Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CO.I([O-])(=O)(=O)=[O:36].[Na+]>O>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])(=[O:36])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CS(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 17 h
Yield: 12.7 %

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-ethoxyamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Example 10 in a mixed solvent of methanol (1.8 mL) and water (0.2 mL) was added sodium metaperiodate (6 mg, 0.026 mmol) at room temperature, and the mixture was stirred for 17 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-ethoxyamino)-methyl]-benzamide (1.3 mg, 13%) as an off-white solid.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[F:16][C:17]1[N:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][CH:18]=1.Cl.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[CH3:27][O:28][N:29]([CH3:30])[C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=1)=[O:25]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cccc(F)n1
Reaction time: 17 h
Yield: 19.6 %

Procedure:
Add N-methylmorpholine (6 mL, 52 mmol) and isobutylchloroformate (3.5 mL, 26.9 mmol) to a solution of 6-fluoropyridine-2-carboxylic acid (3.8 g, 26.9 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 mL, 26.9 mmol). Stir the reaction at 0° C. for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20% acetone/hexanes) to provide the title compound 0.97 g (18% from 2-fluoro-5-methylpyridine) as a clear, yellow oil.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12

Procedure:
This synthesis is depicted in FIG. 1. Ketone 1 (500 mg, 1.84 mmol) Was reduced with sodium borohydride (d, 75 mg, 2 mmol) in THF/MeOH 5:1 (18 ml) at RT (2 h). The crude product was chromatographed on silica gel (60 g) using toluene/ethyl acetate 2:1. After traces of the axial alcohol 2 (9 mg, 2%) were observed, the pure equatorial alcohol 3 (388 mg, 77%) was eluted. An analytical sample was recrystallized from MeOH/water. M.p. 124°-125°, [a]D =+14.2° (c=1.12) ([2]: m.p. 125°-127°, [a]D17 =+11.2° (c=0.76)). --IR. (CDCl3): 3620m, 3430w, 1590w. --1H-NMR. (360 Mhz): 0.77 (s, 3 H); 0.85 (s, 3 H); 3.60 t×t, J=11 and 5, 1 H); 5.70 (m, 1 H); 5.84 (m, 1 H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:40][C:41]1[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=[C:45]([Br:47])[CH:46]=1>C(Cl)Cl>[Br:47][C:45]1[CH:46]=[C:41]([NH:40][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)cc(NC(=O)C2CC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
To a mixture of cyclopropanecarboxylic acid (180 mg, 2.0 mmol), HATU (570 mg, 1.5 mmol) and DIPEA (390 mg, 3.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (230 mg, 1.12 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column chromatography eluting with 20:1 DCM/methanol to afford the 102a (220 mg, 72%). MS-ESI: [M+H]+ 270.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1.CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1cccc(S)c1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol), 3-methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8 mg, 1.58 mmol) was added and reaction stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (345 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]=[O:13])=[CH:5][N:6]2[CH3:11].[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([OH:15])=[O:13])=[CH:5][N:6]2[CH3:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cn1cc(C=O)c2c(F)cccc21
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)O)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
In acetone (95 ml) was dissolved 4-fluoro-1-methylindole-3-carbaldehyde (1.43 g, 8.08 mmol), followed by the addition of potassium permanganate (a 0.2M aqueous solution, 62.0 ml, 12.4 mmol) in portions at room temperature. After the reaction mixture was stirred at room temperature for 16 hours, the precipitate was filtered off through Celite. The filtrate was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give 4-fluoro-1-methylindole-3-carboxylic acid (0.91 g, 58%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9](=[S:11])[NH2:10])=[CH:4][CH:3]=1.[CH2:21](OC(OCC)CBr)[CH3:22]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]2[S:11][CH:21]=[CH:22][N:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(C(c2ccc(Cl)cc2)c2nccs2)cc1

Procedure:
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide (800 mg, 2.608 mmol, 1 equip) and bromoacetaldehyde diethyl acetal (2.055 g, 10.431 mmol, 4 equip) in acetic acid (12.09 mL) and water (0.47 mL) was heated at 100° C. for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, saturated sodium bicarbonate, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC using ethyl acetate-heptane as eluent to yield 2-((4-chlorophenyl)(4-nitrophenyl)methyl)thiazole as a viscous brown oil.
Reaction SMILES: CC12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26]C)=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18]C(C)(C)C)=[O:17])OC1CC1CC2C1(C)C.B(Cl)(Cl)Cl>>[OH:10][B:9]1[C@@H:11]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][NH:35][CH2:34]3)=[O:30])[CH2:12][C:13]2[CH:25]=[CH:24][CH:23]=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[O:26]1
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(N[C@H]1Cc2cccc(C(=O)O)c2OB1O)c1ccc2c(c1)CNC2

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 353 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])(O)[CH3:13])=[N:9][CH:10]=1.CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:22][C:12]([CH3:15])([CH3:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1
Reactant: COCOc1ccc(CC(C)(C)O)nc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)F)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol (7.600 g, 36.0 mmol) was dissolved in 200 ml CH2Cl2 and cooled to −78° C. DAST (9.51 ml, 72.0 mmol) was added drop wise to the solution and stirring was continued for 30 min The mixture was allowed to warm up to 0° C. and was hydrolyzed with NaHCO3 (200 ml). Stirring was continued in the cold until gas evolution had ceased and the phases were separated. The aqueous was extracted 2× with EtOAc and the combined organic layers were dried over MgSO4 and evaporated. Glass col. Chromatography of the crude material provided 2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.80 g, 75.6% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.C([C:18]1[C:19]([N:27]=[CH:28][N:29]([CH3:31])C)=[N:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=1)#N>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([NH:8][C:31]2[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[N:20][C:19]=3[N:27]=[CH:28][N:29]=2)[CH:7]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ncnc2n1
Temperature: 130 °C

Procedure:
The product from Example 5I (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (68 mg, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.94 (t, J=7.4 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.35 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 7.18 (m, 5H), 7.23 (m, 2H), 7.37 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 8.48 (s, 1H), 8.69 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 387 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1.O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][S:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[N:7]=1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)C1CCCCC1
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(Cl)n1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a cooled (ice/water bath) solution of 2,4-dichloro-6-(cyclohexylsulfonylmethyl)pyrimidine (1.65 g, 5.34 mmol) in DCM (25 mL) was added triethylamine (0.820 mL, 5.88 mmol). The resulting solution was treated, dropwise over 8 minutes, with a solution of (3S)-3-methylmorpholine (609 mg, 6.02 mmol) in DCM (5 mL). The mixture was stirred at 6° C. for 30 minutes. The cooling bath was then removed and reaction mixture left to stir overnight. Water (25 mL) was then added and reaction mixture stirred for 5 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give a crude brown oil, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (1.440 g).
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30].[ClH:33]>CN1CCCC1=O.O1CCOCC1>[ClH:33].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CN
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCC(C)(C)O)cc3)cc2s1
Temperature: 150 °C
Yield: 25 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (135 mg, 0.34 mmol) and 1-amino-2-methylpropan-2-ol (153 mg, 1.718 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 20 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate (3×20 ml) and washed with water (4×25 ml). The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on silica, on an 8 g 15-35 μm AIT column, eluting with a 9/1 ethyl acetate/cyclohexane mixture. After evaporating off the solvent, 55 mg of a colorless solid are obtained. The product is dissolved in a minimum amount of dioxane, and 4 N hydrochloric acid dissolved in dioxane is added. The precipitate obtained is filtered off by suction, washed with dioxane and then dried under vacuum at 40° C. to give 42 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride, i.e. a yield of 25%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C

Procedure:
13-(Quinolin-2-ylmethoxy)-phenol (5.2 g, 21 mmol, example 3), methyl 2-bromomethyl-6-methyl-benzoate (example 2) (5.0 g, 21 mmol) and potassium carbonate (4.4 g, 32 mmol) are combined in DMF (50 mL) and heated at 85° C. for 3 h. The reaction is poured into ethyl acetate (500 mL) and washed with water (4×120 mL) and brine (100 mL). The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to provide a residue which is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexane) to provide the title compound. MS (ESI) 414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:26][CH:25]=1
Reactant: CN(C)CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)cc1
Temperature: 90 °C
Yield: 66.4 %

Procedure:
To a suspension of 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (250 mg, 0.78 mmol) in dioxane (8 mL) was added 4-((dimethylamino)methyl)cyclohexanamine (233 mg, 1.55 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (225 mg, 66%) as a yellow solid. ESI MS m/z 434 [C29H20BrN3O2+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH:27]=[O:28]
Reactant: Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1ccc(-c2ccc(C=O)c(Cl)c2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 4.76 g of 3-chloro-4'-methylbiphenyl, 2.94 g of hexamethylenetetramine and 30 ml of trifluoroacetic acid is heated to boiling under reflux for 5 days. The reaction mixture is then concentrated and treated with ice-water, whereupon it is stirred for 15 minutes, made basic with sodium carbonate and extracted with ether. After evaporation of the ethereal extracts and chromatography of the residue on silica gel with methylene chloride/methanol 9:1 as the eluent, there is obtained 2-chloro-4-(4'-methylphenyl)benzaldehyde, b.p. 210°-215°C./25 Pa.
Reaction SMILES: N1(C2N=CN=C(NC3C=C(CS(N)(=O)=O)C=CC=3)N=2)CCCCC1.Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:34]=[C:35]([CH2:39][S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[N:27]=1.[OH:44][CH2:45][CH:46]1[CH2:51][NH:50][CH2:49][CH2:48][NH:47]1>>[OH:44][CH2:45][CH:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[C:26]1[N:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:34]=[C:35]([CH2:39][S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OCC1CNCCN1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCNCC3CO)n2)c1

Procedure:
B13 was prepared following the procedure reported for B1 using A1 and rac-2-(hydroxymethyl)piperazine. MS (ES) C15H21N7O3S requires: 379. found: 380 (M+H)+.
Reaction SMILES: [CH3:1]N(CN(C)C)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=[O:18].C(OC(=O)C)(=O)C>>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[CH2:1])[C:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=[O:18]
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)c1ccc(SC)nc1)c1ccc(F)cc1F
Yield: 50.2 %

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (5.2 ml, 38 mmol) was added to a stirred mixture of the product of part (iii) (7.2 g, 26 mmol) and acetic anhydride (3.6 ml, 38 mmol) and the reaction temperature was moderated by use of water bath at ambient temperature. After 1 hour at room temperature the yellow solution was poured onto ice and the mixture extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with dilute hydrochloric acid (0.2M, 50 ml) followed by saturated sodium bicarbonate solution (50 ml), then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with ether/hexane (1:4) to give the title compound as a yellow solid, (3.8 g).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[CH:26]=[C:25]([C:27]#[N:28])[O:24][N:23]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[CH:26]=[C:25]([C:27]#[N:28])[O:24][N:23]=1
Reactant: N#Cc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3O)no1
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
BCl3 (1M in DCM, 1.6 mL) was added to a solution of 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carbonitrile (104 mg, 0.32 mmol) in dry CH2Cl2 (9 mL) at −78° C. The mixture was stirred −78° C. for 2 hrs and quenched carefully with MeOH (2 mL). The solvents were removed in vacuum and the residue was partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated to afford 3-((2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carbonitrile (45 mg, 60%), which was used directly in the next step. ESI-MS (EI+, m/z): 235.1 [M+H]+.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[O:16]>O.C1(C)C=CC=CC=1>[CH2:7]([CH:6]1[O:14][C:15](=[O:16])[NH:4][CH2:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: NCC(O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCC(Cc2ccccc2)O1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of KOH (9.4 g) in water (85 ml) was added to a stirred solution of the product from step (b) (5.1 g) in toluene (150 ml) at 0° C. A solution of phosgene (9.8 g) in toluene (78.4 ml=12.5% w/v) was added dropwise over 15 minutes and the mixture brought to room temperature, then stirred overnight. The aqueous phase was separated and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give the desired product as a white solid (2.2 g), mp 106°-108° C. Elemental anaylsis was consistent with the proposed structure.