Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][OH:16].C(N(CC)CC)C>ClCCl>[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc2ccccn2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc2ccccn2n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.149 g, 0.13 mmol) in dichloromethane (2 mL) was added to a solution of pyrazolo[1,5-a]pyridin-2-yl-methanol (0.148 g, 0.1 mmol) and triethylamine (0.303 g, 0.3 mmol) in dichloromethane (3 mL) at −10° C. under N2. After the addition was complete, the mixture was stirred at −10° C. for 1 h. Ice water (10 mL) was added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to give methanesulfonic acid pyrazolo[1,5-a]pyridin-2-ylmethyl ester as a yellow oil, which was used for the next step without further purification. A solution of this material (0.22 g, 0.1 mmol) in dry dichloromethane (2 mL) was added to a solution of 1-methyl-4-phenyl-1,3-dihydro-imidazole-2-thione (0.190 g, 0.1 mmol) and DIPEA (0.303 g, 0.3 mmol) in dry DMF (3 mL) at −10° C. under N2. The mixture was stirred at 0° C. for 2 hours, and was then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (50 mg, 15%). LC-MS: m/z=321.1 (MH+), tR=2.16 min, method F.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>CCO>[C:1]1([C:7](=[N:19][OH:20])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CCCc1ccncc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(CCCc1ccncc1)c1ccccc1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To a solution of 1-phenyl-4-(pyridin-4-yl)butan-1-one (2.0 g, 8.7 mmol) in 20 mL of EtOH was added hydroxylamine hydrochloride (0.73 g, 10 mmol) and sodium acetate (1.4 g, 17 mmol). The reaction flask was heated at 80° C. for 4 h and was then cooled to room temperature. Addition of water and filtration of the resultant precipitate afforded 2.0 g (89%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:28][CH3:27])[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) and a 40% aqueous solution (110 mg) of methylamine were added to pyridine (1,160 mg), and the mixture was stirred at 40° C. for 16 hours. The solvent was distilled off under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (58 mg) as a colorless powder.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]1=[O:14])([CH2:3][CH3:4])[CH3:2].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:44][CH2:45][C:46]1[C:47]([OH:54])=[N:48][C:49]([CH3:53])=[CH:50][C:51]=1[CH3:52]>ClCCl.O>[CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:44][CH2:45][C:46]2[C:47]([OH:54])=[N:48][C:49]([CH3:53])=[CH:50][C:51]=2[CH3:52])=[O:13])=[CH:7][C:6]1=[O:14])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCC(C)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)n1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (98 mg, 0.5 mmol) in dichloromethane (20 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol (135 mg, 1 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1 mmol) and triethylamine (253 mg, 2.5 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added and stirred for 4 hours. To the reaction mixture was added water (20 mL), extracted with dichloromethane (20 mL) two times, combined and concentrated the organic layers, the residue was purified by chromatography with petroleum/ethyl acetate=1:1 to afford 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (132 mg, 80% yield). LRMS (M+H+) m/z: calcd for 329.17. found 329. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.48 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 6.84 (s, 1H), 6.53 (dd, J=1.8 and 7.2 Hz, 1H), 5.86 (s, 1H), 4.87-4.79 (m, 1H), 4.23 (d, J=4.8 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1.71-1.61 (m, 2H), 1.25 (d, J=6.9 Hz, 6H), 0.72 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[C:7]([CH2:13]Br)[CH:6]=1)[CH3:2].[O-:16][CH2:17][CH3:18].[K+]>C(O)C>[Br:12][CH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([CH2:13][O:16][CH2:17][CH3:18])[CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Reactant: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CCOCc1cc(CBr)cc(C(=O)OCC)c1
Reaction time: 8 h

Procedure:
A stirred solution of 3,5-bis[bromomethyl]benzoic acid ethyl ester (3g) in ethanol (100 ml) was treated with potassium ethoxide (0.75 g) and stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated and the residue purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 1.3 g.
Reaction SMILES: [C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH2:18][O:19][Si](C)(C)C)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH:18]=[O:19])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)N1C2=CC=CCC2CCC1CO[Si](C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1C2=CC=CCC2CCC1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A mixture of N-ethoxalyl-2-trimethylsilyloxymethyltetrahydroquinoline (15.55 g, 50.92 mmol) and Dess-Martin reagent (32.4 g, 76.37 mmol) in dichloromethane (160 mL) in the presence of trifluoroacetic acid (0.8 mL) was stirred for 1 h at room temperature. Aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate were added successively and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 11.23 g of N-ethoxalyl-2-formyltetrahydroquinoline (84%): 1H NMR (270 MHz, CDCl3) δ9.57 (s, 1H), 7.19 (m, 4H), 5.07 (t, 1H, J=8 Hz), 4.19 (q, 2H, J=7 Hz), 2.76 (m, 2H), 2.45 (m, 1H), 1.96 (m, 1H), 1.15 (t, 3H, J=7 Hz).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cccc(O)c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.08 h

Procedure:
A solution of 4-(difluoromethoxy)phenyl iodide (4.70 g) in deoxygenated dimethylformamide was treated with trans-dichlorobis(triphenylphosphine) palladium(II) (244 mg) and copper(II) iodide 66 mg) followed by triethylamine (7.52 mL), stirred under a nitrogen atmosphere for 5min., treated with 3-hydroxyphenyl acetylene (2.467 g), stirred under nitrogen atmosphere for 16 h, poured into ethyl acetate and was washed with 0.05 N HCl and water. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed, silica gel, 40% ethyl acetate/hexane as eluent, to afford 3-((4-(difluoromethoxy)phenyl)ethynyl)phenol as a tan solid, 5.40 g; 1H NMR (DMSO-d6): δ 9.64 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.27 (t, J=73.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 7.16 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), and 6.77 (m, 1H); MS (ES neg) m/z 260.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=O.N1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)[N:21]=3)=[CH:3][C:2]=2[C:39]2[CH:40]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccncc1
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2-c2ccncc2)CC1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (500 mg), and N-methylpyrrolidone (5 mL) were added pyridin-4-ylboronic acid (407 mg), tetrakistriphenylphosphine palladium (0) (164 mg), and a 2 M aqueous sodium carbonate solution (2.84 mL), followed by stirring in a microwave reaction device at 140° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-15:1:0.1) to obtain 3-{[4-(4-methylpiperazin-1-yl)-3-(pyridin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (64 mg) as a yellow solid.
Reaction SMILES: [Li+].[OH-].[NH:3]1[C:7]2[CH:8]=[CH:9][C:10](/[C:12](/[C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)\[CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[N:4]1.Cl>C1COCC1.CCO.O>[NH:3]1[C:7]2[CH:8]=[CH:9][C:10](/[C:12](/[C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)\[CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]nnc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]nnc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
An aqueous solution of LiOH (0.22 g, 9.4 mmol) was added to a solution of (E)-ethyl 3-(4-((E)-1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate (0.2 g, 0.47 mmol) in THF-EtOH (1:1, 24 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction was monitored by LCMS. Upon completion, 1N aqueous HCl was added until the pH was 3. Then, the mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-20% methanol in dichloromethane affording the title compound as an off-white solid (0.12 g). 1H NMR (300 MHz, DMSO-d6): δ 15.65 (br, 1H), 12.29 (br, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.48-7.35 (m, 3H), 7.24-7.13 (m, 7H), 6.91 (d, 2H), 6.37 (d, 1H), 2.39 (q, 2H), 0.89 (t, 3H); LCMS: 396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+].ClCCl>[Br:10][CH2:11][C:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)=[O:13]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C(Cl)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(NC(=O)CBr)ccc1Br
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
4-Bromo-3-methylaniline (10.08 g, 54.18 mmol) in 2N sodium hydroxide (200 mL) was treated with bromoacetyl chloride (5.00 mL, 60.8 mmol) as a solution in dichloromethane (200 mL) dropwise. After 15 minutes, the layers were separated. The organic phase was washed with 1N hydrochloric acid, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide 11.75 g (71%) of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 3H), 4.01 (s, 2H), 7.23 (m, 1H), 7.44 (d, 1H, J=2.4 Hz), 7.49 (d, 1H, J=8.8 Hz), 8.07 (br s, 1H); MS (DCI/NH3) m/e 306 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][NH:6][OH:7].[CH3:8][C:9](=[CH2:20])[CH2:10][N:11]([CH2:17][CH:18]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CO.C1(C)C=CC=CC=1>[CH3:5][N:6]1[O:7][CH2:8][C:9]2([CH3:20])[CH:18]1[CH2:17][N:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10]2
Reactant: C=C(C)CN(CC=O)C(=O)OCC
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CC2N(C)OCC2(C)C1

Procedure:
21.7 g of 30% strength sodium methylate solution are added dropwise to 10 g (0.12 mol) of N-Methylhydroxylamine hydrochloride in 26 ml of methanol. The sodium chloride is filtered off with suction and washed with 8 ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N-(2-methyl-prop-2-enyl)-N-(2-oxoethyl)-urethane, which is heated under reflux in 160 ml of toluene using a water separator. The mixture is heated under reflex overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydrochloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions, of 200 ml of CHCl3. The extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=1.CI.O>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[C:10]=1[CH3:1]
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1c(Br)ccc(I)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of diisopropylamine (6.06 mL) in THF (100 mL) was cooled to −78° C., n-butyllithium-hexane (24.9 mL, 1.6 mol/L) was added dropwise and, after the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 4-bromo-2-fluoro-1-iodobenzene (10.0 g) in THF (50 mL) was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. Methyl iodide (2.90 mL) was added dropwise at −78° C. and the mixture was further stirred at −78° C. for 2 hr, and the mixture was warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield: 10.5 g, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]2[CH2:33][CH2:32]2)=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29]([NH:30][CH:31]2[CH2:33][CH2:32]2)(=[O:35])=[O:34])=[CH:25][C:19]=1[C:20]1[NH:22][C:23](=[O:24])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.123 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g, of pure product. 1H NMR (400 MHz, DMSO de): δ 0.39-0.41 (m, 2H), 0.49-0.52 (m, 2H), 2.17-2.20 (m, 1H), 7.52-7.55 (d, J=8.0 Hz, 2H), 7.91-8.00 (m, 5H), 8.14 (m, 1H), 12.60 (br s, 1H); MS (m/z): 425.10 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])(OCC1C=CC=CC=1)(OCC1C=CC=CC=1)=O.[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49]2[C:50](=[O:76])[N:51]([CH2:68][O:69][C:70](=[O:75])[NH:71]CCO)[C:52](=[O:67])[C:53]=2[C:54]2[C:62]3[C:57](=[CH:58][C:59]([N+:63]([O-:65])=[O:64])=[CH:60][CH:61]=3)[N:56]([CH3:66])[CH:55]=2)=[CH:41]1>C1COCC1>[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49]2[C:50](=[O:76])[N:51]([CH2:68][O:69][C:70](=[O:75])[NH2:71])[C:52](=[O:67])[C:53]=2[C:54]2[C:62]3[C:57](=[CH:58][C:59]([N+:63]([O-:65])=[O:64])=[CH:60][CH:61]=3)[N:56]([CH3:66])[CH:55]=2)=[CH:41]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(COC(=O)NCCO)C2=O)c2ccccc21
Agent: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(COC(N)=O)C2=O)c2ccccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Triphenylphosphine (95 mg, 0.36 mmol) and dibenzyl phosphate (101 mg, 0.36 mmol) were added to a solution of (2-Hydoxy-ethyl)-carbamic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester, prepared as in example 19 (150 mg, 0.289 mmol) in THF (6 mL). The mixture was cooled at −78° C. Diethyl azodicarboxiate (0.057 mL, 0.36 mmol) was added dropwise over 5 min. The cooling bath was removed and the mixture was stirred overnight. The mixture was then evaporated. Chromatography of the residue over silica gel using 2:1-4:1 EtOAc/hexanes gave [2-bis-benzyloxy-phosphoryloxy)-ethyl]-carbamic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester (121 mg, 54%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.O.[OH:10][C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]>CN(C=O)C>[CH3:1][O:10][C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2c(c1O)OCCO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(C(C)=O)ccc2c1OCCO2
Temperature: 80 °C
Yield: 70.9 %

Procedure:
In a round-bottomed flask, 500 mg of 1-(5-Hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one was dissolved in 1 mL of DMF. To this solution was added, 414 mg of K2CO3, and methyl iodide (1 mL, excess). The reaction was heated to 80° C. overnight. The reaction was poured into water and extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to afford 0.38 g (70%) of the acetophenone 8.
Reaction SMILES: [ClH:1].Cl.C1(O)CCCCC1.[OH:10][C:11]1([CH:17]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:35][CH:34]=2)[C:18]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[ClH:1].[ClH:1].[C:42]1([CH2:41][CH2:40][O:39][C:36]2[CH:35]=[CH:34][C:33]([CH:17]([C:11]3([OH:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:18][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(OCCc3ccccc3)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: OC1CCCCC1
Product: OC1(C(CN2CCNCC2)c2ccc(OCCc3ccccc3)cc2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 1-}1-[4-(2-phenylethoxy)phenyl]-2-piperazin-1-ylethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclohexyl)(4-(2-phenylethoxy)phenyl)acetyl]piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].C1(C(O)=O)CC=CCC1>C(O)(=O)C>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:19]([O-:24])=[O:20])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: BrCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 50 g. (0.137 mole) of the product of step A in 1100 ml. of acetic acid is added 18.9 g. (0.206 mole) of dinitrogen tetraoxide and 26.0 g. (0.206 mole) of 4-cyclohexene carboxylic acid in 25 ml. of acetic acid dropwise. The reaction mixture is maintained at 45° C. for about four hours, then allowed to cool to about 20° C. The yellow solid is collected, washed with water and petroleum ether and dried to provide 5-bromomethyl-2-nitro-3-phenylbenzofuran, crude melting point 171°-180° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(OCC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
After stirring the reaction mixture for an additional 0.5 hour at 0°-5°C, a solution of 3860 grams (18 moles) of m-phenoxybenzoic acid in tetrahydrofuran was added dropwise over a 4 hour period while maintaining a reaction temperature of 0°-10°C. When the addition was complete, the reaction mixture was stirred for 12 hours at 20°C followed by 2 hours at 40°C. The reaction mixture was then transferred to a 10 gallon bottle containing 6 liters of water and 8 liters of diethyl ether. After mixing thoroughly, the aqueous layer was removed and the organic layer was extracted with water (1 × 4 liters), extracted with aqueous saturated sodium bicarbonate solution (1 × 4 liters), extracted with aqueous saturated sodium chloride solution (1 × 4 liters), dried over anhydrous potassium carbonate, filtered, and concentrated on a rotary evaporator. Short-path distillation gave 3000 grams (83% yield) of m-phenoxybenzyl alcohol, bp 135°-140°C/0.10 mm, n20D 1.5935.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:16]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (200 mg, 1.01 mmol), tert-butyl (3-methylpiperidin-3-yl)carbamate (227 mg, 1.06 mmol) and triethylamine (281 μL, 2.01 mmol) in isopropyl alcohol (1.2 mL) was stirred at 100° C. for 20 min. After cooling, the sub-title compound precipitated out and was collected by vacuum filtration, followed by washing with cold ether to give the sub-title compound as light yellow powder. LCMS calc. for C19H29N4O4 (M+H)+: m/z=377.2. Found: 377.2.