Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.C([C:62]1[CH:63]=[C:64]([F:69])[C:65]([Cl:68])=[N:66][CH:67]=1)C=C.S([O-])([O-])=O.[Na+].[Na+].[C:76]([OH:80])(C)([CH3:78])[CH3:77]>O>[Cl:68][C:65]1[N:66]=[CH:67][C:62]([CH2:77][C@@H:76]([OH:80])[CH2:78][OH:22])=[CH:63][C:64]=1[F:69]
Reactant: CC(C)(C)O
Reactant: C=CCc1cnc(Cl)c(F)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
AD-mix-beta (45 g) was added portion wise to a solution of 2 (4.5 g, 26.2 mmol) in t-butanol (135 mL) and H2O (135 mL) at 5° C. The mixture was stirred at room temperature for 16 hrs, and then cooled to 5° C. and treated with excess sodium sulfite for 20 min. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated, and chromatographed on silica gel eluted with 67% ethyl acetate in hexanes and ethyl acetate to afford 5.0 g (92%) of 3 as a colorless oil. 1HNMR (CDCl3) δ 2.04 (2 H, brs), 2.81 (2 H, m), 3.54 (1 H, t, J=5.0 Hz), 3.75 (1 H d, J=11.0 Hz), 3.94 (1 H, m), 7.46 (1 H, d, J=9.0 Hz), 8.10 (1 H, s); LC/MS (M+1) 207.
Reaction SMILES: CC1(C)COB([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=2)[N:13]=4)OC1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]([O:44][C:45]([N:47]1[CH:52]2[CH2:53][CH2:54][CH:48]1[CH:49]=[C:50](OS(C(F)(F)F)(=O)=O)[CH2:51]2)=[O:46])([CH3:43])([CH3:42])[CH3:41]>COCCOC.O>[C:40]([O:44][C:45]([N:47]1[CH:52]2[CH2:53][CH2:54][CH:48]1[CH:49]=[C:50]([C:8]1[CH:29]=[CH:28][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=4)[CH2:51]2)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OCC(C)(C)CO3)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CC4CCC(C3)N4C(=O)OC(C)(C)C)cc1OCC2
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A vessel was charged with 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (237 mg, 0.56 mmol), PdCl2dppf.DCM (46 mg, 0.06 mmol, 10 mol %) and cesium carbonate (456 mg, 1.40 mmol) before being evacuated and refilled with nitrogen. To the resultant mixture was added a solution of 3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (402 mg, 0.56 mmol) in DME (2 mL), followed by water (0.2 mL). The reaction was evacuated and refilled with nitrogen before being stirred at 110° C. for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester as a colourless oil (177 mg, 0.35 mmol, 63%). LCMS RT=4.84 min, [M+H]+=503
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 523.15 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH:37]1[O:41][C:40](=[O:42])[NH:39][CH2:38]1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][CH:37]3[O:41][C:40](=[O:42])[NH:39][CH2:38]3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: O=C1NCC(CCl)O1
Product: O=C1NCC(CN2CN(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)O1

Procedure:
The title compound, MS: m/e=604.9 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 5-chloromethyl-2-oxazolidinone.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([N:19]([CH3:25])[CH2:20][C:21](OC)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C>CO>[CH2:10]([CH:9]1[C:17](=[O:18])[N:19]([CH3:25])[CH2:20][C:21](=[O:22])[NH:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CC(=O)NC(Cc2ccccc2)C1=O

Procedure:
The compound obtained in Step (i) was treated with trifluoroacetic acid (30 ml), and then the resultant was heated under reflux in methanol in the presence of triethylamine to give the subtitle compound.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]#[N:22])=[C:12]2[NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([Cl:36])[CH:25]=1.[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH3:42].[I-].[Na+]>C1COCC1>[Cl:36][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[S:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[NH:23][C:12]1[C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([NH:8][C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH3:42])[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:21]#[N:22]
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(Sc4nccs4)c(Cl)c3)c2cc1N
Reactant: CNCCOC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(Sc4nccs4)c(Cl)c3)c(C#N)cnc2cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-[(2-methoxyethyl)(methyl)amino]-2-butenamide was prepared by adding dropwise, 3.43 g (18.71 mmol, 1.95 mL) 4-bromocrotonyl chloride in 12 mL THF over 45 minutes to a stirred solution of 4.7 g (10.69 mmol) 6-amino-4-[3-chloro-4-(thiazol-2-ylsulfanyl)-phenylamino]-7-methoxy-quinolin-3-carbonitrile in 588 mL THF containing 3.73 mL (21.36 mmol) diisopropylethylamine, at 0° C. under nitrogen. The reaction produced a mixture of 4-bromo-(and chloro)-but-2-enoic acid {4-[3-chloro-4-(thiazol-2-ylsulfanyl)-phenylamino]-3-cyano-7-methoxy-quinolin-6-yl}-amide. A 300 mL portion of the solution was cooled to 0° C. and 2.38 g (26.7 mmol) (2-methoxyethyl)-methylamine in 11 mL THF was added dropwise. After the reaction had warmed to room temperature, 401 mg (0.5 eq) of sodium iodide was added and the solution was stirred overnight. The solvents were evaporated to leave a red gum, which was partitioned between EtOAc and saturated NaHCO3. After standing overnight, the layers were separated and the organic layer was dried and evaporated. Chromatography of the residue on a short column of Kieselgel 60, eluting with EtOAc, then EtOAc/15% MeOH, and finally EtOAc/15% MeOH/1% Et3N yielded 1.3 g (41%) of the product as a yellow glass; HRMS (ESI) m/z 595.13338 (M)+, Δ=−2.28 mmu.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:39](=[O:41])[CH3:40])[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), acetic anhydride (21 μL) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.24 min.
Reaction SMILES: IC.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][CH:19]3[CH2:22][O:21][CH2:20]3)[CH2:13]2)=[CH:8][C:7]=1[O:23][CH:24]([CH3:26])[CH3:25])([O-:5])=[O:4].[C:27](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:27][N:18]([CH:19]1[CH2:22][O:21][CH2:20]1)[C@@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[C:7]([O:23][CH:24]([CH3:26])[CH3:25])[CH:8]=2)[CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cc(N2CCC[C@@H](NC3COC3)C2)ccc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 15.4 %

Procedure:
65 μl of iodomethane are added, at a temperature of about 20° C., under an argon atmosphere and with magnetic stirring, to a mixture of 293 mg of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine and 427 mg of caesium carbonate in 8 ml of anhydrous DMF. After stirring for 3 hours, 100 μl of iodomethane are added and the mixture is left to stir for a further 2 h. 10 ml of water are then added and the mixture is then extracted three times with 15 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum so as to give an oily yellow residue. The residue is purified by flash chromatography on silica gel, using a dichloromethane/methanol (98/2) eluent, so as to obtain 47 mg of (3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine in the form of an orangey-yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:20]=[C:19](OC2C=CC=CC=2)[N:18]=1>C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:20]=[C:19]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[N:18]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 150 °C
Reaction time: 4.5 h
Yield: 57 %

Procedure:
A 300 mL three-necked, round-bottomed flask fitted with a magnetic stirrer, an acid trap, a gas inlet and a heat lamp to prevent sublimation is charged with 29.9 g (0.272 mol) of resorcinol and 2.00 g (0.00525 mol) of the product of Example 2. The mixture is heated to 150° C. and hydrogen chloride gas is bubbled slowly through the molten mixture for 25 minutes. The mixture is stirred at this temperature for another 4.5 hours and then allowed to cool to room temperature. Portions of water and toluene are added and the mixture is refluxed till the solids are dissolved. The mixture is allowed to cool to room temperature and the layers separated. The organic layer is washed once with water, twice with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous magnesium sulfate and filtering, the solvent is removed under reduced pressure to afford 1.56 g of crude product. Purification by flash chromatography on silica gel with 3:1 heptane:ethyl acetate gives 1.19 g (57% yield) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[N:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:5](=[O:15])[C:4]2[S:16][CH2:17][CH2:18][S:19][C:3]1=2.[H-].[Na+].Cl[C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24].C(O)C>O1CCCC1>[CH3:14][O:13][C:10]1[N:9]=[N:8][C:7]([N:6]2[CH:2]([O:1][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[C:3]3[S:19][CH2:18][CH2:17][S:16][C:4]=3[C:5]2=[O:15])=[CH:12][CH:11]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COc1ccc(N2C(=O)C3=C(SCCS3)C2O)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(N2C(=O)C3=C(SCCS3)C2OC(=O)N2CCN(C)CC2)nn1
Temperature: 5 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
A solution of 5-hydroxy-6-(6-methoxypyridazin-3-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.9 g.) in anhydrous tetrahydrofuran (90 cc.) is treated for 30 minutes at about 15°-20°C, with sodium hydride (0.87 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (19.5 g.) in anhydrous tetrahydrofuran (120 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is taken up in an ice-cold normal aqueous solution of methanesulphonic acid (150 cc.). The acid solution obtained is rapidly washed twice with diethyl ether (total 100 cc.) and then rendered alkaline by adding 10N sodium hydroxide solution (25 cc.). The oil which separates out is extracted three times with methylene chloride (total 300 cc.). The combined organic extracts are washed twice with distilled water (total 100 cc.), dried over anhydrous magnesium sulphate and evaporated. The crystals obtained (8.7 g.; m.p. 196°-198°C.) are dissolved in boiling ethanol (300 cc.). After filtering the boiling solution and then cooling it for three hours at 2°C, the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20mm.Hg). 6-(6-Methoxypyridazin-3-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (7.7 g.), melting at 200°C, is thus obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]3[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=C(F)C=1I.CCN(CC)CC.Cl[CH:52](Cl)/[CH:53]=[N:54]/[NH:55]S(C1C=CC(C)=CC=1)(=O)=O>CO>[F:23][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:1]3[CH:52]=[CH:53][N:54]=[N:55]3)[O:7][C:6]2=[O:8])[CH:14]=[C:13]([F:15])[C:12]=1[CH:16]1[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)N/N=C/C(Cl)Cl)cc1
Reactant: NC[C@H]1CN(c2cc(F)c(C3CCC(=O)NC3)c(F)c2)C(=O)O1
Agent: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CCC(c2c(F)cc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CN1
Reaction time: 16 h

Procedure:
5-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-difluorophenyl}piperidin-2-one (0.1 g, 0.31 mmol) (prepared by the route described in Example 1, substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide) is dissolved in MeOH (2 mL). To this mixture is added Et3N (0.125 ml, 0.9 mmol) and N′-[(1E)-2,2-dichloroethylidene]-4-methylbenzenesulfonohydrazide (0.17 g, 0.6 mmol)(Prepared in Example 26 step 1). The reaction is stirred at 0° C. to RT for 16 hours. The mixture was concentrated to dryness, reconstituted in CH2Cl2 (125 mL) and extracted with H2O. The organic layer was dried (MgSO4), loaded onto a SIM and purified on a Biotage 12M column to yield (0.033 g, 30%). 1H-NMR (DMSO) δ: 8.17, 7.77, 7.61, 7.25, 5.16, 4.83, 4.21, 3.87, 3.28, 3.18, 2.29, 1.86
Reaction SMILES: [C:1]([C:6]1[N:7](C)[S:8](=[O:18])(=[O:17])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])([O:3]CC)=O.[NH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1>C1(C)C(C)=CC=CC=1>[OH:12][C:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8](=[O:17])(=[O:18])[NH:7][C:6]=1[C:1](=[O:3])[NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1
Reactant: Cc1cc(N)no1
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2)no1

Procedure:
A mixture of 15.3 g. (0.06 mole) of 3-carbethoxy-4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, 5.9 g. (0.06 mole) of 3-amino-5-methylisoxazole, and 800 ml. of xylene was refluxed for 24 hr. in a Soxhlet apparatus, the thimble of which contained 20 g. of Linde type 4A molecular sieve. The mixture was cooled to 25° and the resulting precipitate was collected and washed with ether to give 11.5 g. of crude product, m.p. 242-248° dec. Recrystallization from 300 ml. of 1,4-dioxan gave 11.2 g. of crystalline product, m.p. 254-257° dec.
Reaction SMILES: [CH3:1][C:2]([CH2:4][Cl:5])=[CH2:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>ClCCl>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][C:9]=1[C:2]([CH3:3])([CH3:1])[CH2:4][Cl:5]
Reactant: C=C(C)CCl
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)(C)CCl
Yield: 49.4 %

Procedure:
β-Methallyl chloride (90.5 g, 1.0 mole) was added dropwise to a stirred mixture of p-bromoanisole (200 g, 1.07 mole) and sulphuric acid (34.2 g, 0.35 mole) at 35°-40° C. over about 2 hours. After 21/2 hours at ambient temperature, the mixture was dissolved in dichloromethane, washed with water, aqueous sodium bicarbonate and water again, dried over magnesium sulphate and run down. Distillation of the residue gave a small forerun b.p. about 54° C. at 0.2 mm Hg and a main fraction of 182 g (62%) b.p. 99°-120° C. at 0.15-0.2 mm Hg. Recrystallisation from petroleum ether (b.p. 80°-100° C.) gave 137 g pure title product m.p. 82°-4° C. Reduction in volume of the mother liquors afforded a further 14 g product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:8]1[C:7]2[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])=[O:20])[CH3:23]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
50% Oily sodium hydride (0.21 g) was suspended in N,N-dimethylformamide (5 ml), and the resultant suspension was cooled to 0° C. 6-Fluoro-5-nitro-2-(3H)-benzothiazolone (1.0 g) was portionwise added thereto at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (0.86 g) was added to the reaction mixture at 0° C., and the temperature was gradually elevated to a temperature of 50° to 60° C., followed by stirring at that temperature for 3 hours. Water was added to the mixture, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and toluene (1:9) to give 0.35 g of 3-ethoxycarbonylmethyl-6-fluoro-5-nitro-2(3H)-benzothiazolone. m.p., 139.0°-140.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[C@H:22]([OH:23])[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC[C@@H]([C@@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (71 mg, 0.154 mmol)(Example 210, StepA) in THF (2 mL) was sparged with argon for 5 minutes. The mixture was cooled to 0° C. and methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol) was added at such a rate that the internal temperature did not get above 4° C. The mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (2×4 g stacked columns, eluent: 5 to 15% isopropanol/hexanes) to give the title compound as the more polar diastereomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[S-:25][C:26]#[N:27].[K+].BrBr.O>C(O)(=O)C>[NH2:27][C:26]1[S:25][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=1)[N:6]=2
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)cn3)c2)n(C)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a suspension of N-{3-[(5-aminopyridin-2-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.75 g, 5.41 mmol) and potassium thiocyanate (4.21 g, 43.3 mmol) in acetic acid (10 mL) was added dropwise with stirring under ice-cooling a solution of bromine (1 mL) in acetic acid (4 mL), and the mixture was stirred at 0° C. for 2 hr and at room temperature for 15 hr. Water (10 mL) was added to the reaction mixture, and the mixture was heated to 80° C. and filtered through celite. The filtrate was neutralized with 8N aqueous sodium hydroxide solution, and the precipitated solid was collected by filtration and washed with water to give the title compound (1.05 g, 51%) as a white solid.