Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:10][C:11](O)=[O:12])=[C:4]([CH2:27][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[CH:3]=1.C([N:38]1CCOCC1)C.ClC(OCC)=O.N>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:10][C:11]([NH2:38])=[O:12])=[C:4]([CH2:27][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)O)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: CCN1CCOCC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(CCC(N)=O)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 1 h

Procedure:
To 0.8 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]-β-alanine dissolved in 16 ml of tetrahydrofuran are added, at 0° C., 0.21 ml of N-ethylmorpholine and 0.16 ml of ethyl chloroformate. The mixture is left at room temperature for 1 hour, and 1.36 ml of ammonia (20%) in water are then introduced. After 48 hours at room temperature, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue is chromatographed on a column of silica gel, eluting with a 98/2 (v/v) dichloromethane/methanol mixture to give 0.295 g of the expected product.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:31])C.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16](=[O:31])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Product: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 0.5 h

Procedure:
2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate (466 mg.) was added to acetic acid (2 cc), and sodium percarbonate (377 mg.) was added thereto while cooling in an ice bath. The mixture was stirred for 30 minutes, and sodium tungstate dihydrate (40 mg.), acetic acid (1 cc) and water (1 cc) were added thereto. The mixture was stirred for 3 hours, and then water (50 cc) was added thereto. The precipitate was collected by filtration, washed with water and dried to yield crude crystals (400 mg.) of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide, m.p. 165°-167° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18].CCOC(C)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CS(=O)(=O)c1ccccc1I
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1S(C)(=O)=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a stirred suspension of Cu(0) (496 mg, 78 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added ethylbromodifluoroacetate (0.5 mL, 39 mmol). The reaction mixture was stirred at 35° C. for 30 min. Then the solution was brought to room temperature and 1-iodo-2-methanesulfonylbenzene (1.0 g, 35 mmol), as prepared in the preceding step, was added. The reaction mixture was stirred at 35° C. for 12 h. The reaction mixture was cooled to room temperature and passed through a bed of Celite using EtOAc to rinse. The filtrate was washed with saturated NH4Cl (50 mL) until the blue color dissipated. The organic phase was then washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 772 mg crude product. The residue was purified by flash column chromatography (20-40% ethyl acetate in hexanes) to yield the desired compound (264 mg, 27%). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=7.6 Hz, 1H), 7.94 (dd, J=7.7 Hz, 1.7 Hz, 1H), 7.76 (pd, J=7.6 Hz, 1.5 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (m/z) [M+1]+ 279.3 (calculated for C11H13F2O4S, 279.3).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]2[C:9]3[CH:10]=[CH:11][C:12]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[C:8]=3[NH:7][S:3](=[O:5])(=[O:4])[N:2]2[CH3:1])=[CH:21][CH:22]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
N-Methylsulfamoyl chloride (Intermediate 213) (161 mg, 1.24 mmol) was added to suspension of (8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone (Intermediate 367) (110 mg, 0.41 mmol) in pyridine (10 ml) and the mixture was stirred room temperature for 18 h. NaBH4 (16 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for a further 18 h. The reaction was quenched with water (20 ml) and the aqueous phase was extracted with EtOAc (30 ml). The organic phase was washed with brine (15 ml), dried (Na2SO4) and concentrated n vacuo. The crude residue was purified by column chromatography heptane/EtOAc (80:20-50:50 gradient) as the eluent to give the title compound (20 mg, 14%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH2:31][C@@H:27]3[CH2:26][O:25][CH3:24])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: COC[C@H]1CCCN1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: COC[C@H]1CCCN1c1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (R)-2-(methoxymethyl)pyrrolidine (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (44 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 1.90-2.18 (m, 4 H) 3.24 (s, 3 H) 3.37 (dd, J=9.47, 7.20 Hz, 1 H) 3.54 (dd, J=9.73, 3.66 Hz, 1 H) 3.68-3.79 (m, 1 H) 3.83-3.98 (m, 1 H) 5.25 (br. s., 1 H) 6.28 (d, J=2.27 Hz, 1 H) 7.06 (s, 1 H) 7.61 (d, J=8.59 Hz, 2 H) 7.98 (d, J=8.59 Hz, 2 H) 8.04 (d, J=2.02 Hz, 1 H) 10.81 (s, 1 H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([CH2:33]O)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.COCCN(S(F)(F)[F:46])CCOC.C(=O)([O-])O.[Na+]>ClCCl>[F:46][CH2:33][CH:30]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:9]=[C:10]([O:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:35])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:24][CH:25]=2)=[N:32][CH2:31]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(CO)O3)[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(CF)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol (100 mg, 0.20 mmol) synthesized in Example 29 was dissolved in dichloromethane (5 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (81 μL, 0.44 mmol) was added at 0° C. After stirring at room temperature for 6 hours, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with dichloromethane (60 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired product (61 mg, yield 61%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Temperature: 80 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.10 mmol) from Example 72, Step B, in N,N-dimethylformamide (1.5 mL) was added benzyl bromide (0.017 mL, 0.15 mmol) and potassium carbonate (41 mg, 0.29 mmol). The resulting mixture was warmed to 80° C. After 4 h the reaction was cooled to room temperature, diluted with ethyl acetate, washed with 50% saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (31 mg, 80%). MS (ESI) 395.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH2:41][OH:42]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH:41]=[O:42])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 17.7 g of N-benzyloxycarbonyl-glycin. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 600 ml of THF. To this solution was added 9.2 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of a 1-M Na2CO3 solution, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 38.7 g of WSCD.HCl and 155 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Successively, 7.7 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 360 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 250 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 300 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 4.5 g (15.6%).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:19])[C:16](O)=[O:17].ClC(OCC)=O.[BH4-].[Na+].C(=O)([O-])OCC.C1C2CC3C(=CC=CC=3)OC=2C=CC=1C(C(=O)OC(=O)OCC)C>O.C1COCC1.C(N(CC)CC)C>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:19])[CH2:16][OH:17]
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1ccccc1O2
Agent: CCOC(=O)Cl
Agent: CCOC(=O)OC(=O)C(C)c1ccc2c(c1)Cc1ccccc1O2
Agent: CCOC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2
Reaction time: 0.5 h

Procedure:
2.54 g. of 2-(2-xanthenyl)-propionic acid is dissolved in 20 ml. of absolute THF and combined with 1 ml. of triethylamine. At -10°, a solution of 0.6 ml. of ethyl chloroformate in 4 ml. of THF is added dropwise within 15 minutes, the mixture is stirred for 30 minutes at -10° and then 0.5 g. of NaBH4 is introduced into the solution which contains the mixed anhydride of monoethyl carbonate and the aforementioned acid, 2-(2-xanthenyl)-4,6-dioxaoctane-3,5-dione. Thereafter, the mixture is stirred for 90 minutes at 25°, 10 ml. of water is added, the mixture extracted with ether, evaporated, and the thus-obtained residue refluxed for 30 minutes with a solution of 0.25 g. of KOH in 10 ml. of ethanol. After the ethanol has been distilled off, the mixture has been worked up as usual, and the product chromatographed on Al2O3, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[CH:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:15](/[CH:14]=[CH:13]/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:45][C:42]2[CH:43]=[CH:44][C:39]([C:38]([F:37])([F:46])[F:47])=[CH:40][CH:41]=2)[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 392 mg (0.72 mmol) of methyl 4-[(4E)-5-[2-(4-bromobutoxy)phenyl]-3-(4-cyanobenzyl)pent-4-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 174 mg (1.08 mmol) of 4-trifluoromethylphenol and 148 mg (1.08 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. 450 mg (0.61 mmol, purity 86%, 86% of theory) of a yellowish oil are isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:23][S:24]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 53.1 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.30 g, 1.0 mmol), methanesulfonyl chloride (0.08 ml, 1.0 mmol) and triethylamine (0.32 ml, 4.0 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. 5-(4-methansulfonylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.20 g, 52%) was obtained by flash column chromatograph (30% ethyl acetate in hexanes). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.90 (s, 3H), 3.20 (t, J=5.3 Hz, 4H), 3.42 (t, J=5.3 Hz, 4H), 6.46 (d, J=3.6, 1H), 6.62 (dd, J=3.6, 9.7 Hz, 1H), 7.21-7.46 (m, 5H), 8.05 (d, J=9.7 Hz, 1H), 9.74 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 34.2, 44.7, 45.9, 95.9, 106.6, 123.5, 124.8, 128.3, 129.6, 138.9, 144.3, 154.9.
Reaction SMILES: [O:1]=O.[CH2:3]([C:5]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6]1)[CH3:4]>>[CH2:3]([C:5]1([C:9]([OH:1])=[O:10])[CH2:8][O:7][CH2:6]1)[CH3:4]
Reactant: O=O
Reactant: CCC1(CO)COC1
Product: CCC1(C(=O)O)COC1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
The procedure as in Example 10 is carried, but at an oxidation temperature of 50° C. After 2 hours, 0.9 mol of oxygen has been taken up per mol of 3-ethyl-3-hydroxymethyl-oxetane. After working up, 3-ethyl-oxetane-3-carboxylic acid is obtained in a yield of 86.2% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30](OCC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][CH2:30][OH:31])=[C:20]([F:19])[C:25]=2[F:26])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Product: OCCCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared by reacting the product prepared in Step D of Example 1 and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Step E, and then according to Example 2.
Reaction SMILES: [OH-:1].[Na+].C1(CO[C:11](=O)[CH2:12][C:13](=[O:32])[NH:14][C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[O:30][CH3:31])C=CC=CC=1>CO>[OH:1][CH:12]([C:11]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[C:13]([NH:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[O:30][CH3:31])[C:21]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:29])=[O:32]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)CC(=O)OCc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)C(O)c1ccccc1

Procedure:
1N Sodium hydroxide (3 mL) was added to (2-methoxy-5-phenylcarbamoyl-phenylcarbamoyl)-acetic acid phenylmethyl ester from Example 252 (1.29 g, 3.1 mmol) in methanol (80 mL) and the reaction mixture boiled until most of the solvent was gone. Additional 1N sodium hydroxide (4 mL) and methanol (80 mL) were added and the mixture again concentrated to near dryness. Ethyl acetate (100 mL), water (100 mL), and 1N HCl (10 mL) were added, the layers separated, the organic layer washed with brine (50 μL), dried over magnesium sulfate, and concentrated to an oil. Trituration in hexanes/ethyl acetate (4:1) afforded the product (0.826 g); m.p. 173-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:20])=[C:13]([NH:18][CH3:19])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C:32](=O)[O:33]CC)(=[O:30])=[O:29])=[CH:25][CH:24]=1>CC(O)=O>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([F:20])=[C:13]([NH:18][CH3:19])[CH:14]=4)[C:9]3=[O:21])=[CH:4][CH:3]=2)=[O:33])(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CC2
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of 2-(4-aminophenyl)-7-fluoro-6-(methylamino)-3,4-dihydroisoquinolin-1(2H)-one (62 mg, 0.22 mmol) in HOAc (4 mL) at 100 C, ethyl 5-chlorothiophen-2-ylsulfonylcarbamate (119 mg, 0.44 mmol) was added. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by RP-HPLC to give the titled compound as a powder (25 mg). ES-MS (M+H)+=509, 511 (Cl pattern).
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])[CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]1([O:5][C:4]([CH2:3][CH:2]([C:7]([O:9][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])[CH2:1][C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCCC1
Reactant: O=C(O)CC(CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(CC(CC(=O)OC1CCCCC1)C(=O)OC1CCCCC1)OC1CCCCC1
Yield: 83.4 %

Procedure:
A mixture of 1,2,3-propanetricarboxylic acid (25 g), cyclohexanol (55 g), and p-toluenesulfonic acid (100 mg) in toluene (500 mL) was refluxed for 2 days and water removed from the reaction mixture. After reaction was complete, solvent was removed in vacuuo to yield a viscous oil. The crude material was redissolved in heptane and passed through a pad of silica gel to obtain 1,2,3-propanetricarboxylic acid tricyclohexyl ester (50 g) as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.O>CS(C)=O.CCOC(C)=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]4[C:21]5=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]5[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4[nH]ccc4c3)C2=N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN2CCCC(c3ccc4c(ccn4CCc4ccc(F)cc4)c3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 2 %

Procedure:
To a mixture of cesium carbonate (435 mg) and 9-(1H-indol-5-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in DMSO (5 mL) was added 1-(2-bromoethyl)-4-fluorobenzene (136 mg). The mixture was stirred at room temperature for 1 day. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc), concentrated and dissolved in THF (dry) (25 ml) and MeOH (25 mL). Then platinum(IV) oxide (46 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was purified by column chromatography (1st: NH silica gel, eluted with MeOH in EtOAc, 2nd: silica gel, eluted with EtOAc) to give the title compound (5.7 mg) as a white solid.