Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:17]O.C([O-])(=O)C.[Na+].C([O-])(=O)C.[NH4+]>CO.C(O)C.N.[Zn]>[NH2:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: NC(c1ccccc1)c1cccc(O)c1
Temperature: 25 °C

Procedure:
(3-Hydroxyphenyl)(phenyl)methanone (400 g, 2 mol) was dissolved in methanol (4 L). Hydroxylamine hydrochloride (168 g, 2.4 mol) and sodium acetate (331 g, 4 mol) were added to the resulting solution. The mixture was heated at reflux for 18 hours. After cooling to RT solvent was evaporated at reduced pressure, then water (3 L) was added to the residue. The product was extracted with ethyl acetate (3×3 L). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, brine, dried (sodium sulfate), filtered and the solvent evaporated at reduced pressure. The crude residue (1085 g) was used in the next step without purification. The crude oxime, 362 g, (287 g, 1.3 mol of pure oxime based on analysis) was dissolved in ethanol (860 mL) and 25% aqueous ammonia (3000 mL). To this mixture ammonium acetate (52 g, 0.7 mol) was added followed by portion wise addition of zinc powder (440 g, 6.7 mol) to maintain an internal not exceeding 40° C. The mixture was stirred without heating for 18 hours then filtered through a pad of celite. The filter cake was washed with ethyl acetate. The filtrate was collected and the formed layers were separated. The aqueous layer was extracted with ethyl acetate (5×5 L). The combined organic extracts layers were washed with brine (×2) and the solvent was evaporated at reduced pressure. The product was dried in vacuo (35° C., 18 hours).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1.[I:32]I.Cl>[NH4+].[OH-].CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[C:15]([I:32])[C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1
Reactant: II
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(2-Bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-hydroxy-chromen-2-one (2.734 g, 5.26 mmol) in NH4OH (22 mL), MeOH (55 mL) and CH2Cl2 (33 mL) was added I2 (1.334 g, 5.26 mmol), and the resulting mixture was stirred at r.t for 30 min. Aqueous 4 M HCl was then added to lower the pH of the aqueous layer to 5. The resultant layers were separated and the aqueous phase was extracted with AcOEt (3×). The combined organic layers were washed with brine (2×), dried (MgSO4) and concentrated in vacuo. The residual beige solid (3.25 g, 96%) was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 11.43 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.51–7.42 (m, 3H), 7.02 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 4.21 (t, J=5.0 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.70 (d, J=15.5 Hz, 1H); MS (ESI) m/z 642.7 (M−H)−; HPLC tR 7.27 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[O:5][CH:6]1[CH2:10][NH:9][CH:8]([CH2:11][OH:12])[CH2:7]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[O:5][CH:6]1[CH2:10][N:9]2[C:19](=[O:20])[O:12][CH2:11][CH:8]2[CH2:7]1
Reactant: O=[N+]([O-])c1cc(F)cc(OC2CNC(CO)C2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1OCC2CC(Oc3cc(F)cc([N+](=O)[O-])c3)CN12
Yield: 128.1 %

Procedure:
To a solution of 1.29 g of [4-(3-fluoro-5-nitro-phenoxy)-pyrrolidin-2-yl]-methanol in 20 mL of anhydrous dichloromethane was added in one portion 0.82 g of 1,1′-carbonyldiimidazole and the resultant mixture stirred at room temperature under N2 for 3 hours. The reaction mixture was diluted with 30 mL of dichloromethane and washed with H2O (2×25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1.82 g of a light yellow solid. Purification over silica gel resulted in 0.825 g of 6-(3-Fluoro-5-nitro-phenoxy)-tetrahydro-pyrrolo[1,2-c]oxazol-3-one as a white solid.
Reaction SMILES: C([Mg]Br)C.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.Cl[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([Mg]Br)=[CH:48][CH:47]=1.[Cl-].[NH4+]>C1COCC1>[F:43][C:38]1[CH:37]=[C:36]([C:49]2[CH:50]=[CH:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=2)[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Fc1ccc(Cl)cc1F
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A THF solution of ethylmagnesium bromide (0.55 mL, 1.08 M, 0.60 mmol) was added to CoF2.4H2O (17.0 mg, 0.10 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (85.4 mg, 0.20 mmol) at 0° C. under argon atmosphere. The following process was also performed under argon atmosphere. After stirring for four hours at room temperature, 4-chloro-1,2-difluorobenzene (297.0 mg, 2.0 mmol) and a THF solution of p-methoxyphenylmagnesium bromide (3.40 mL, 0.88 M, 3.0 mmol) was added to the mixture. The reaction was performed at 60° C. for 12 hours. After cooled to the ambient temperature, 2.0 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture. The water layer was extracted five times using Et2O. The total organic extract was filtrated by Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). After removing the solvent under reduced pressure, the crude product was purified by silica gel chromatography (toluene=5% in hexane), thereby obtaining the above compound, which was a white solid (0.428 g, yield=97%, purity=>98% (GC analysis)).
Reaction SMILES: C1COCC1.C([O-])(=O)C1C=CC=CC=1.[Li+].[OH-].[OH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([CH:25]([CH3:27])[CH3:26])[C@@H:20]1[CH3:28]>O>[OH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([CH:25]([CH3:27])[CH3:26])[C@H:20]1[CH3:28]
Reactant: CC(C)N1C(=O)O[C@H](CO)[C@H]1C
Agent: O=C([O-])c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1C(=O)O[C@H](CO)[C@@H]1C

Procedure:
A THF (87 ml) solution of 4.80 grams of (S)(S)-oxazolidinone from Step G was stirred at 22° C. and treated with 87 ml of 1N LiOH in H2O. After 2.5 hours at 22° C. the THF was removed by rotary evaporation and the product extracted with CH2Cl2. The combined organic portions were washed with saturated aqueous Na2CO3, H2O, and brine, dried (Na2SO4) and concentrated to essentially pure product as a white foam; yield 2.93 g (95%). ##STR25## Similarly prepared is the 5(S)-hydroxymethyl-4(R)-methyl-3-(1-methylethyl)oxazolidin-2-one.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCC)(OCC)OCC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: CCOP(OCC)OCc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 200 °C
Yield: 87 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 15 parts of benzyl diethyl phosphite are mixed and heated to 200° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 33 parts of water are removed in the course of 5 hours. After distilling off excess α-naphthol and aniline, 381 parts of phenyl-α-naphthylamine, boiling at 202° - 204° C/5 mm Hg. are obtained; the product has a melting point of 55° - 58° C and corresponds to a yield of 87% of theory.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl.C(#N)C>[CH3:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])=[C:10]1[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OC(=O)C(C)(C)C)c(=O)ccn1C
Reaction time: 0.25 h

Procedure:
5.6 ml of triethylamine are added to a suspension of 5.56 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 400 ml of methylene chloride and 400 ml of acetonitrile, followed by the addition, over 30 minutes, of 7.38 ml of trimethylacetyl chloride. The reaction is complete after 15 minutes. The resultant solution is concentrated by evaporation under reduced pressure, the residue is taken up in water and extracted with methylene chloride. The residue of the organic extract is crystallised from 500 ml of ethyl acetate, affording 1,2-dimethyl-3-pivaloyloxy-4(1H)-pyridinone, which melts at 112°-113° C. (sinters from 103° C.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]N(CCN(C)C)C.[Li]C(CC)C.S(OC)(OC)(=O)=O>CCOCC.O>[C:1]([N:8]1[CH:13]([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CCC1CCCC(C)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of N-Boc-2-ethylpiperidine (1.5 g, 7.0 mmol) in 28 mL of ether was cooled to −60° C. and treated with TMEDA (1.6 mL, 10.85 mmol), followed by sec-BuLi (8.5 mL, 10.85 mmol) dropwise. The mixture was slowly warmed to −20° C., stirred for 30 min, and then cooled to −78° C. The mixture was treated with a solution of dimethyl sulfate (1.6 mL, 16.69 mmol) in ether and slowly warmed to room temperature. The mixture was diluted with water and then extracted with ether. The combined extracts were dried over K2CO3 and concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane to give 0.88 g (59%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ3.91-3.87 (m, 1 H), 3.69-3.65 (m, 1 H), 1.83-1.41 (m, 17 H), 1.21-1.19 (d, 3 H), 0.85-0.82 (t, 3 H); 13C NMR (62.7 MHz) 155.2 (s), 78.6 (s), 53.0 (s), 46.8 (s), 28.5 (s), 27.2 (s), 26.7 (s), 22.4 (s), 20.7 (s), 13.4 (s), 11.4 (s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7](COCC[Si](C)(C)C)[N:6]=[CH:5]2.N1CCCCC1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (543 mg, 0.819 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 10 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. After washing with several volumes of methanol, the product was eluted with 2M ammonia in methanol. Concentration gave the crude piperidine. The piperidine was dissolved in dichloromethane (5 mL) and treated with di-tert-butyl dicarbonate (224 mg, 1.02 mmol). After 1 h, the reaction was quenched by addition of 2M ammonia in methanol and concentrated. The residue was suspended in water and extracted with diethyl ether. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (EtOAc/Hex) gave 420 mg (96%). 1H-NMR (CDCl3, 500 MHz) δ 10.05 (bs, 1H), 7.89 (s, 1H), 7.71 (d, J=1.8, 1H), 7.23 (m, 2H), 7.08 (d, J=1.5, 1H), 7.02 (m, 2H), 4.48 (q, J=6.7, 1H), 3.70 (m, 2H), 3.34 (d, J=9.2, 1H), 3.23 (d, J=8.9, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.72 (m, 1H), 1.41 (s, 9H), 1.40 (d, J=6.7, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 162.6, 160.6, 155.0, 138.1, 135.9, 133.7, 128.7 (d, J=7.7), 127.9, 126.5, 125.5, 122.3, 115.7, 115.6, 113.6, 79.6, 78.6, 78.0, 41.2, 40.1, 32.5, 32.1, 28.5, 22.2, 14.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])=[C:5]2[OH:23].C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:23][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)[CH:3]=2)[N:8]([CH3:12])[C:7](=[O:13])[C:6]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: C1COCCN1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(N3CCOCC3)ccc21
Temperature: 80 °C
Reaction time: 21 h
Yield: 11 %

Procedure:
A solution of ethyl 2-(6-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (202 mg, 527 μmol), Pd2dba3.CHCl3 (55 mg, 53 μmol), X-Phos (50 mg, 105 μmol) and morpholine (115 μl, 1318 μmol) in 1,4-dioxane (3 ml) was treated with sodium tert-butoxide (203 mg, 2109 μmol). The reaction was stirred at 80° C. in a sealed tube. After 21 hours, the solution was adsorped onto silica gel, concentrated in vacuo and purified by silica gel chromatography (eluant: 4% methanol/dichloromethane, followed by/dichloromethane+1% AcOH) and subsequently by RP HPLC (0-100% MeCN/water+1% TFA, 10 min) affording 21 mg (11%) of 2-(4-hydroxy-1-methyl-6-morpholino-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid as an yellow solid.
Reaction SMILES: C([Li])(C)(C)C.C1(C)C=C(C)C=C(C)C=1Br.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1.C(=O)=O.CC(C)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](=[O:42])[C:36]2=[O:43].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](=[O:42])[C:36]2([OH:43])[C:23]1[C:18]([O:17][CH3:16])=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(C)cn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C=O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
Under nitrogen atmosphere and under dry ice-acetone cooling, tert-butyl lithium (64.0 ml; 1.42 mol/L n-pentane solution) was added to THF (150 ml), then, mesityl bromide (6.57 ml) was added dropwise over 2 minutes. The solution was stirred for one hour under the same conditions. 4.07 g of 2-methoxy-5-methylpyridine was added dropwise to the solution over 3 minutes and then the reaction mixture was stirred under ice cooling for one hour and at room temperature for 30 minutes. The solution was dry ice-acetone-cooled again, a suspension of 3.00 g of 5-chloroisatin in THF (75 ml) was added dropwiseover 2 minutes, then the reaction mixture was warmed to room temperature and was stirred for 18 hours. To the reaction solution was added a saturated aqueous solution of NH4Cl and EtOAc, then liquid separation was performed, the aqueous layer was extracted with EtOAc, the combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH/NH4OH=97/3/0.3; v/v/v) to obtain 2.05 g of the title compound (yellow solid).
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.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[CH2:1]([S:8]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Nc1ccccc1NS(=O)(=O)Cc1ccccc1

Procedure:
The sulfonamide was synthesized from benzylsulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:9][NH:10][CH2:11]1)=[O:5]
Reactant: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.40 g, 0.9 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.20 g, 64%) which was used without further purification. Propane-1-sulfonyl chloride (0.04 ml, 0.34 mmol) was added to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.10 g, 0.28 mmol) and triethylamine (0.08 g, 0.56 mmol) in dichloromethane (2 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on a silica cartridge eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%) led to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an off-white solid. m/z (M++H) 464, 1H NMR (500 MHz, DMSO): δ 9.34 (s, 1 H); 7.58 (t, J=6.7 Hz, 1 H); 7.43 (s, 1 H); 4.07 (t, J=12.7 Hz, 1H); 3.91 (d, J=7.8 Hz, 1 H); 3.79 (d, J=7.8 Hz, 2 H); 3.65 (d, J=8.1 Hz, 1 H); 3.53 (d, J=10.8 Hz, 1 H); 3.17 (s, 2 H); 3.05 (t, J=7.4 Hz, 2 H); 2.80 (s, 1 H); 2.56 (s, 2 H); 1.75 (s, 1 H); 1.67 (dd, J=7.8, 15.0 Hz, 5 H); 1.39 (s, 2 H); 0.96 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-4-carboethoxymethylpiperazine (20.8 g, 76.5 mmol) and lithium hydroxide (6.71 g, 160 mmol) in tetrahydrofuran (100 mL) and water (100 mL). After 60 minutes, concentrate in vacuo to give a solid. Combine the solid and water, extract with diethyl ether. Combine the aqueous layer and a 1M aqueous solution of potassium hydrogensulfate (160 mL). Extract three times with chloroform. Evaporate the aqueous layer to give a solid. Triturate the solid repeatedly with warm ethyl acetate and isopropanol and filter. Evaporate each triturate to give solids. Combine the solids obtained by evaporation of the triturates, dissolve in chloroform and evaporate to remove solvent. Dry in vacuo at 50° C. to give 1-t-butoxycarbonyl-4-carboxymethylpiperazine as a solid, mp: 195-197° C. IR (KBr) nmax 3007, 2934, 1691, 1631, 1479, 1453, 1427, 1415, 1393, 1366, 1301, 1283, 1232, 1209, 1177, 1139, 1084 cm-1 ; 1H NMR (CDCl3) ppm 3.71 (br s, 4 H), 3.56 (br s, 2 H), 3.12 (br s, 4 H), 1.46 (s, 9 H); 13C NMR (CDCl3) ppm 169.10, 154.13, 80.70, 58.49, 52.38, 28.25; MS (CI/NH3) m/z 245 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH2:13][N:14]2[C:18]([CH3:19])=[C:17]([Br:20])[CH:16]=[N:15]2)[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)[CH:2]=C.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:30].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[Br:20][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:5]2([O:4][CH2:1][CH2:2][OH:30])[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6]2)[C:18]=1[CH3:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: Cc1c(Br)cnn1CC1(OCCO)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 180A (2.80 g) in dioxane/water (30 mL/10 mL) was added to 2,6-dimethylpyridine (1.909 mL) and sodium periodate (7.02 g) followed by the addition of osmium tetroxide (2.5% solution, 1.0 mL) and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in methanol (20 mL) and sodium borohydride (0.16 g) was added. The mixture was stirred at room temperature for 1 hour. An aqueous work up followed by silica gel chromatography using 2-30% ethyl acetate in hexanes provided the title compound.