Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
6-Aminonicotinic acid (Aldrich; 2 g, 14.48 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 1.82 g, 15.92 g) were suspended in DMF (20 mL), DIPEA (7.5 mL, 43.44 mmol) and HATU (6.05 g, 15.92 mmol) were added and the reaction stirred at ambient temperature for 18 hrs. The solvent was evaporated and the residues stirred with water (50 mL for 1 hr filtered, acidified with 2M aq HCl and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then the crude product eluted with 2M ammonia in MeOH and evaporated. The residue was dissolved in DCM with a little MeOH to help solubility and purified on silica eluting with a gradient of 10-20% 2M ammonia in MeOH/DCM. Fractions containing product combined and evaporated to give the title compound as a cream solid (1.75 g, 52%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[NH:9][CH2:10][CH2:11][N:12]2[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:6].N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=2)[N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10]1)=[O:39]
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cccc(Cl)c1)c1cccc2c1N(C(=O)CBr)CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (50 g, 123 mmol) in DCM (500 mL) at 0° C. was added pyridine (14.91 ml, 184 mmol). Bromoacetyl bromide (26.7 ml, 307 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to afford benzyl 4-(2-bromoacetyl)-5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1E (55 g, 104 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.0 (1H, bs), 7.85 (1H, s), 7.75 (1H, m), 7.6 (2H, m) 7.4 (7H, m), 7.10 (1H, m), 5.3 (2H, s), 4.15 (2H, m), 4.0 (2H, m), 3.8 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27]>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[O:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Oc1cc(F)ccc1F
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(F)ccc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5 g) in THF (200 mL) at room temperature was treated with K2CO3 (19 g), followed by 2,5-difluorophenol (3.7 g). After stirring at room temperature for 18 hrs, the solid was filtered off and rinsed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated aqueous NaHCO3 solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residual was triturated with hexanes and collected by suction to furnish the desired product 21, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals, m.p.=101-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)(=[O:18])=[O:19])=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1-n1ccnc1
Temperature: 150 °C
Yield: 77 %

Procedure:
2,4-Difluoro-1-(2-{4-[(2-fluorophenyl)sulfonyl]phenyl}ethyl)benzene (Example 124, 100 mg, 0.26 mmol), potassium carbonate (126 mg, 0.39 mmol) and imidazole (26 mg, 0.39 mmol) were combined in dimethylsulfoxide (1.3 mL) and heated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% ethanol/ethyl acetate to yield the title compound as a white solid (85 mg, 77%). δH (400 MHz, d6 DMSO): 8.31-8.29 (1H, m), 7.87-7.79 (2H, m), 7.41-7.39 (2H, m), 7.31-7.23 (5H, m), 7.16-7.12 (1H, m), 6.99-6.95 (1H, m), 6.88 (1H, t, J=1.1 Hz), 6.85 (1H, t, J=1.3 Hz), 2.92-2.84 (4H, m). m/z (ES+) 425 [MH+].
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:22]1(O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:12])(=[O:3])[CH3:2]
Reactant: OC1CCc2ccccc21
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Product: CC(=O)NCCSCC(CC(=O)OC1CCc2ccccc21)C(=O)c1cccnc1
Yield: 55 %

Procedure:
The title compound was prepared from 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid and indanol as described in the above Example 26 in 55% yield; ESMS (M+1+) 427.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][N:6]1[S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])=O.O.[NH2:34][NH2:35]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@H:8]2[CH2:7][N:6]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[C@H:5]([C:3]([NH:34][NH2:35])=[O:2])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(step 8) To a solution of 5 g (10.6 mmol, 1 eq) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 20 ml methanol were added 6.45 ml (110 mmol, 10 eq) hydrazine-hydrate and the solution was stirred at RT for 3 days. The solvent was evaporated, followed by solving and evaporating with EtOH, ether and hexane. The light yellow solid was dried in vacuo giving (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid hydrazide, mp 130° C., MS: 472 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19])([CH2:7][CH2:8][CH3:9])[CH3:6]>O>[CH:18]([O:17][C:12]1[CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[CH:15]=[CH:16][C:11]=1[O:10][CH:5]([CH2:7][CH2:8][CH3:9])[CH3:6])([CH2:20][CH2:21][CH3:22])[CH3:19]
Reactant: CCCC(C)Oc1ccccc1OC(C)CCC
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCC(C)Oc1ccc([N+](=O)[O-])cc1OC(C)CCC
Reaction time: 1 h

Procedure:
To a mixture of 300 ml. of conc. HNO3 and 300 ml. of H2O was added dropwise 80 g. (0.32 m.) of o-di(sec-amyloxy)benzene (part A) while maintaining a temperature of 10°C. Stirring was continued for an additional 60 minutes at 10°C, then the solution was poured into 2000 ml. addition was poured into 2000 ml. of ice. The aqueous layer was decanted, and the red oil was dissolved in benzene, dried over anhydrous MgSO4 and concentrated to dryness in vacuo. A chromatographic column 32 inches long with O.D. 3/4 inch, was packed with 20 inches of neutral alumina. The crude product was dissolved in a 250 ml. mixture of 50/50 CHCl3 and CCl4. After the solution was placed on the column, it was washed several times with the same solvent mixture. The first fraction was collected and concentrated to dryness in vacuo to yield 10 g. of amber-colored oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][S:9][CH2:8]1)=[O:5].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][S+:9]([O-:41])[CH2:10]1)=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1C[S+]([O-])C1
Reaction time: 0.17 h

Procedure:
To a suspension of 2-methyl-N-(thietan-3-yl)-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide in dichloromethane (92 mL) was added m-CPBA (24.3 mmol, 5.58 g) portion wise at 0-5° C., and the reaction mixture was stirred for 10 min. A saturated Na2S2O3 solution was added, and the mixture was stirred for 10 min. The organic layer was washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, filtered and evaporated. Purification over silica gel (eluent: CH2Cl2/EtOAc) yielded the title compound. LCMS (Method GR) 1.13 min, M+ 539/541; 1H NMR (400 MHz, CDCl3) 2.50 (s, 3H), 3.28 (m, 1H), 3.70 (d, 1H), 4.10-4.20 (m, 4H), 4.70 (m, 1H), 6.50 (d, 1H), 7.40-7.70 (1d+4s, 5H), 19F-NMR (CDCl3, 376 MHz): −79.43. Chiral HPLC Method Column: Daicel CHIRALPAK® IB, 3 μm, 0.46 cm×10 cm Mobile phase: Heptan/EtOH 80/20 Retention times of eluting isomers: 4.85 min (8.2%) 5.66 min (91.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C@@H:9]([CH3:40])[C:10]([NH:12][C@@H:13]([CH:37]([CH3:39])[CH3:38])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:41])[C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:15])[CH:37]([CH3:39])[CH3:38])[CH3:40])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccccc1
Yield: 69.3 %

Procedure:
To the stirred solution of toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (Intermediate 2) (50 mg, 0.085 mmol) in 1,4-dioxane (0.5 mL), K2CO3 (29.3 mg, 0.127 mmol), was added aniline (0.012 mL, 0.127 mmol) and the reaction mixture irradiated in a microwave at 125° C. for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water and brine and the separated organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC (X Bridge Prep C18 (250×19.0 mm) 5μ, acetonitrile and 0.05% formic acid) to give methyl-{(S)-1-[(S)-2-methyl-1-((S)-2-phenylaminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (30 mg), m/z=510.6 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH3:23][C:24]1[NH:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:25]4[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=[C:24]4[CH3:23])[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.110 g, 0.29 mmol), 2-methyl-4-(trifluoromethyl)-1H-imidazole (0.080 g, 0.53 mmol) and K2CO3 (0.080 g, 0.58 mmol) in DMF (1.8 mL) was stirred at 65° C. for 2 hrs. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.035 g, TFA salt, 21%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.27 (s, 1H), 5.03 (dd, J=10.4, 8.8 Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 3.04 (heptet, J=6.8 Hz, 1H), 2.88 (m, 1H), 2.58 (s, 3H), 2.40 (m, 1H), 1.23 (m, 6H); MS: (ES) m/z calculated for C21H21ClF3N5O [M+H]+452.1. found 452.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15]N1C(=O)CCC1=O>CO>[Cl:15][C:5]1[C:4]([OH:8])=[C:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CCc1c(O)cccc1O
Solvent: CO
Product: COC(=O)CCc1c(O)ccc(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 30 (5.0 g, 25.5 mmol) in 50 ml of methanol was added 3.4 g (25.5 mmol) of N-chlorosuccinimide. The reaction was stirred overnight at room temperature and concentrated. The residue was suspended in a mixture of hexane and ethyl acetate and the precipitated succinimide was removed by filtration. Crude product obtained after evaporation of the solvent was chromatographed on silica eluting with 4:1 hexane-ethyl acetate. Concentration of the pure product fractions afforded 4.4 g of the title compound as colorless oil that slowly crystallized during prolonged drying under vacuum. 1H NMR (d6-DMSO) δ: 9.52 (s, 1H), 8.95 (s, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 3.59 (s, 3H), 2.81 (t, J=7.5 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3O[C:13](=O)[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)O.[NH2:34][NH:35][C:36]([NH2:38])=[NH:37]>N1C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:34]4[N:35]=[C:36]([NH2:38])[N:37]=[C:13]4[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN1CCN(c2cc(F)c3c(=O)oc(Cc4ccc5c(c4)OCO5)nc3c2)CC1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: O
Product: CN1CCN(c2cc(F)c3c(c2)nc(Cc2ccc4c(c2)OCO4)n2nc(N)nc32)CC1
Temperature: 180 °C
Yield: 46 %

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]3[CH2:15][CH:16]([CH2:17]O)[CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][CH:16]1[CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=3[CH:13]([C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:15]1
Reactant: [Br-]
Reactant: OCC1CC2c3ccccc3C1c1ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC1CC2c3ccccc3C1c1ccccc12

Procedure:
9,10-Dihydro-9,10-ethanoanthracene-11-methanol (2 gm) was combined with triphenylphosphine dibromide (5.3 gm) in carbon tetrachloride (60 ml). The mixture was heated to reflux 1 hour, filtered, and the filtrate was concentrated on a rotary evaporator. The residue was boiled in n-heptane (75 ml), filtered hot, and the filtrate cooled. The white precipitate was filtered and air dried to provide the product (mp=103°-106° C.).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:27]=[CH:26][C:18](/[CH:19]=[N:20]/[NH:21][C:22](SC)=[S:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:30][N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>CN(C=O)C>[CH3:30][N:31]([CH3:39])[C:32]1[CH:33]=[C:34]([NH:38][C:22]([NH:21][N:20]=[CH:19][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:28])([F:1])[F:29])=[CH:9][CH:8]=4)[N:11]=3)=[CH:27][CH:26]=2)=[S:23])[CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CSC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CN(C)C=O
Product: CN(C)c1cccc(NC(=S)NN=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a 50 mL round-bottomed flask containing (E)-methyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbodithioate (250 mg, 0.571 mmol) in DMF (3 mL) was added N1,N1-dimethylbenzene-1,3-diamine (195 mg, 1.43 mmol). The contents were heated at 150° C. with stirring for 5 h before the solution was allowed to cool overnight. The mixture was filtered, and the filtrate was purified via RP-HPLC to afford the desired material (235 mg, 78%) as an off-white solid: mp 192-194° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.04 (s, 1H), 9.41 (s, 1H), 8.19 (s, 1H), 8.16-7.99 (m, 6H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.01 (m, 1H), 6.87 (m, 1H), 6.58 (m, 1H), 2.88 (s, 6H); ESIMS m/z 526 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]=[N+]=[N-])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=N[C@H]1CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 62 %

Procedure:
The compound (3S)-1-benzyl-3-azidopyrrolidine (0.9 g, 4.5 mM) was dissolved in a mixture of tetrahydrofuran (36.0 ml) and water (7.0 ml). To it, triphenylphosphine (2.3 g, 8.9 mM) was added and the reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature and tetrahydrofuran was evaporated under vacuum. The residue was taken in water (50.0 ml) and the pH was adjusted to about 2 and washed with chloroform. The pH of the aqueous solution was adjusted to about 12-13 with 1N sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to give the title compound. Yield=62% (0.5 g, 2.8 mM).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[C:25]1([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[C:25]1([C:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.5 g), triethylamine (3.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (3.9 g) in toluene (150 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (10 cc), 2-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.5 g) is obtained, m.p. 106° C.