Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=S)[NH2:10])[CH2:4][CH2:3]1.C1(S(N)(=O)=[O:20])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].N([O-])=O.[Na+]>O1CCOCC1.CC(C)=O.CC(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:20])[NH2:10])[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC1(C)CCC(NC(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1(C)CCC(NC(N)=O)CC1

Procedure:
2.9 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)- benzene-sulfonyl]-N'-(4.4-dimethylcyclohexyl)-thiourea (prepared by reaction of 4-[β-<2-methoxy-5-chlorobenzamido>-ethyl]-benzenesulfonamide with cyclohexyl mustard oil in dioxane/acetone in the presence of potassium carbonate) melting point 175°-177°C and decomposition, are dissolved in 250 ml acetone. An aqueous solution of 0.7 g sodium nitrite is added and while stirring is continued at 5°C, 15 ml of 5N acetic acid are added dropwise. After stirring for 21/2 hours acetone is distilled off. The residue is dissolved in dilute sodium hydroxide solution, the solution is clarified with charcoal and acidified. There is obtained a crystalline precipitate of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4.4-dimethylcyclohexyl)-urea, which is filtered off with suction and recrystallized from dilute methanol. The substance melts at 174°-176°C. 2. (a) 5.38 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)benzene-sulfonyl]-N'-(4.4-dimethylcyclohexyl)-thiourea are dissolved in 5 ml dioxane and 250 ml methanol. Then 2.16 g of mercury peroxide are added and stirring is continued for 4 hours at 60°C. The mercury sulfide formed is filtered off, and the filtrate is half concentrated and water is added. After abandoning during the night a crystalline precipitate has formed, which is filtered off with suction and recrystallized from dilute methanol. The N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4.4-dimethylcyclohexyl)-isoureamethylether thus obtained melts at 149°-151°C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.[NH:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[CH:14]1.[OH-].[Na+]>OS(O)(=O)=O>[NH:13]1[CH:17]=[C:16]([CH:18]=[C:6]2[C:5](=[O:12])[C:4]3[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[N:15]=[CH:14]1
Reactant: Cc1ccc2c(n1)C(=O)CCC2
Reactant: O=Cc1c[nH]cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(n1)C(=O)C(=Cc1c[nH]cn1)CC2
Temperature: 110 °C

Procedure:
A mixture of 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3) (15.1 g, 93.8 mmol) and imidazole-4-carbaldehyde (15 g, 156 mmol) in 40% H2SO4 (65 mL) was heated at 110° C. for 12 h. The reaction mixture was cooled to room temperature, poured onto crushed ice and basified with 2M NaOH until pH>8. The solids were collected on a glass frit, washed with water, dichloromethane and dried under vacuum to give unpurified 7-(1H-imidazol-4-yl-methylene)-2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A4) as a yellow solid, 22 g (98%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Yield: 94 %

Procedure:
2-Fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) and N-methylpiperazine (1.29 mL, 2 eq) were heated at 130° C. for 1 h. The reaction mixture was then diluted with 25 mL of THF and washed with a saturated aqueous solution of Na2CO3 and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (1.38 g, 94% yield). m/z (ESI) 252.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16]>Br>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cccc(Cl)c1-c1ccccc1Cl
Agent: Br
Product: Oc1cccc(Cl)c1-c1ccccc1Cl
Yield: 84 %

Procedure:
Treatment of 2,2′-dichloro-6-methoxybiphenyl (5.0 g, 20.9 mmol) with hydrogen bromide (33% in acetic acid, 60 mL) according to the procedure described for Example 69, Step 2 provided 4.2 g (89%) of 2′,6-dichlorobiphenyl-2-ol as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CC(O)=O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C1Cc2ccccc2N1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 116.5 %

Procedure:
To a solution of 2-tert-butyl-1H-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH4 at 10° C. The mixture was stirred for 20 minutes at 10° C. before being treated dropwise with H2O under ice cooling. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-tert-butylindoline (9.8 g), which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:24])[C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.C(C(C(C([O-])=O)O)O)([O-])=O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([N:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: C[C@@H]([C@@H](O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Product: CC(C(O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1

Procedure:
A preferred compound, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol ((1S,2S) free base), and its tartrate salt, can be prepared as described in U.S. Pat. No. 5,272,160, referred to above. The resolution of racemic 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol to form the (1S,2S) free base and the corresponding (1R,2R) enantiomer can be carried out as described in U.S. provisional patent application entitled "(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-Hydroxy-4-Phenylpiperidin-3-yl)-1-Propanol Methanesulfonate Trihydrate", referred to above, and as exemplified in Example 1 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=Cc1c(Cl)cnc2[nH]ccc12
Solvent: C1CCOC1
Solvent: O
Product: OC(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (3.0 g, 16 mmol, Adesis) in THF (100 mL) at about 0° C. was added cyclohexylmagnesium chloride (2 M in Et2O, 22.8 mL, 45.7 mmol). The reaction mixture was stirred at ambient temperature for about 2 h, then additional cyclohexylmagnesium chloride (2 M in Et2O, 8.3 mL, 16.6 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 h. Water (10 mL) was added to quench the reaction and the volatiles were removed under reduced pressure. The product was extracted into DCM (3×20 mL) and the combined organic phases were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure and the crude material was purified by chromatography over silica gel using a gradient of 10 to 45% EtOAc in heptane as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanol as an off white solid (1.97 g, 45%): LC/MS (Table 2, Method a) Rt=2.32 min; MS m/z: 265 and 267 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:24]1([C:30]2[O:34][C:33]([C:35]([N:37]3[CH2:40][CH:39]([O:41][C:42]4[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=4)[CH2:38]3)=[O:36])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[N:8]1([CH2:46][C:45]2[CH:44]=[CH:43][C:42]([O:41][CH:39]3[CH2:38][N:37]([C:35]([C:33]4[O:34][C:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)=[O:36])[CH2:40]3)=[CH:49][CH:48]=2)[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: C1CNC2(C1)CCOC2
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC34CCOC4)cc2)C1
Yield: 60.7 %

Procedure:
7-Oxa-1-azaspiro[4.4]nonane TFA salt (0.07 g, 0.29 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.044 ml, 0.32 mmol) was added, followed by 4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.101 g, 0.29 mmol) and finally sodium triacetoxyhydroborate (0.123 g, 0.58 mmol. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.081 g (61%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62-1.74 (m, 3H), 1.79-1.9 (m, 2H), 2.10 (dt, 1H), 2.37-2.45 (m, 1H), 2.54 (dd, 1H), 3.41 (d, 1H), 3.48 (d, 1H), 3.63 (d, 1H), 3.69 (q, 1H), 3.80 (d, 1H), 3.91 (td, 1H), 4.10 (dd, 1H), 4.56 (dd, 1H), 4.63 (ddd, 1H), 5.07-5.18 (m, 2H), 6.84 (d, 2H), 7.25 (d, 2H), 7.64-7.73 (m, 3H), 8.08 (dd, 2H). MS (APCI+) m/z 461.2 [M+H]+, LC purity: 97%
Reaction SMILES: [C:1]([N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C:5]1([CH3:18])[CH3:17])(=[O:3])[CH3:2].C[OH:20].O.OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[CH2:14]([CH:13]=[N+:12]([CH:7]1[CH2:6][C:5]([CH3:17])([CH3:18])[N:4]([C:1](=[O:3])[CH3:2])[C:9]([CH3:10])([CH3:11])[CH2:8]1)[O-:20])[CH2:15][CH3:16]
Reactant: CO
Reactant: CCCCNC1CC(C)(C)N(C(C)=O)C(C)(C)C1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC=[N+]([O-])C1CC(C)(C)N(C(C)=O)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred mixture of 12.4 g (48.6 mmol) of 1-acetyl-4-n-butylamino-2,2,6,6-tetramethylpiperidine, 0.8 g (2.4 mmol) of sodium tungstate, 85 ml of methanol and 20 ml of water at 0° C. is added 19.9 ml (195 mmol) of 30% aqueous hydrogen peroxide. After stirring for one hour at 0° C., the reaction mixture is allowed to warm to room temperature and is stirred for an additional 2.5 hours. Ethyl acetate is added and the organic phase is then washed with water, and brine, dried over anhydrous sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (12:2:1, ethyl acetate:hexane: methanol) to yield 4.8 g (37%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12].[Na]>CO>[CH3:1][C:2]1[C:6]2[C:5](=[C:8]([CH3:7])[CH:9]=[CH:10][C:11]=2[CH3:12])[CH2:4][CH:3]=1
Reactant: CC1=CC=CC1
Reactant: CC(=O)CCC(C)=O
Agent: [Na]
Solvent: CO
Product: CC1=CCc2c(C)ccc(C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 12 g (150 mmol) of methylcyclopentadiene and 17.1 g (150 mmol) of 2,5-hexanedione was added dropwise to a solution of 8.6 g (975 mmol) of sodium in 200 ml of methanol at 0° C. in the course of 1 hour. After stirring at room temperature for 18 hours, the dark red mixture was poured onto ice-water and extracted with ether. After the extract had been dried over sodium sulfate, the solvent was stripped off and the oil which remained was chromatographed on 600 g of silica gel 60. Using hexane as the mobile phase, first 3.2 g (13%) of 3,4,7-trimethylindene and then 1.5 g (6%) of 2,4,7-trimethylindene were eluted in close succession. Subsequent recrystallization from hexane gave the pure products.
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>C(O)CCC>[C:21]12([NH:20][C:14]3[N:13]=[C:12]([NH:11][C:1]45[CH2:2][CH:3]6[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]6)[CH2:8]4)[CH2:10]5)[CH:17]=[C:16]([Cl:18])[N:15]=3)[CH2:22][CH:23]3[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]3)[CH2:30]1)[CH2:28]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(Cl)n1
Solvent: CCCCO
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reaction time: 75 h

Procedure:
26.0 g (87.25 mmoles) of 4-(1-adamantylamino)-2,6-dichloropyrimidine and 39.5 g (261.6 mmoles) of 1-aminoadamantane are dissolved in 200 ml of n-butanol, the reaction mixture is boiled for 75 hours and evaporated. The residue is suspended in 400 ml of ether and filtered. The filtered substance is chromatographed after drying on a silica gel column by using chloroform as eluent. The substance obtained is a mixture of the title isomers. The isomers are separated on a silica gel column by using as eluent a 49:1 mixture of hexane and ethyl acetate. 2,4-Bis(1-adamantylamino)-6-chloropyrimidine is obtained which is recrystallized from hexane to obtain a yield of 21.67 g (60.14%). Its melting point and 1H-NMR are identical to those of the product according to Example 11.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[CH2:41]([O:43][C:44](=[O:49])[CH2:45][CH:46]([NH2:48])[CH3:47])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][CH:46]([CH3:47])[CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:49])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: CCOC(=O)CC(C)N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)NC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1F
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 116 (75 mg; 0.17 mmol) in dry THF, DIEA (103 μl; 0.60 mmol) was added followed by ethyl-3-aminobutyrate (45 mg; 0.34 mmol) and the reaction mixture stirred for 2 h30 at RT. The solvent was then removed under vacuum and the crude material purified by flash chromatography (EtOAc/cHex) to afford the title compound as a colorless oil (82 mg, 89%). 1H NMR: (CDCl3, 300 MHz) δ 8.42 (m, 1H), 8.23 (t, J=8 Hz, 1H), 8.16 (dd, J=1.9, 8 Hz. 1H), 8.09 (dd, J=1.5, 8.1 Hz, 1H), 7.96 (dd, J=1.3, 12.4 Hz, 1H), 7.47 (m, 1H), 7.38-7.22 (m, 5H), 7.12 (m, 1H), 4.62 (m, 1H), 4.21 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.33 (s, 3H), 2.65 (m, 2H), 2.07 (s, 3H), 1.37 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). UPLC/MS: 532.3 (M+H)+ 530.3 (M−H)−. HPLC (Method A) Rt: 5.52 min (purity: 98.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([CH2:25][C:24]([F:35])([F:34])[F:23])[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cn(CC(F)(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 65.5 %

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dehydrated DMF (40 ml) was added 60% NaH in oil (596 mg) while stirring under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hr. Then, trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (2.6 g) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added methanol, and the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:49](=[O:50])C1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[C:49]3=[O:50])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCNCCNc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN(CCCCc4ccc([N+](=O)[O-])cc4)Cc4ccccc4)c3c2)C1=O
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a solution of N-[3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N′-ethyl-ethane-1,2-diamine (20 mg in 3 mL dry methylene chloride) at 0° C. was added 9.6 mg N,N′-disuccinimidyl carbonate followed by triethylamine (0.110 mL of a 10% solution in methylene chloride) and the mixture stirred at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the crude title compound (21 mg).
Reaction SMILES: [C:1](Cl)(=O)C.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([OH:11])=[O:10]>CO>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([O:11][CH3:1])=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution prepared by the dropwise addition of 12 ml acetyl chloride to 150 ml methanol was added 7.0 grams 3-fluoro-4-nitrobenzoic acid and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 2% sodium carbonate solution. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 6 gramsof methyl 3-fluoro-4-nitrobenzoate as an orange oil which graduallyhardened to a yellow solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[O:6][CH:7]=1.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:26](O)=[O:27])[C:14]=2[CH:13]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH:8][C:26]([CH:15]2[C:14]3[CH:13]=[C:12]([Cl:11])[CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:27])[O:6][CH:7]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccc(Cl)cc21
Reactant: Nc1nc(C(F)(F)F)co1
Product: O=C(Nc1nc(C(F)(F)F)co1)C1c2ccccc2Oc2ccc(Cl)cc21

Procedure:
The title compound, white solid, m.p. 235° C. and MS: m/e=395.2, 397.2 (M+H+) is prepared in accordance with the general method of example 3c from 4-trifluoromethyl-oxazol-2-ylamine and (RS)-2-chloro-9H-xanthene-9-carboxylic acid (CAS:[188027-67-0]).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:13]1[CH2:20][O:19][S:16](=[O:18])(=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[CH2:6]([O:5][C:3]([C:2]([CH3:1])([C:8](=[O:9])[CH3:10])[CH2:20][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17])=[O:4])[CH3:7]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: O=S1(=O)CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Temperature: 25 °C
Yield: 122.6 %

Procedure:
Ethyl 2-methylacetoacetate (43.2 g) in N,N-dimethylformamide (25 ml) was added to a suspension of sodium hydride (12.0 g of 60% NaH in mineral oil) in N,N-dimethylformamide (100 ml), dropwise with ice-bath cooling. This mixture was allowed to warm to ambient temperature for 30 mins before re-cooling. 1,4-butanesultone (40.8 g) in N,N-dimethylformamide (25 ml) was then added dropwise. The final mixture was heated at 50° C. for 18 hrs, then quenched with 50 ml of water. The solvent was evaporated under vacuum; the residue was partitioned between water and diethyl ether. The aqueous layer was collected, washed with fresh diethyl ether and evaporated under vacuum; final drying was under high vacuum over phosphorus pentoxide. A yield of 103 g of 5-(ethoxycarbonyl)-5-methyl-6-oxoheptane-1-sulfonic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:14][CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc(CCO)c(Cl)cc1[N+](=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCBr)c(Cl)cc1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
A solution of 2-(2-chloro-5-methoxy-4-nitrophenyl)ethanol (7.0 g, 30.22 mmol), triphenylphosphine (12.68 g, 48.3 mmol) and carbon tetrabromide (14.03 g, 42.3 mmol) in DCM (150 mL) was stirred at room temperature for 2 hours. The mixture was partitioned between water (150 mL) and EtOAc (100 mL), and then the separated aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were washed with water (80 mL), brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 0-1% methanol in DCM to give the title compound (8.0 g, 90%) as a solid.