CH3:11])=[O:12]
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(Cl)c1C

Procedure:
141 g. of 3-chloro-2-methylaniline (1 mol.) was added to a stirred mixture of 200 ml. of acetic acid and 102 g. (1 mol.) of acetic anhydride and heated to 95° C. for approximately one hour. The mixture was poured into water and filtered to give 3-chloro-2-methylacetanilide.
Reaction SMILES: C(O[C:5](=O)[C@:6]([NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:20])C1C=CC=CC=1)N)N)C#C.[C:31](#N)[CH3:32].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C(Cl)(Cl)(Cl)Cl>[CH:5]([C:6]1([NH:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:9][CH2:10][NH:12][C:13]1=[O:20])=[C:31]=[CH2:32]
Reactant: CC#N
Reactant: C#CCOC(=O)[C@@](N)(CCC(N)NC(=O)c1ccccc1)NC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C=CC1(NC(=O)c2ccccc2)CCCNC1=O
Reaction time: 2 h

Procedure:
An 11.04 g aliquot of 2,5-di(benzoylamino)ornithine propargyl ester was added to 80 ml of dry acetonitrile, 21.97 ml of triethylamine, 12.48 carbon tetrachloride and 30.69 g of triphenylphosphine. After about 2 hours at room temperature, 50 ml of methanol were added and the solution left at room temperature overnight. The reaction mixture was concentrated in vacuo, and to this residue was added 80 ml of tetrahydrofuran and 40 ml of 10% acetic acid and stirring. After 24 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and 10% HCl. The organic layer was extracted several times with 10% HCl after which the combined aqueous fractions were washed exhaustively with methylene chloride. The pH of the aqueous portion was adjusted to 10 with concentrated sodium hydroxide to induce lactam formation. On cooling, a precipitate formed which was filtered and recrystallized from methanol-ethyl acetate to give the title compound, mp 203°-204° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22]([C:38](OC)=[O:39])=[N:23][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:25](=[O:27])[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:38]([C:22]1[C:21]([O:20][CH3:19])=[CH:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[N:23]=1)=[O:39]
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c(=O)cc1OC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (1.58 g, 16.2 mmol) and iPr2NEt (2.82 mL, 16.2 mmol) in CH2Cl2 (13 mL) was added AlMe3 (1.8 M solution in toluene, 9.0 mL, 16.2 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 4-methoxy-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxylate (1.77 g, 5.4 mmol) in CH2Cl2 (15 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (1.48 g, 83% yield) as a white solid: mp 127-129° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.37 (3H, s), 3.64 (3H, s), 3.91 (3H, s), 6.30 (1H, s), 7.55-7.60 (1H, m), 7.62-7.65 (1H, m), 7.82-7.86 (1H, m), 7.88 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.47; H, 3.99; N, 11.83.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Yield: 72.1 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-1-tetralone (5.00 g, 30.8 mmol), 6-chloronicotinamide (4.38 g, 28.0 mmol) and K2CO3 (5.81 g, 42.0 mmol) gives the title compound (5.7 g) as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.09 (d, 1H), 2.92 (t, 2H), 2.58 (t, 2H), 2.03 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.O>CO.[Ni]>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1
Reactant: CCCc1nc(COC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CCCc1nc(COC)sc1Cc1ccc(N)cc1

Procedure:
0.9 of 2-methoxymethyl-4-propyl-5-(4-nitrobenzyl)thiazole in 50 ml of methanol is hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up with acidified water. The aqueous phase is extracted with ether, rendered basic with dilute sodium hydroxide and extracted with ethyl acetate. The organic phase is dried and concentrated to give 0.5 g of 2-methoxymethyl-4-propyl-5-(4-aminobenzyl)thiazole in the form of an orange oil, which is used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>CC(C)CC(=O)C>[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Oc1ccc(CC(=O)N(c2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To a stirred mixture of 7.5 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine and 80 parts of 4-methyl-2-pentanone are added dropwise 9 parts of [4-(2-chloro-2-oxoethyl)phenyl] ethyl carbonate. Upon completion, the whole is heated to reflux and stirring is continued for one hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.5 parts of {4-[2-{(4chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl} ethyl carbonate as an oily residue.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.CCO.[Pt]=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:40])([CH3:41])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCC#Cc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Yield: 92.4 %

Procedure:
A solution of (5R)-3-[6-({5-[3-(cyclopentylsulfonyl)phenyl]-4-pentyn-1-yl}oxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (215 mg) in EtOAc (10 ml) and EtOH (10 ml) was hydrogenated over platinum oxide (30 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent was evaporated in vacuo to give the title compound (200 mg). LCMS RT=3.83 min.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:30]([C:25]1[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=1[O:34][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:34][C:24]2[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(C)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, 2,6-di-tert-butyl-4-methylphenol and triethylamine to give the title compound.