Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C(Cl)Cl>[OH:17][C@:18]1([C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1cccc(-c2cccc(Br)c2)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1cccc(-c2cccc([C@]3(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Magnesium (0.513 g, 21.11 mmol) was stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 3-bromo-3′-vinylbiphenyl (5.21 g, 20.10 mmol) in THF (100 mL), was added in dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (5.78 g, 20.11 mmol) in DCM (110 mL) at 0° C. and stirred for 1 hr and then quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.9 g, 6.20 mmol, 31% yield) as a yellow foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 0.05 (d, J=2.44 Hz, 9H) 0.99 (dd, J=9.77, 7.32 Hz, 1H) 1.04 (dd, J=9.61, 7.17 Hz, 1H) 1.27 (t, J=7.17 Hz, 1H) 2.38-2.53 (m, 1H) 2.66-2.82 (m, 1H) 3.67-3.83 (m, 1H) 3.82-3.89 (m, 3H) 3.96-4.09 (m, 1H) 4.17-4.32 (m, 2H) 4.52-4.69 (m, 1H) 5.32 (d, J=10.99 Hz, 1H) 5.83 (d, J=17.40 Hz, 1H) 6.80 (dd, J=17.55, 10.83 Hz, 1H) 7.39-7.46 (m, 2H) 7.46-7.52 (m, 3H) 7.55 (ddd, J=4.58, 2.14, 1.83 Hz, 1H) 7.61 (br. s., 1H) 7.73 (s, 1H). LCMS: rt=2.32 min. [M+H]+=468; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]=[C:9]=[S:10])=[C:5]([C:11]([O:13]C)=O)[CH:4]=1)[CH3:2].[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=1>>[CH2:1]([C:3]1[S:7][C:6]2[NH:8][C:9](=[S:10])[N:24]([CH2:23][CH2:22][CH2:21][N:19]3[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]3)[C:11](=[O:13])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Cc1cn(CCCN)cn1
Reactant: CCc1cc(C(=O)OC)c(N=C=S)s1
Product: CCc1cc2c(=O)n(CCCn3cnc(C)c3)c(=S)[nH]c2s1

Procedure:
The compound was synthesized starting from methyl 5-ethyl-2-isothiocyanatothiophene-3-carboxylate (0.100 g. 0.44 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.061 g, 0.44 mmol) as described above.
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2.C(#N)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O.C(Cl)(Cl)Cl>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][N:9]2[CH:6]3[CH2:7][CH2:8][CH:2]2[CH2:3][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]3)=[CH:25][CH:26]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: N#Cc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2CCOc1ccc(C#N)cc1

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate hydrochloride (1.36 g, 5.5 mmol; see Preparation A) was dissolved in H2O/CHCl3/saturated K2CO3 solution (40:40:5) and the resulting mixture was shaken. The phases were separated, dried and evaporated giving 1.1 g (100%), of the free base. Acetonitrile (100 mL), 4-(2-bromoethoxy)benzonitrile (1.49 g, 6.6 mmol; from step (a) above) and K2CO3 (2.4 g, 17.5 mmol) were added. The mixture was stirred at 70° C. for 24 h, the solids were filtered off and the residue evaporated and purified by chromatography on silica, eluting with CHCl3:MeOH (95:5), to give 1.5 g (4.3 mmol) of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].S(Cl)(Cl)(=O)=O.[N+:33]([C:36]1[CH:37]=[C:38]([S:42]([CH2:45][CH2:46][O:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=2)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]>C(Cl)Cl.O>[N+:33]([C:36]1[CH:37]=[C:38]([S:42]([CH2:45][CH2:46][O:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:57])=[O:56])[CH:50]=2)(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccc(C(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 80 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (600 mg, 1.62 mmol) in CH2Cl (10 mL) was added NaH (45 mg, 1.95 mmol) at room temperature, resulting in a clear solution. To this clear mixture was added the sulfonyl chloride (Intermediate 1, 845 mg, 1.95 mmol, 1.2 eq), in CH2Cl2 at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added and the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated. The residual oil was purified by column chromatography (3% MeOH in CH2Cl2) to yield 1.0 g (80%) of yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([NH:22][C:23]([NH:17][S:14]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:16])=[O:15])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Yield: 94 %

Procedure:
A mixture of 7.7 g (0.029 mol) 2-chloro-6-phenylbenzenesulfonamide, 3.6 ml (0.032 mol) n-butylisocyanate and 4.1 g (0.03 mol) potassium carbonate was heated in 80 ml dry acetonitrile for 18 hours at reflux. The solvent was evaporated and the residue treated with 1N HCl and ethyl acetate and the insoluble solids were collected, washed with water and then ether. Additional material was obtained from the organic phase of the filtrate to afford a total of 10 g of the title compound, m.p. 184°-186°. NMR (90 MHz, CDCl3), 0.9 (CH3, t, br), 1.4 (4H, m), 3.05 (q, J=7 Hz, 2H), 5.9 (t, br, NH), 7.2-7.6 (m, 8H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15](/B(O)O)=[CH:16]\[CH3:17].[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[CH:16]/[CH3:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C/C=C/B(O)O
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C/C=C/c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-5-methylsulfonylnitrobenzene (1.50 g; 5.36 mmol), trans-propenylboronic acid (690 mg; 8.03 mmol), caesium fluoride (2.44 g; 16.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (376 mg; 0.54 mmol) was degassed with nitrogen, then treated with dioxane (30 ml) and water (15 ml). The resulting reaction mixture was heated at 80° C. for 2 hours, taken up in EtOAc and washed with water and brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as an off-white solid (1.10 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:22][CH2:23][CH2:24][N:12]4[CH:11]=2)[CH:15]=[C:16](I)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:27]([OH:30])[C:28]#[CH:29].O>C(NCC)C.CO.[Cu+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:22][CH2:23][CH2:24][N:12]4[CH:11]=2)[CH:15]=[C:16]([C:29]#[C:28][CH2:27][OH:30])[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(I)cc3c1=O)OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+]
Solvent: O
Solvent: CO
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(C#CCO)cc3c1=O)OCC2
Reaction time: 18 h

Procedure:
To a mixture of 539 mg of N-(4-chlorobenzyl)-9-iodo-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide of Preparation 10, 78 mg of copper (I) odide, and 30 mg of bis(triphenylphosphine)palladium dichloride in 11 mL of diethylamine, stirred vigorously under argon, is added 82 μL of propargyl alcohol. The mixture is stirred for 18 hours, then diluted with a little methanol and added to 120 mL of stirred water. The precipitated solid is filtered, washed well with water, and dried in vacuo. The solid is then dissolved in chloroform-methanol, and the solution is filtered to remove copper salts and then absorbed onto silica gel. Flash chromatography eluting with 2-6% methanol in dichloromethane provides 217 mg of the title compound.
Reaction SMILES: [Br-:1].[Li+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1>CS(C)=O.O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19]([Br:1])[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 110 °C
Reaction time: 1.75 h
Yield: 54.6 %

Procedure:
Lithium bromide (19.2 g, 220.2 mmol) was added to a stirred solution of ditosylate (42) (40.0 g, 88.1 mmol) in dimethyl sulfoxide (200 mL) under an atmosphere of argon. The mixture was heated at 110° C. for 8 hours then at 120° C. for 1.75 hours. The mixture was diluted with water (500 mL) then extracted with tert-butyl methyl ether (4×250 mL). The organic phase was washed with water (3×250 mL) then brine (250 mL), dried (MgSO4), filtered and reduced in vacuo to leave an orange solid. Recrystallisation from methanol (100 mL) gave bromotosylate (47) (17.47 g, 55%) as a pale yellow solid. [□]D15+49.5° (c=11.7, CHCl3).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([CH3:32])([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH3:26])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][C:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([N:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[CH3:26]
Reactant: CC(C)(c1nnc2ccc(F)cn12)N1CCCC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)N1CCCC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 135 mg, 3.37 mmol) in DMF (4.50 mL) was added Intermediate A (137 mg, 0.84 mmol) and the reaction stirred for 20 min. Intermediate 80b (209 mg, 0.84 mmol) was added in DMF (1.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (180 mg, 55%). LCMS (Method 4): Rt 0.31, m/z 392.2 [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[S:13][C:14]4[CH2:20][CH2:19][CH2:18][C:17](=O)[C:15]=4[N:16]=3)[CH:9]=[N:8]2)[CH:2]=1.Cl.[CH3:23][O:24][NH2:25].C([O-])(=O)C.[Na+]>C1COCC1>[CH3:23][O:24][N:25]=[C:17]1[C:15]2[N:16]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[S:13][C:14]=2[CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21

Procedure:
2-[1-(3-pyridyl)pyrazol-4-yl]-6,7-dihydro-5H-1,3-benzothiazol-4-one (0.40 mmol, 0.119 g) was suspended in 4 ml THF, and O-methylhydroxylamine hydrochloride (0.44 mmol, 0.0367 g) followed by sodium acetate (0.80 mmol, 0.0656 g) were added. The reaction mixture was heated at reflux. After evaporation of the solvent, the residue was submitted to chromatography (Combiflash) to yield the title compound as a yellow solid.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:35])[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]C(C)(C)C)=[O:29])=[O:22])[CH2:17][CH3:18])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl.O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:17]([N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:35])[CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([OH:30])=[O:29])=[O:22])[CH3:18]
Reactant: CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred solution of 85 mg (0.17 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and lyophilization, 63 mg (97%) of the title compound as a yellow crystalline solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:16]1[CH:15]=[CH:14][C:13]2[O:8][CH2:9][CH2:10][O:11][C:12]=2[C:17]=1[C:18]([OH:20])=[O:19])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1c([N+](=O)[O-])ccc2c1OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1,600 ml of acetic acid, 1,600 ml of acetic anhydride, and 1000 g of 1,4-benzodioxane-5-carboxylic acid were introduced in a 6-liter balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and a solution of 400 ml of nitric acid in 400 ml of acetic acid was added. After the introduction, the mixture was stirred at 40°-45° C. for two hours and then cooled to 5° C. The precipitate was dried off, washed with 600 ml of acetic acid and then with water and dried at 40° C. 700 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were collected, the structure of which was confirmed by nuclear magnetic resonance (M.P.: 246° C.). The mother liquors were diluted with 25 liters of water and the obtained precipitate was dried off, washed with water and dried. 6-nitro-1,4-benzodioxane-5-carboxylic acid was obtained (M.P.: 188° C.).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[N:3]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl>[Br:24][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[NH2:11])[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:3]=[C:2]2[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(N)cc32)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 147.7 %

Procedure:
3-Methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (301 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (80 ml) and methanol (40 ml) at room temperature. The mixture was heated to 80° C. and then the tetrabutylammonium tribromide (1.0 eq, 482 mg) was added. Stirring was continued for 10 minutes, and then the mixture was partitioned between diethyl ether and saturated aqueous sodium sulfite solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (280 mg, 73.7%) as a white powder.
Reaction SMILES: [CH2:1]([P:7]([O:12][CH2:13][CH3:14])(=[O:11])[O:8][CH2:9][CH3:10])[CH:2]=[CH:3][CH2:4][CH:5]=[CH2:6].CI.[CH2:17](P(OCC)(=O)OCC)C=CC.C(Br)C1C=CC=CC=1>>[CH3:17][CH:1]([P:7]([O:8][CH2:9][CH3:10])(=[O:11])[O:12][CH2:13][CH3:14])[CH:2]=[CH:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCC=CCP(=O)(OCC)OCC
Reactant: CC=CCP(=O)(OCC)OCC
Agent: BrCc1ccccc1
Solvent: CI
Product: C=CCC=CC(C)P(=O)(OCC)OCC
Yield: 92.7 %

Procedure:
The same procedure as in Example A-1 was repeated except that 2.18 g of diethyl 2,5-hexadienephosphonate and 1.42g of methyl iodide were used instead of 1.92 g of the diethyl 2-butenephosphonate and 1.7 g of the benzyl bromide respectively. Vacuum distillation of the reaction mixture afforded 2.15 g of diethyl 1-methyl-2,5-hexadienephosphonate having a boiling point of 102° C. (3 mmHg) in yield of 93%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]([NH2:31])([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH3:22][C:23]([NH:31][C:19](=[O:21])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.0 g of powdery N-(t-butoxycarbonyl)-O-benzyl-L-serine were added to 200 ml of a methylene chloride solution containing 5.0 g of α,α-dimethylbenzylamine and 10.0 g of triphenylphosphine. 20 ml of a methylene chloride solution containing 8.2 g of 2,2'-dipyridyl disulfide were then added dropwise. The mixture was then stirred for 1 hour at room temperature, after which the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The title compound was obtained as an oil from the fraction eluted with a 2:1 by volume mixture of ethyl acetate and hexane. Yield 9.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of Example 100 (1.00 g, 2.18 mmol) in methanol (5 ml), lithium hydroxide (0.856 g, 20.40 mmol) in water (5 ml) and THF (19 ml) were added and stirred at RT. After 12 h, pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.900 g, 93%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[N:30]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 45.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.400 g), tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.400 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.250 g of the desired product.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:24]=[CH:23][C:20]([CH2:21][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(CN4CCOCC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of water (1 mL), acetic acid (1 mL), 4-[4-(4-nitro-phenyl)-piperazin-1-yl]-benzaldehyde (700 mg, 2.25 mmol) and morpholine (215 mg, 2.47 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (212 mg, 3.37 mmol) was added at room temperature then the mixture was heated at reflux for 10 h. The tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated in vacuo to afford a residue which was purified by column chromatography on silica gel (60-120 mesh) using 1% methanol in chloroform as eluent to afford 4-{4-[4-(4-nitro-phenyl)-piperazin-1-yl]-benzyl}-morpholine (450 mg, 52%) as a brownish yellow solid.