Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][O:13][C@H:14]1[CH2:17][C@H:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>CC#N.[Pd]>[F:8][C:6]1[CH:7]=[C:2]([NH:18][C@H:16]2[CH2:17][C@H:14]([O:13][CH3:12])[CH2:15]2)[C:3]([NH2:9])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CO[C@H]1C[C@H](N)C1
Agent: [Pd]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1C[C@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.2 mL, 1.7 mmol) in CH3CN (3 mL) were added trans-3-methoxycyclobutylamine (0.18 g, 1.7 mmol) and DIPEA (0.3 mL, 1.7 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was carried to the next step without further purification (0.41 g, quantitative). To a solution of the product thus obtained (1.7 mmol) in EtOAc (15 mL) was added Pd/C (350 mg) and the reaction mixture was stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound as a dark oil (0.36 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.68-6.59 (1H, m), 6.33 (1H, dt, J=19.6 Hz, 2.7 Hz), 6.18 (1H, dd, J=13.6 Hz, 2.7 Hz), 4.00-3.90 (1H, m), 3.76-3.63 (1H, m), 3.53 (3H, br s), 3.27 (3H, s), 2.49-2.37 (2H, m), 2.36-2.12 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Na].N1C=CC(=O)NC1=S.[Cl-].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH+:28]([CH3:30])[CH3:29]>[O-]CC.[Na+].C(O)C>[CH3:29][N:28]([CH3:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][S:8][C:6]1[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: C[NH+](C)c1ccccc1CCl
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: CC[O-]
Agent: O=c1cc[nH]c(=S)[nH]1
Agent: [Cl-]
Solvent: CCO
Product: Cc1cc(=O)[nH]c(SCc2ccccc2N(C)C)n1
Reaction time: 1 h
Yield: 41.7 %

Procedure:
355 mg (2.5 mmol) of 6-methyl-2-thiouracil are dissolved in a sodium ethoxide solution prepared from 116 mg (5.05 mmol) of sodium metal and 15 ml of anhydrous ethanol. The mixture is gently warmed to dissolve the thiouracil, then 515 mg (2.5 mmol) of (2-chloromethylphenyl)-dimethylammonium chloride are added and the reaction mixture is refluxed under stirring for 1 hour. Sodium chloride is immediately precipitated from the solution. After evaporation under reduced pressure the residue is taken up in water, extracted 3 times with 20 ml of chloroform each, then the combined organic phase is washed with 20 ml of water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The pale yellow oily residue is rubbed with an 1:1 mixture of benzene and petroleum ether to obtain 287 mg (47.7%) of the title compound as a white crystalline product, m.p.: 151°-153° C.
Reaction SMILES: C([NH:9]C(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.NC1C=CC=CC=1[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH:40]=[C:41]([CH3:47])[C:42]([O:44]CC)=[O:43].[OH-].[Na+].Cl>O1CCCC1>[NH2:9][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH:40]=[C:41]([CH3:47])[C:42]([OH:44])=[O:43]
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Reactant: CCOC(=O)C(C)=Cc1ccc(Cl)cc1-c1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=Cc1ccc(Cl)cc1N)C(=O)O
Yield: 94 %

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.24 g (5.18 mmol) of (E) ethyl 3-(2-aminophenyl-4-chlorophenyl)-2-methyl-2-propenate were dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction was verified by TLC, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto. The precipitated crystal was filtered out, whereby 1.03 g of the aimed compound were obtained (yield: 94%).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]1([CH2:21][C:22](=O)[CH2:23][C:24]([O:26]CC)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:21]([C:22]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[N:2]=[N:3][C:23]=1[C:24]([OH:26])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
4-Azido-N-ethylbenzamide (0.571 g, 3.00 mmol) and ethyl 4-phenyl-3-oxobutyrate (0.692 g, 3.60 mmol, 1.25 eq.) were dissolved in ethanol (15 ml), sodium ethoxide (284 mg, 3.60 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 2 hr. 2% aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, and the mixture was further stirred for 30 min. Ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate (40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, concentrated to about 30 ml, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (35 ml×2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (796 mg, 2.27 mmol, 75.7%).
Reaction SMILES: [OH:1][C:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[Si:23]([O:1][C:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1O[Si](C)(C)C(C)(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of ethyl 4-hydroxy-3-nitro-5-propylbenzoate (1.5 g, 5.9 mmol), TBSCl (1.3 g, 8.9 mmol) and imidazole (800 mg, 11.8 mmol) in DMF (20 mL) was stirred at 30° C. overnight. A standard aqueous/EtOAc workup was followed by a purification by column chromatography (PE:EtOAc=15:1) to give product as a yellow oil (1.9 g, yield 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:55][CH2:56][C:57]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:58]=1[C:59]([NH:61][CH3:62])=[O:60]>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:67][C:64]1[CH:65]=[CH:66][C:57]([CH2:56][NH:55][C:21]([C:10]2[N:11]=[C:12]3[C:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:22])=[C:58]([C:59](=[O:60])[NH:61][CH3:62])[CH:63]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Intermediate 6, 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylic acid, (79 mg, 0.25 mmol) was placed together with O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HATU, (114 mg, 0.3 mmol) in 2 mL DMF under N2 and stirred for 20 min. 4-(Dimethylamino)pyridine, DMAP, (100 mg, 0.8 mmol) and intermediate 3, 2-aminomethyl-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (89 mg, 0.3 mmol) in 1 mL DMF were added and stirring continued for 20 min. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 and washed with H2O. The CH2Cl2 layer was separated, dried (MgSO4), filtered and concentrated to give 118 mg of a the title compound as a solid (Yield=95%). 1H NMR (300 MHz, CDCl3) δ ppm: 8.31–8.46 (1 H, m) 7.24–7.46 (5 H, m) 6.95–7.15 (3 H, m) 6.88 (1 H, s) 5.23 (2 H, s) 4.48 (2 H, d, J=6.6 Hz) 3.95–4.10 (2 H, m) 2.93 (3 H, t, J=5.1 Hz) 2.00–2.16 (2 H, m) 1.34 (6 H, s); LC/MS m/z 479 (M+H).
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)[CH:25]([NH:42]C(OC(C)(C)C)=O)[C:24]2=[O:50])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[NH2:42][CH:25]1[C:24](=[O:50])[N:23]2[CH:26]1[S:27][CH2:28][C:29]([C:30]1[S:34][C:33]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)=[C:22]2[C:20]([O:19][CH:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
A solution of methanesulphonic acid (10 cc) is added to a solution of 2-benzhydroxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in acetonitrile (100 cc). The mixture is stirred for 5 minutes and is poured into a 50:50 (by volume) mixture (500 cc) of saturated sodium bicarbonate solution and ethyl acetate. The organic phase is decanted and then washed successively with distilled water (200 cc) and saturated sodium chloride solution (200 cc). It is dried over anhydrous magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 7-Amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-yl-methyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.36 g) is obtained in the form of a chestnut-coloured froth.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:9]=1)C>O.C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:27])=[O:5])=[CH:9][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=1[Cl:26]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Sodium hydroxide (0.72 g) in water (40 ml) was added to the product from step (v) (3.6 g) in THF (40 ml) and stirred at RT overnight. The reaction was quenched with 2M HCl, extracted with EtOAc, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from EtOAc/isohexane to give the subtitle compound (2.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[CH:5]=1)[CH3:2].C(NC(C)C)(C)C.[Li].CN(C)[CH:22]=[O:23].C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([CH:22]=[O:23])=[C:6]([F:11])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(F)c(F)c1
Agent: [Li]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(F)c1C=O

Procedure:
In a manner similar to the method described in example 52a, 4-ethoxy-1,2-difluoro-benzene (10 g, 63 mmol) prepared in example 91a was reacted with lithium diisopropylamine (39 mL, 1.8 M in THF, 70 mmol), N,N-dimethylformamide (5.88 mL, 76 mmol) and quenched with acetic acid (15.2 g, 253 mmol) in tetrahydrofuran to give 6-ethoxy-2,3-difluoro-benzaldehyde as a off white solid (Yield: 8.9 g, 76%).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH2:26][OH:27].Cl>N1C=CC=CC=1>[N:26](=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:27]
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=NO

Procedure:
A stirred solution of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (5.48 g., 0.015 mole) and hydroxylamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 36 hours then poured into aqueous hydrochloric acid affording (1-hydroximino-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=O)[N:15]([CH2:16][C:17](OC)=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:18][CH2:17][CH2:16][N:15]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:4])[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)CN1C(=O)CCCc2c(OC(C)=O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCN1CCCCc2c(O)cccc21
Temperature: 0 °C
Yield: 81.2 %

Procedure:
Methyl (6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate (1080 mg) was dissolved in THF (15 ml) under an argon atmosphere, and the resultant solution was stirred at 0° C. Lithium aluminum hydride (355 mg) was added to the solution, and the mixture was stirred at 0° C. After disappearance of the raw materials was confirmed, the reaction solution was added to water (100 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=2/1) to obtain the object compound (624 mg, yield 81%).
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1([C:11]#[C:12][Br:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (31.4 g) in water (160 ml) was cooled to 6° C. and bromine (18 ml) was added dropwise, the temperature being kept below 20° C. Phenylacetylene (20 g) in dimethoxethylene (80 ml) was added over 15 minutes and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added, and the mixture was extracted with ether (4×60 ml), dried (MgSO4) and the solvents removed at room temperature to yield phenylbromoacetylene.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH:24]1([C:28]([CH2:30]Br)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:28]([CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:29]
Reactant: O=C(CBr)C1CCC1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)C2CCC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and bromomethyl cyclobutyl ketone*.
Reaction SMILES: [CH3:1][C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH2:8])=[O:7].[O-:14]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].CC#N>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[CH:1]([C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH2:8])=[O:7])=[O:14]
Reactant: Cc1cccc(OCC(N)=O)c1C
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(OCC(N)=O)c1C=O
Yield: 10.7 %

Procedure:
12.0 g of 7, 50.82 g of potassium peroxodisulfate and 17.05 g of copper(II) sulfate pentahydrate are dissolved in a solvent mixture comprising 250 ml of MeCN and 250 ml of water, and the mixture is subsequently stirred under reflux for 2 h. The mixture is then subjected to conventional work-up, giving 1.38 g (11%) of 2-(2-formyl-3-methylphenoxy)acetamide 8; MS-EI (M+)=193.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:48])[C@@H:30]([CH3:47])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:46])([CH3:45])[C:35](=[N:38][N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:48])[C@@H:30]([CH3:47])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:46])([CH3:45])[C:35](=[N:38][N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To the above Compound (60) (265 mg, 0.40 mmol) was added 2.0 ml of 4N HCl/dioxane solution, and the mixture stirred for one hour at room temperature. The reaction mixture was made basic with 7% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 10 g; ethyl acetate:methanol=97:3) to give 224 mg (100%) of Compound (61).
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[NH2:22][CH:23]([CH:39]([CH3:41])[CH3:40])[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]>C(Cl)Cl.CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:29]2[CH2:28][CH2:27][N:26]([C:24](=[O:25])[CH:23]([NH:22][S:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])[CH:39]([CH3:41])[CH3:40])[CH2:31][CH2:30]2)=[CH:33][CH:34]=1
Reactant: CC(C)C(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with benzylsulfonyl chloride (14 mg), DIEA (50 μL) and 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) in DCM (0.3 mL). The reaction mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 200. MS found: (M+H)+=450.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[OH:18][CH2:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:27][C@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][OH:18])=[O:10]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 2-(3-chloro-phenoxy)-nicotinic acid (0.25 grams, 1.0 mmole) in thionyl chloride (10 ml) was heated to reflux. After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a solution of (S)-2-hydroxy-1-phenyl ethylamine (0.14 grams, 1.0 mmole) in pyridine (5 ml) at 0° C. After 30 minutes the mixture was warmed to room temperature. After 1 hour the mixture was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The combined organics were washed with 1 N hydrochloric acid followed by brine and dried over Na2SO4. Concentration under reduced pressure resulted in a yellow oil that was purified by chromatography on silica gel eluting with 1:1 ethyl acetate/hexane to give a colorless oil. Anal. calcd. for C20H17N2O3Cl: C, 65.13; H, 4.65; N, 7.60. Found: C, 65.20; H, 4.78; N, 7.38; M.S. m/z [M+] 369; 1H NMR (400 MHz, CDCl3) d 2.54 (s, broad, 1H), 3.95 (m, 2H), 5.32 (m, 1H), 7.23 (m, 10H), 8.22 (m, 1H), 8.58 (m, 2H).
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:16]2[CH2:17][CH2:18][CH2:19][C:14](=[O:20])[CH2:15]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1C=CCCC1
Reactant: C1CCC(PC2CCCCC2)CC1
Product: O=C1CCCC(P(C2CCCCC2)C2CCCCC2)C1
Temperature: 60 °C

Procedure:
A 250 ml round-bottomed flask fitted with a condenser, nitrogen purge, and addition funnel was charged with a solution of 89.7 g (0.45 mol) dicyclohexylphosphine and heated to 60° C. with stirring. To the flask was added 50.8 g (0.53 mol) 2-cyclohexen-1-one over a period of 0.5 hour. When addition was complete, the temperature of the contents of the flask was slowly raised to 90° C. and maintained at that temperature for 6 hours, then cooled. Unreacted starting materials were removed by evaporation under reduced pressure at 150° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[C:13]([C:14](OCC)=[O:15])=[C:12]([CH2:19][CH3:20])[O:11][N:10]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH2:19][CH3:20])[O:11][N:10]=1)[CH3:8]
Reactant: CCOC(=O)c1c(CC)noc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1noc(CC)c1CO
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To a 0° C. mixture of LAH (270 mg, 7.1 mmol) in anhydrous THF (10 mL) was slowly added a solution of ethyl 3,5-diethyl-1,2-oxazole-4-carboxylate (826 mg, 4.7 mmol) in anhydrous THF (10 mL). The mixture was stirred at 0° C. for 5 hours, and the mixture was then quenched with 5 N NaOH. Water (50 mL) and EtOAc (50 mL) were added. The mixture was stirred for 30 minutes. The solids were filtered, and the organic layer was recovered. The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic extracts were washed with brine (1×200 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (3,5-diethyl-1,2-oxazol-4-yl)methanol (710 mg, 97% yield), which was used without further purification.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([NH:17][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=2[Cl:27])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Into 5 mL of a tetrahydrofuran solution comprising 420 mg of 4-phenoxyaniline and 250 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 500 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added under cooling with ice. After stirring for about 30 minutes, water was added thereto, and precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 730 mg of N-(4-phenoxyphenyl)-2-chloro-5-nitrobenzamide (Compound No. 27) having a melting point of 128° C.