Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([F:28])[CH:22]=1.BrC1C=CC([O:36]C)=C(F)C=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:36])=[C:23]([F:28])[CH:22]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(F)c(F)c4)ccc3c2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(O)c(F)c4)ccc3c2)CC1

Procedure:
20 g of 1-fluoro-2-(3-fluoro-4-hydroxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene (obtained in the same manner as in (5-f) except that 1-bromo-3-fluoro-4-methoxybenzene was used instead of 3,4-difluoro-1-bromobenzene to obtain 1-fluoro-2-(3-fluoro-4-methoxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene which was then demethylated with hydrobromic acid) was dissolved in 80 ml of dichloromethane. To the solution was then added dropwise 15.8 g of trifluoromethanesulfonic anhydride under cooling with ice. To the reaction mixture was then added dropwise 10 ml of pyridine in such a manner that the temperature thereof didn't exceed 5° C. After the termination of dropwise addition, the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was then added 20 ml of water to terminate the reaction. The resulting organic phase was washed twice with 20 ml of water, and then dehydrated and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 24.3 g of 1-fluoro-2-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C=CCCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol ) and 3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.75 g (62%).
Reaction SMILES: C(O[CH2:5][CH2:6][C:7](=O)[CH3:8])(=O)C.[CH3:10][O-:11].[Na+]>CO>[CH3:5][C:6]1[C:10](=[O:11])[CH:7]([CH3:8])[CH2:6][CH2:5][C:7]=1[CH3:8]
Reactant: C[O-]
Reactant: CC(=O)CCOC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1=C(C)C(=O)C(C)CC1

Procedure:
130 g of 1-acetoxybutan-3-one and sodium methylate solution in methanol are dripped in the course of one hour from separate supply vessels while stirring into 400 g of boiling diethyl ketone at such a rate that the reaction mixture remains constantly alkaline. A total of 190 g of a 30% by weight sodium methylate solution is used up in this way. The whole is then heated under reflux for another hour and then neutralized with glacial acetic acid. Deposited sodium acetate is filtered off and the filtrate is subjected to fractional distillation. 81 g of 2,3,6-trimethyl-2-cyclohexen-1-one is obtained as well as traces of 4-methyl-3-ethyl-2-cyclohexen-1-one. The yield with reference to 1-acetoxybutan-3-one is 59%.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1([CH3:16])[C:7]([CH3:9])([CH3:8])[CH:6]1[CH:10]([CH:14]=O)C([O-])=O.[CH2:17]([OH:19])C>>[CH3:16][C:5]1([CH3:4])[C:7]([CH3:8])([CH3:9])[CH:6]1[C:10]1[CH2:14][C:17](=[O:19])[NH:3][N:2]=1
Reactant: CCO
Reactant: NN
Reactant: CC1(C)C(C(C=O)C(=O)[O-])C1(C)C
Solvent: O
Product: CC1(C)C(C2=NNC(=O)C2)C1(C)C

Procedure:
Hydrazine hydrate (1.1 g, 0.024 mol) was added to a solution of ethyl 3-(2,2,3,3-tetramethylcyclopropyl-3-oxopropionate (4.41 g, 0.020 mol) in anhydrous ethanol (60 ml). The reaction mixture refluxed for 3 h. After cooling, the solvent was evaporated, and the residue was triturated with hexane to give a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:22]([OH:24])C>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH:13]=1)[CH:22]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: 4-Phenoxyphenol (20.0 g, 107 mmol) and sodium hydroxide (3.8 g, 845 mmol) are dissolved in a water/ethanol (130 ml/26 ml) mixture and heated at 70° C. To this reaction mixture is added chloroform (24.6 g, 215 mmol) dropwise over 45 minutes, and heating is continued for 3 hours. The mixture is cooled to room temperature, and then evaporated. The aqueous phase is acidified with conc. HCl to pH 1-3, and extracted twice with ether. The extracts are dried (MgSO4) and evaporated. Silica gel chromatography (10% ethyl acetate/hexane) of the residual oil yields 5-phenoxy-2-hydroxybenzaldehyde as a yellow solid, m.p. 54°-55° C., which is converted to 3-(N-hydroxyaminomethyl)-6-phenoxy-2H-1-benzopyran as described under (a).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.COCN[C:23]([C:25]1[C:29]([CH3:30])=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:27]([CH3:38])[N:26]=1)=[O:24].C(O)(=O)C>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([CH2:18][C:23]([C:25]2[C:29]([CH3:30])=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:27]([CH3:38])[N:26]=2)=[O:24])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: COCNC(=O)c1nn(C)c(-c2ccc(F)cc2)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cc2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To 10 ml of dry THF cooled to −65° C. were added 1.35 ml of a 2M solution of Sodium-bis(trimethylsilyl)amide in THF. Then a solution of 0.32 g 2-Chlor-4-methyl pyridine in 1 ml of dry THF was added dropwise maintaining the temperature at −70° C. for 30 min. Then a solution of 0.50 g of 5-(4-Fluoro-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid methoxymethyl-amide in 5 ml of dry THF was added dropwise over a 10 min period maintaining the temperature below −65° C. The solution was stirred for 2 h at −60° C., and then allowed to warm up to 0° C. and stirred for 20 min at this temperature. Then 0.31 ml of Acetic acid was added dropwise at −50° C., and the solution was allowed to warm up to room temperature and stirred overnight. The mixture was concentrated in vaccuo. The residue was taken up in Ethyl acetate. The organic phase was washed with saturated bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (0.67 g, yellow oil) was purified by chromatography on silica gel (Heptane/Ethyl acetate 4:1). The desired product was obtained as a white solid (0.27 g, 70%), MS: m/e=344.0 ([M+1]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.Cl.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].OS(O)(=O)=O>C(O)(=O)C.O>[CH3:1][N:2]1[CH2:8][CH2:7]/[C:6](=[CH:18]\[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)/[C:5](=[O:9])/[C:4](=[CH:18]/[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)/[CH2:3]1
Reactant: CN1CCCC(=O)CC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CN1CC/C(=C\c2ccc([N+](=O)[O-])cc2)C(=O)/C(=C/c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h

Procedure:
N-methylazepan-4-one.HCl (50 mg, 0.30 mmol) and 4-nitrobenzaldehyde were dissolved in acetic acid (5 mL) and stirred for 10 min, then conc. H2SO4 (50 μL) was added slowly and the mixture was stirred at rt overnight. More concentrated H2SO4 (100 μL) was added and stirring was continued at rt for 6 h. Additional 500 μL of concentrated H2SO4 was added and the reaction stirred overnight. A further 350 μL of conc. H2SO4 was added and stirring continued for additional 5 h, during which period further H2SO4 was added in two portions (500 μL and 250 μL). Then water (3× reaction volume) was added and the mixture was stirred until rt was reached. The reaction mixture was extracted with ethyl acetate (3× reaction volume). The phases were separated and the organic phase concentrated to yield a dark yellow viscous oil. The crude product was purified by preparative HPLC, (XBridge column; eluents 50 mM ammonium carbonate buffer at pH 10 and methanol) giving the title product as a yellow solid (26.3 mg). LCMS System A: Rt 1.87 m/z [M+H]+ 394.1, System B: Rt 2.57.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([O:30]CC)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.35 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.98 g, 76%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[CH3:26][NH:27][NH2:28]>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][CH:21]=3)[N:27]([CH3:26])[N:28]=2)[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=1[OH:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: CNN
Reactant: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Product: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nn(C)c2n1
Yield: 91 %

Procedure:
A mixture of 1.8 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol and 0.7 g of methylhydrazine is reacted in a similar manner as Example 1 and the resulting product is recrystallized from ethanol to give 1.6 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenvl)-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 178°-181° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([O:20][CH2:21]C)=[O:19])=[C:4]([NH:16]C)[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:14])[C:6]=2[N:15]=1.C([O-])(=O)/C=C\C([O-])=[O:27]>>[NH2:16][C:4]1[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:27])[CH:12]=3)[N:7]([CH3:14])[C:6]=2[N:15]=[C:2]([CH3:1])[C:3]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2c(c1NC)c1ccccc1n2C
Reactant: O=C([O-])/C=C\C(=O)[O-]
Product: COC(=O)c1c(C)nc2c(c1N)c1cc(O)ccc1n2C

Procedure:
2,9-dimethyl-4-methylamino-9H-pyrido[2,3-b]indole-3-carboxylic acid, ethyl ester, (Z)-2-butenedioate, or
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:14][CH:15]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)c(F)c3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc(F)c(F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.540 g of tert-butyl 4-{4-[3-(3,4-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.353 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.26 (1:1 EtOAc-heptane); Rt=5.98.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][C@@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:21]#[N:22].[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.O>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]([CH2:23][C@H:20]([NH:19][C:45]([C@@H:44]2[CH2:48][CH2:49][CH2:50][N:43]2[C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[O:46])[C:21]#[N:22])=[CH:25][CH:26]=1
Reactant: N#C[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of propane phosphonic acid anhydride (T3P, 50% in DMF, 344 mg) was added to a stirred solution of (S)-2-amino-3-(biphenyl-4-yl)propanenitrile (100 mg), N-tert-butoxycarbonyl-(L)-proline (107 mg) and triethylamine (0.314 mL) in DMF (3 mL) at 20° C. The resulting solution was stirred at 20° C. for 1 hour. Water (15 mL) was added and the mixture extracted with ethyl acetate (3×5 mL). The organics were washed with saturated brine (5×5 mL), dried over sodium sulfate and evaporated to afford the subtitle compound (178 mg).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCCO
Reactant: Br
Product: OCCCCCCCCCCBr
Temperature: 25 °C

Procedure:
A solution of 50 g of decane-1,10-diol in 300 ml of 48% aqueous hydrobromic acid was heated at 90° C. for 24 hours while the solution was extracted continuously with petroleum ether 100-140. After cooling to room temperature, the petroleum ether solution was evaporated and the residue was purified by distillation. Boiling point 121°-124° C. (0.1 mm Hg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[OH:18])=[CH:3][N:2]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].COC1C=C(OC)C=CC=1C[N:34]([C:47]1[S:48][CH:49]=[N:50][N:51]=1)[S:35]([C:38]1[CH:43]=[C:42]([CH3:44])[C:41](F)=[CH:40][C:39]=1[F:46])(=[O:37])=[O:36].C(Cl)Cl.FC(F)(F)C(O)=O>Cl>[F:46][C:39]1[CH:40]=[C:41]([O:18][C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)[C:42]([CH3:44])=[CH:43][C:38]=1[S:35]([NH:34][C:47]1[S:48][CH:49]=[N:50][N:51]=1)(=[O:36])=[O:37]
Reactant: Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2nncs2)c(F)cc1Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation 888, 30 mg, 0.12 mmol) was taken up in dimethyl sulfoxide (1 mL, 20 mmol) and potassium carbonate (30 mg, 0.22 mmol) added, followed by N-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 889, 51.7 mg, 0.117 mmol). The reaction was heated at 60° C. for 72 hours. The reaction was cooled and diluted with 1N HCl. The resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride (1.0 mL, 16 mmol) and dried over magneisum sulfate. The solution was then treated with trifluoroacetic acid (45 uL, 0.58 mmol) and stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC. Product fractions were combined and the solvent removed in vacuo to give a residue. The product was purified a second time by column chromatography (4 g silica gel column, 0 to 10% methanol in methylene chloride gradient elution). Product fractions were combined and concentrated in vacuo to give 11.2 mg of colorless glass.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:25][C:26](=[O:40])[C:27]4[N:32]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[N:31]=[C:30]([CH3:39])[C:28]=4[N:29]=3)=[C:20]([O:41][CH3:42])[CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:43]C(OC(Cl)C)=O>ClCCl>[ClH:43].[CH:33]1([N:32]2[C:27]3[C:26](=[O:40])[NH:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([S:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)(=[O:17])=[O:16])=[CH:19][C:20]=4[O:41][CH3:42])=[N:29][C:28]=3[C:30]([CH3:39])=[N:31]2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1cc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)NC2CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a 2 ml dichloromethane solution of 30 mg (0.05 mmol) of the compound obtained in Example 219, 11 μl (0.101 mmol) of 1-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was distilled under reduced pressure, 2 ml of methanol was added to the residue, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 12 mg (45%) of the captioned compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[N:6]=1)[CH2:2][CH3:3].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)C1C=CC=CC=1.C(O)(=O)C>O>[CH:17](=[N:10][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[NH:9][N:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCNc1nc(N)n[nH]1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Solvent: O
Product: CCCNc1nc(N=Cc2ccccc2)n[nH]1

Procedure:
A 5-liter flask equipped with a reflux condenser, thermometer, and mechanical stirrer was charged with 251.8 g (1.75 mole) of N5-Propyl-1H-[1,2,4]triazole-3,5-diamine, 1.75 liter of toluene, 203.4 g (1.92 mole) of benzaldehyde and 5.2 g (0.087 mole) of acetic acid and then heated to reflux for 1˜3 hours. During the reaction, water was formed as by-product and removed azeotropically. After checking the end of the reaction by LC (peak area of N5-Propyl-1H-[1,2,4]triazole-3,5-diamine is less than 1%), the mixture was cooled down and gave the crude N3-Benzylidene-N5-propyl-1H-[1,2,4]triazole-3,5-diamine suspension solution, which was used for the next stage without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[CH:8]=[C:9]4[C:23]([CH3:25])([CH3:24])[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:10]4=[CH:11][C:12]=3[C:13](=O)[C:14]=2[CH:15]=1.I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[CH:13][C:12]1[CH:11]=[C:10]3[C:17]4[C:22]([C:23]([CH3:25])([CH3:24])[C:9]3=[CH:8][C:7]=1[CH:6]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(=O)c1ccc(Br)cc1C3=O
Agent: I
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3cc4cc(Br)ccc4cc3cc21
Reaction time: 48 h
Yield: 59.5 %

Procedure:
8-bromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (20 g, 0.05 mol) was dissolved in acetic acid (200 ml) and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water 500 ml. The produced solid was filtered and dissolved in toluene 200 ml and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 8-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (11.1 g, yield 60%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.C(OP(C#N)(=O)OCC)C>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][C:21](=[O:22])[CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.2 ml of triethylamine are added dropwise at 0° to a solution of 3.36 g (16 mmol) of (L)-valine-tert-butyl ester.HCl, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml of DMF. The reaction mixture is stirred for 48 h at RT, and then diluted with methylene chloride and washed with 10% citric acid as well as saturated sodium hydrogen carbonate solution. The organic phase is filtered through cotton wadding and, after removal of the solvent by evaporation, yields N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester, which is directly further used in a).
Reaction SMILES: [CH3:1]N(C)[CH:3]=[O:4].[C:6]([NH:10][C:11]([CH3:18])([CH3:17])[CH2:12][S:13]([O-:16])(=[O:15])=[O:14])(=[O:9])[CH:7]=[CH2:8].[Na+].[CH3:20]OC1C=CC(O)=CC=1>C1C=CC=CC=1>[S:13]([O:4][CH3:3])([O:16][CH3:20])(=[O:14])=[O:15].[C:6]([NH:10][C:11]([CH3:18])([CH3:17])[CH2:12][S:13]([O:16][CH3:1])(=[O:14])=[O:15])(=[O:9])[CH:7]=[CH2:8]
Reactant: CN(C)C=O
Reactant: COc1ccc(O)cc1
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)OC
Product: COS(=O)(=O)OC
Reaction time: 3 h

Procedure:
An addition product of dimethyl sulfate and dimethylformamide is prepared according to the method of Example 3. To 0.5 mole of this product is added a mixture of 59 grams (0.25 mole) of sodium 2-acrylamido-2-methylpropanesulfonate, 0.1 gram of p-methoxyphenol and 500 ml. of benzene. The mixture is heated under reflux, with stirring, for 3 hours, after which the benzene is evaporated under vacuum. The remaining solid is recrystallized from a benzene-cyclohexane mixture to yield the desired methyl 2-acrylamido-2-methylpropanesulfonate.