Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]([OH:16])=O)[C:4]1=[O:17])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:23]1([C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28]1)[CH2:22]2.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>[O:33]=[C:29]1[NH:28][C:23]2([CH2:22][C:21]3[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14](=[O:16])[CH2:13][N:5]4[C:4](=[O:17])[CH:3]([CH2:1][CH3:2])[O:8][C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]4=5)[CH:20]=3)[CH2:24]2)[C:31](=[O:32])[NH:30]1
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reactant: CCC1Oc2ccccc2N(CC(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1Oc2ccccc2N(CC(=O)Nc2ccc3c(c2)CC2(C3)NC(=O)NC2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-ethyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid (0.2 mmol, 47 mg), 5′-amino-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (0.2 mmol, 43 mg) and DIPEA (0.6 mmol, 104.5 μl) in DMF (1 ml) was added HATU (0.2 mmol, 76 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=435.2; tR=2.71. H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.24 (q, 1H), 7.03 (d, 1H), 6.87-6.92 (m, 4H), 4.65 (q, 2H), 4.41 (q, 1H), 3.34 (q, 2H), 3.00 (q, 2H), 1.78 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [Cr](O)(O)(=O)=O.[C:6]1([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CC(C)=O>[C:6]1([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCCCC#Cc1ccccc1
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC#Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
Brown's chromic acid reagent (133 mL, 88 mmol, 0.66 M) was added slowly in drops to a magnetically stirred solution of 7-phenylhept-6-yn-1-ol (6) (7.53 g, 40 mmol) in acetone (400 mL) at 0° C. After the chromic acid had been added, the reaction mixture was stirred for 1 hour at 0° C. and then at room temperature until all the base material has been converted as indicated by TLC. Water (300 mL) was added and the aqueous phase was then extracted with petroleum ether (boiling point 40-60° C.)/Et2O 1:1 (6×50 mL). The combined organic phases were washed with water (2×25 mL) and dried (MgSO4). Distillation on a rotary evaporator yielded 7.3 g (90%) of a pale yellow viscous oil, which crystallized when left to rest. TLC and NMR indicated a pure product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccccc2)CC1
Reaction time: 7.5 h
Yield: 44.1 %

Procedure:
Potassium carbonate (2.2 g) and 5-phenoxypentyl chloride (1.2 g) were added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide (40 ml), an the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.82 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenoxypentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:12])[CH3:11].C.[CH:14](=[O:16])[CH3:15]>C(O)(=O)C>[OH:16][CH:14]([CH3:15])[CH2:11][C:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CC(=O)C1=C(C)C=CCC1(C)C
Reactant: CC=O
Agent: C
Solvent: CC(=O)O
Product: CC1=C(C(=O)CC(C)O)C(C)(C)CC=C1
Temperature: 10 °C

Procedure:
Into a 2-liter reaction flask equipped with a mechanical stirrer, cooling bath, 250 ml addition funnel, nitrogen purge, water-cooled condenser, gas bubbler and thermometer, is magnesium chloride in tetrahydrofuran. 200 Grams (1.22 moles) of 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene are added dropwise from the addition funnel at a rate sufficient to produce methane. Cooling is applied as necessary to maintain the reaction temperature between 30° and 35° C. Following completion of the addition of the 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene, the reaction mass is stirred until no further methane is evolved. The reaction mass is then cooled to a temperature in the range of from 0° C. to 5° C., and 59 grams of acetaldehyde is added dropwise with stirring while maintaining the reaction mass temperature at about 10° C. The reaction is slightly exothermic. 15 Minutes after the completion of the addition of acetaldehyde, acetic acid is added dropwise while maintaining the temperature of the reaction mass at about 10° C. Following the addition of acetic acid, the reaction mass is permitted to reach room temperature. The reaction mass is then washed into a separatory funnel with water to dissolve the salt therein. The resulting organic layer is washed with saturated sodium chloride, saturated sodium bicarbonate, and then saturated sodium chloride. The washed organic layer is then dried over anhydrous magnesium sulfate and concentrated on a rotovap yielding 256 grams of residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20](I)[CH2:21][CH3:22]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH2:21][CH3:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Reactant: CCCI
Product: CCCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using n-propyl iodide as a reagent, reaction was performed as in Example 29 to give 227 mg of the titled compound (yield, 99%).
Reaction SMILES: C(OC(NOS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:44]O)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]3[N:44]=2)=[CH:32][CH:31]=1
Reactant: ON=C(Cc1ccccn1)c1ccc(F)cc1
Agent: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cc3ccccn3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (17.26 54.6 mmol) was added portionwise with stirring to TFA (50 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (˜250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in chloroform (200 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 1-(4-fluorophenyl)-2-pyridin-2-ylethanone oxime (6.29 g 27.3 mmol) in chloroform (100 ml) was added. The reaction was stirred at room temperature for 18 hours, washed with water (2×50 ml) and dried. Removal of solvent gave a brown solid which was purified by biotage chromatography. Elution with cyclohexane/ethyl acetate (20/1) gave the title compound as a yellow solid (4.09 g 71%). MH+: 213; NMR: (CDCl3): δ 6.75 (2H, m) 7.10 (3H, m) 7.50 (1H, d) 7.95 (2H, m) 8.45 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)([C:17](OCC)=[O:18])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:30]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)([C:17](=[O:18])[NH2:30])[CH3:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(C)(NC(=O)C1CCCN1C(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NC(C)(C(N)=O)c1ccc(Br)cc1
Reaction time: 72 h
Yield: 64 %

Procedure:
To a stirred solution of 2-[1-(4-bromo-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 0.6 mmol) in ethanol (8 mL) was bubbled through NH3 gas for 5 minutes at −78° C. The solution was stirred at ambient for 3 days in a sealed tube. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (169 mg, 64%). m/z 439.8, 441.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[Li+].[CH3:29][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:24])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[CH3:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(C)O

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of example S.1, Step 1, 0.50 g) and lithium chloride (53 mg, 1.24 mmol, 1.00 equiv.) in THF (15 mL) was added a solution of methyl magnesium bromide (1.78 mL, 1.4 M in THF/toluene, 2.49 mmol, 2.00 equiv.) at −70° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].[CH3:14][C:15]([CH3:17])=O.C(=O)([O-])[O-].[K+].[K+].ICC=C>C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:17][CH:15]=[CH2:14])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Reactant: CC(C)=O
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=CCOc1c(CC=C)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2-allyl-6-nitrophenol (100 mg, 0.0006 mol) in acetone (4 mL, 0.06 mol) at 0° C. in an ice bath was added potassium carbonate (0.092 g, 0.00067 mol) followed by 3-iodo-1-propene (0.11 g, 0.00067 mol) under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h at 0° C. then warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% HCl, water, dried over magnesium sulfate and concentrated in vacuo. The reaction mixture was purified by ISCO chromatography on silica gel (12 g) using ethyl acetate-hexane (10%-50%) to give 1-allyl-2-allyloxy-3-nitrobenzene as a yellow oil (93 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=8.08, 7.8 Hz), 5.90-6.13 (m, 2H), 5.40 (d, 1H, J=17 Hz), 5.29 (d, 1H, J=10 Hz), 5.15 (d, 1H, J=10 Hz), 5.09 (d, 1H, J=17 Hz), 4.50 (d, 2H, J=5.8 Hz), 3.49 (d, 2H, J=6.3 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[S-:17].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[SH:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(I)cc2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(-c2ccc(S)cc2)cc1
Temperature: 100 °C
Yield: 106.6 %

Procedure:
3.25 g (10.8.10-3 mol) of 4-(4-iodophenyl)benzonitrile are dissolved in 50 ml of hexamethylphosphoramide, and 3.05 g (43.4.10-3 mol) of sodium thiomethylate are then added to the solution. The reaction mixture is heated at 100° C. for 1.5 hours and then, after cooling, hydrolyzed in a 1N hydrochloric acid/ice mixture. The expected product is extracted with ethyl acetate. The resulting organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and then evaporated under reduced pressure to give 2.4 g (quantitative yield) of a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCn1ccnc1-c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1-c1ccccc1)c1ccco1

Procedure:
A mixture of 2.0 g. of 2-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0 ml. of 2-furoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The desired product was obtained as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:20]([O:19][CH2:17][CH3:18])=[O:21])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 73.3 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane 1.49 g (6.6 mmol) (as prepared in Example 1) was reacted with ethylchloroformate 1.3 mL (13.2 mmol) and pyridine (3.3 mL) as described in example 2 to give 1.51 g of the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.[CH3:26][O:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O-])=O.[NH2:35][C:36]1[CH:37]=[C:38]([C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]#[N:46])[CH:39]=[CH:40][C:41]=1[NH2:42]>CN(C=O)C>[C:45]([C:44]1[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=1[C:38]1[CH:39]=[CH:40][C:41]2[NH:42][C:31]([CH2:30][CH2:29][C:28]([O:27][CH3:26])=[O:34])=[N:35][C:36]=2[CH:37]=1)#[N:46]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: COC(=O)CCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
Dicyclohexylcarbodiimide (0.11 moles, 2.26 g), hydroxybenzotriazole (0.011 moles, 1.48 g) and monomethylsuccinate (0.011 moles, 1.45 g) were dissolved in 75 ml of DMF. 2-(3,4-Diaminophenyl)benzonitrile (0.01 moles, 2.0 g) was added. The reaction was stirred at room temperature for 48 hours The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed thoroughly with brine. The ethyl acetate solution was dried over sodium sulfate and filtered. The solvent was removed. The residue was purified by HPLC on silica gel eluted with ethyl acetate. The material was dissolved in 400 ml toluene with 5 mg of p-toluenesulfonic acid and refluxed for 8 hours. The solvent was removed. The residue was purified by HPLC on silica gel eluted with ethyl acetate to yield 2.3 g of methyl 3-[5-(2-cyanophenyl)-1H-benzimidazole-2-yl]propionate. (MS).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C(OC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(Oc1ccccc1)N1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added ,50% KOH (aq.) (100 g of KOH in 100 g H2O at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjusting the pH to about two using HCl (con., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH (aq.). The product was extracted into 10:1 dichloromethane/isopropylalcohol. The combined organics were dried (MgSO4), filtered, and concentrated to give 13.0 g of desired 3-piperazin-1-yl-1H-indazole as a brown solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:18](=O)[CH2:17][CH2:16][C@@:15]2([CH3:20])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:21])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:23].Cl.[NH2:25][CH2:26][CH2:27][O:28][NH2:29]>O1CCOCC1.O.[Cl-].[Na+].O>[ClH:23].[NH2:25][CH2:26][CH2:27][O:28]/[N:29]=[C:18]1/[C:2]([CH3:1])=[C:3]2[C@:15]([CH3:20])([CH2:16][CH2:17]/1)[C@@H:14]1[C@H:6]([C@H:7]3[C@@:11]([CH2:12][CH2:13]1)([CH3:21])[C@@H:10]([OH:22])[CH2:9][CH2:8]3)[CH2:5][CH2:4]2
Reactant: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reactant: NCCON
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC/C1=N\OCCN
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 4-methyltestosterone (203 mg) in dioxane (3.7 ml), a solution of 2-aminoethoxyamine dihydrochloride (259 mg) in water (2 ml) was rapidly added dropwise. After 24 h dioxane (20 ml) and brine (10 ml) were added and the mixture was stirred for 10 min. The phases were separated and the aqueous phase was extracted with dioxane (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was triturated with Et2O for 5 h and the precipitate was filtered. The crude product was dissolved in water and freeze-dried to give the title compound (I-aa) as a white solid (197 mg, 74%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])([OH:3])=[O:2].[CH3:42][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:42][O:2][C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)O)NC(=O)c1cnc2ccccc2c1
Solvent: CO
Solvent: CCCCCC
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OC)NC(=O)c1cnc2ccccc2c1
Reaction time: 48 h

Procedure:
To a solution of (3S)-3-[(2S)-5-carboxy-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (100 mg) in methanol (10 ml) was added 2M solution of trimethylsilyldiazomethane in hexane (2 ml) at room temperature. After being stirred at the same temperature for 2 days, the solvent was removed under reduced pressure and the resulting solid was triturated with ethyl ether to give (3S)-3-[(2S)-5-methoxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (68.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([NH:18][CH3:17])=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
In 100 ml of EtOH on reflux was dissolved 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene, and with refluxing continued, a solution of 1.94 g of 40% aqueous methylamine solution in 10 ml of EtOH was added dropwise over a period of 50 minutes. After completion of dropwise addition, the mixture was further refluxed for 15 minutes, at the end of which time it was cooled with ice-water, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that orsder, and dried. The procedure gave 1.66 g of the title compound as white crystals.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].Cl>CN(C)C=O>[O:16]=[C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:21])[N:15]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:1]([OH:10])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
To a solution of 3H-isobenzofuran-1-one (18 g, 134 mmol) in dry N,N-dimethylformamide (110 mL) was added potassium phthalimide (27 g, 145 mmol). The mixture was stirred at reflux for 6 hours then cooled to 0° C. and treated with 1N hydrochloric acid (180 mL). The yellow solid thus formed was filtered, washed with water, with ethanol and dried in oven. Crystallization with ethanol afforded the title compound as white solid (27 g).
Reaction SMILES: [CH:1]1([N:7]([C:34](=[O:48])[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:8][CH2:9][N:10]([CH2:21][CH2:22][C:23]2[C:31]3[S:30][C:29](=[O:32])[NH:28][C:27]=3[C:26]([OH:33])=[CH:25][CH:24]=2)C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:49].C(O)(=O)C.C1(C)C=CC=CC=1>C(O)(=O)C>[BrH:49].[BrH:49].[CH:1]1([N:7]([CH2:8][CH2:9][NH:10][CH2:21][CH2:22][C:23]2[C:31]3[S:30][C:29](=[O:32])[NH:28][C:27]=3[C:26]([OH:33])=[CH:25][CH:24]=2)[C:34](=[O:48])[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1F)C1CCCCC1
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(CCNCCc1cccc(F)c1F)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of the carbamate from step (i) (0.4 g) in acetic acid (2 mL) was treated with hydrogen bromide/acetic acid (33%, 2 mL) and stirred for 1 h. Toluene (10 mL) was added, the mixture was evaporated in vacuo, the residue purified by reverse phase HPLC with 0.2% aqueous TFA/acetonitrile as eluent and the pure fractions evaporated in vacuo. The solid residue was dissolved in a mixture of ethanol (5 mL) and acetonitrile (15 mL) and treated with hydrobromic acid in aqueous acetonitrile (16%, 1.8 mL). A solid gradually precipitated and was filtered off, washed with acetonitrile and slurried in ethanol. The solid was filtered off, washed with a little ethanol and dried to afford the title product (0.036 g) as a white solid.