Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCc1ccccn1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)CCc3ccccn3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-(2-pyridin-2-yl-ethyl)-amine to give 66 mg of {6,8-dimethoxy-4-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H32N4O5+H 481.6; found 481.0.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][S:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[Cl:31]C1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[ClH:31].[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][S:10](=[O:39])[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[CH:4]=[C:3]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.8 g of 2-(dimethylamino)ethyl 5,6-dihydro-8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate in 90 ml of methylene chloride were treated with 9 ml of 3N ethanolic hydrochloric acid, whereupon the mixture was cooled to -10°. The mixture was treated dropwise with 1.72 g of about 90 percent m-chloroperbenzoic acid in 45 ml of methylene chloride. After warming to room temperature, the mixture was washed with 100 ml of 5 percent sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel and then dissolved in 34 ml of methylene chloride. After the addition of 3N ethanolic hydrochloric acid until an acidic reaction was obtained, the mixture was stirred at room temperature for an additional 15 minutes. After removal of the solvent in vacuo and recrystallization from methanol, there was obtained 2-(dimethylamino)ethyl 5,6-dihydro-8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate 4-oxide hydrochloride as yellow crystals of m.p. 148°-152° (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:8](=[O:10])[C:6]2[CH:5]=[C:4]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1cc(Oc2cncnc2)cc(C(=O)O)n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Oc2cncnc2)cc(C(=O)Nc2ccc(F)cn2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
6-methyl-4-(pyrimidin-5-yloxy)picolinic acid (610 mg, 2.64 mmol, 1 eq) and 5-fluoro-2-aminopyridine (296 mg, 2.64 mmol, 1 eq) were dissolved in pyridine (40 mL) in a flame-dried round-bottom flask. The reaction was cooled to −15° C. and phosphorus oxychloride (270 μL, 2.90 mmol, 1.1 eq) was added dropwise while keeping the temperature below −15° C. After stirring for 30 minutes at −15° C. and the reaction was quenched with ice-water and neutralized with 10% K2CO3. The mixture was extracted with EtOAc (3×) and the combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 310 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J=3.0 Hz, 1H), 8.27 (dd, J=9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J=8.6, 3.1 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 2.58 (s, 3H); ES-MS [M+1]+: 326.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1ccnc2cc(-c3ccc(O)cc3)ccc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Yield: 55.9 %

Procedure:
A solution of 90 mg (0.32 mmol) of methyl 7-(4-hydroxyphenyl)-4-quinolinecarboxylate, 196 mg (0.64 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 178 mg (1.29 mmol) of K2CO3 in 2.5 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 98 mg (56%) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-quinolinecarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J=4 Hz, 1H), 8.81 (d, J=9 Hz, 1H), 8.29 (s, 1H), 7.88-7.85 (m, 2H), 7.64 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.32 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.79 (s, 2H), 4.05 (s, 3H), 3.34 (septet, J=7 Hz, 1H), 1.43 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:26])[N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH:16](OC)=[O:17].[Na].Cl>C(OCC)C>[OH:17][CH:16]=[C:9]([C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:8]=[CH:7][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=O
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)C(=CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(aa) 26.2 g of methyl 3-trifluoromethylphenylacetate were dissolved in 100 ml of diethyl ether and, after the addition of 8.2 ml of methyl formate, treated with 2.76 g of sodium. The mixture was stirred at room temperature until the reaction was completed and treated with 1N hydrochloric acid while cooling. The organic phase was separated and the aqueous phase was extracted twice with ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Distillation yielded methyl 3-hydroxy-2-(α,α,α-trifluoro-m-tolyl)acrylate as a colorless oil of b.p. 59°-62°/0.2 mm.
Reaction SMILES: [SH:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CC(C)=O>[OH:10][C:7]1[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]2[O:4][C:13]([CH3:18])([CH3:14])[S:1][C:2]=2[C:8]=1[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(C)c(O)c(S)c(C)c1O
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)SC(C)(C)O2
Yield: 7.7 %

Procedure:
A mixture of 4.8 g of 2-mercapto-3,5,6-trimethylhydroquinone, 1 g of p-toluenesulfonic acid, 10 g of molecular sieve 4A and 100 ml of acetone was heated under reflux for 5 hours under a stream of nitrogen. At the end of this time, the acetone was distilled off, and an aqueous solution of sodium bicarbonate was added to the residue. This mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled from the extract. Benzene was added to the resulting residue. Substances which were not soluble in benzene were filtered off, and crystals precipitating from the benzene solution were removed. The portion which was readily soluble in benzene was separated by silica gel column chromatography. The portion eluted with benzene was recrystallized from petroleum ether to yield 0.1 g of the title compound, melting at 62°-64.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.[CH2:15](I)[CH3:16]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: CCI
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Product: CCN(C(C)=O)c1ccc(CCCl)cc1C
Yield: 88 %

Procedure:
N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-N-ethyl-acetamide was prepared according to the general method as outlined in Preparation 43 starting from N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.40 g, 1.89 mmol) and ethyliodide (0.189 mL, 2.36 mmol). After chromatographic purification, the product was isolated as a viscous oil (0.399 g, 1.66 mmol).
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>O>[C:15]([NH:3][C@H:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17].[Na+:2].[Na+:2]
Reactant: C=C1CC(=O)O1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
8.1 parts of sodium hydroxide were dissolved in 100 parts by volume of water and the solution cooled to 0°-5° C. 13.3 parts of L-aspartic acid were added and stirred until all dissolved, then 15.8 parts by volume of diketene were added dropwise over 90 minutes, stirred at 0°-10° C. for an additional 2.5 hours, and filtered. The homogeneous solution was evaporated to dryness under vacuum at 35°-40° C. Disodium N-acetoacetylaspartate was obtained as a white foam.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[O:37][CH3:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[O:37][CH3:38])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
Analogously to Example 4A, 5.00 g (13.8 mmol) of the compound from Example 3A are reacted with 2.59 g (15.1 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene. The product is purified by chromatography on silica gel (mobile phase pentane/ethyl acetate=5:1), giving 2.70 g (38% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH3:31])[S:12](=[O:30])(=[O:29])[C:13]2[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=2[C:15]=1S(C1C=CC=CC=1)(=O)=O)=[O:9].Cl.[OH2:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH3:31])[S:12](=[O:30])(=[O:29])[C:13]2[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=2[C:15]=1[OH:33])=[O:9]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(S(=O)(=O)c2ccccc2)c2ccccc2S1(=O)=O
Reactant: O
Agent: Cl
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Yield: 91.1 %

Procedure:
2.36 g (0.005 mole) N-(2-pyridyl)-4-(benzenesulfonyl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was dissolved in 50 ml water containing 1.0 g sodium hydroxide. After it was completely hydrolysed, the solution was neutralized with conc-hydrochloric acid to form precipitates. The obtained precipitates were filtered and recrystalized with methanol and N,N-dimethyl formamide and n-hexane to obtain 1.51 g of the title compound. Yield: 91%. m.p. 198°-201° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[NH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.8 %

Procedure:
To a solution of 4-(4-(benzyloxy)-3-nitrophenyl)pyridine 13.0 (1.52 g, 4.97 mmol) in ethyl acetate (20 mL) was added tin(II) chloride dihydrate (4.49 g, 19.87 mmol). The mixture was heated to reflux for 2 hours, then quenched with 100 ml 1N NaOH. The resulting mixture was stirred overnight at room temperature, then partitioned between AcOEt and water. The organic phase was dried on MgSO4 and concentrated to afford 2-(benzyloxy)-5-bromobenzenamine 13.D (1.59 g, 115% yield) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[CH2:4][C:5](OC)=[O:6].C(=O)(O)O.[NH2:16][C:17]([NH2:19])=[NH:18]>C(O)C>[NH2:19][C:17]1[N:18]=[C:5]([OH:6])[CH:4]=[C:3]([C:2]([CH3:11])([CH3:10])[CH3:1])[N:16]=1
Reactant: N=C(N)N
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: O=C(O)O
Solvent: CCO
Product: CC(C)(C)c1cc(O)nc(N)n1
Yield: 75.4 %

Procedure:
Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][O:19][CH2:20][CH2:21][OH:22].[OH-].[Na+]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 36.5 g of ethylene glycol monomethyl ether, and 13.2 g of 50 percent strength aqueous sodium hydroxide solution are added dropwise at 60° C. in the course of 30 minutes. The mixture is then subsequently stirred at 70° C. for two hours, a further 12 g of ethylene glycol monomethyl ether and 4.5 g of sodium hydroxide solution are added, the mixture is subsequently stirred at 70° C. for a further two hours and 100 ml of water are then added. The oil which has separated out is separated off, washed twice with 30 ml of water each time and dried. This gives 17.6 g (57% of the theoretical value) of yellowish oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[NH:10][C:11](=[O:14])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]([N:23]([CH:32]([CH3:34])[CH3:33])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:22]>>[CH:32]([N:23]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:21](=[O:22])[CH2:20][N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH2:12][C:11]1=[O:14])([CH3:33])[CH3:34]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Product: COc1ccc(N(C(=O)CN2C(=O)CN=C(c3ccccc3)c3ccccc32)C(C)C)cc1

Procedure:
By employing conditions similar to those described in Intermediate 11, 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Bock et. al., J. Org. Chem. 1987, 52, 3232-3239. 3.00 g, 12.71 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (3.820 g, 13.35 mmol) are converted to the title compound, which is obtained as a wet white solid. The product is dissolved in anhydrous DCM, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue is triturated with n-hexane, filtered and dried overnight under vacuum to provide the title compound as a white solid (5.380 g, 12.18 mmol). 1H NMR (300 MHz, d6-DMSO) δ=0.91-0.97 (m, 6H); 3.70 (d, J=10.4 Hz, 1H); 3.76 (s, 3H); 4.08 (s, 2H); 4.51 (d, J=10.6 Hz, 1H); 4.67-6.78 (m, 1H); 6.97-7.63 (m, 13H). MS (FAB): [M+H]+ =442.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH3:20][NH:21][CH2:22][CH2:23][NH:24][CH3:25]>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][CH3:25])[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: CNCCNC
Solvent: CC#N
Product: CNCCN(C)c1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 25 °C

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (18 mmol; see Example 1(a) above) was suspended in 50 mL of CH3CN along with 5 eq. of N,N′-dimethyl-ethane-1,2-diamine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-furan-2-yl-N5-methyl-N5-(2-methylamino-ethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine.
Reaction SMILES: [NH2:1][C:2]1[N:6](S(C(C)C)(=O)=O)[C:5]2[CH:13]=[CH:14][C:15]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:4]=2[N:3]=1.O.[OH-].[Na+]>CC(C)=O>[CH:21]1[CH:20]=[CH:19][C:18]([C:17]([C:15]2[CH:14]=[CH:13][C:5]3[N:6]=[C:2]([NH2:1])[NH:3][C:4]=3[CH:16]=2)=[O:24])=[CH:23][CH:22]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2cc(C(=O)c3ccccc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C

Procedure:
A slurry of 50 g of 2-amino-1-isopropylsulfonyl-5-benzoylbenzimidazole was heated in 300 ml of acetone and 500 ml of water with 350 ml of 1N sodium hydroxide on a steam bath for two hours. The heating was continued to remove the acetone. Afterwards the solution was cooled to room temperature with stirring. When the cleavage was complete, the precipitate title compound was filtered and washed with water. m/e=237, 160, 105, 77.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[C:18](=O)[CH2:17]1)=[O:15])[CH3:12]>C1COCC1.CCOC(C)=O>[CH2:11]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[C:18](=[CH2:1])[CH2:17]1)=[O:15])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)N1CCc2ccsc2C(=O)C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OCC)CCc2ccsc21
Reaction time: 0.5 h

Procedure:
MePPh3 Br (785 mg, 2.2 mmol) was dissolved in 7 mL THF and treated with KHMDS (408 mg, 2.04 mmol). After stirring for 30 minutes, the product of step d) (350 mg, 1.5 mmol) was added as a solution in 3 mL THF. After stirring for 1 hour, the reaction was diluted with EtOAc and washed with water. The organic layer was concentrated and the product was purified by silica gel chromatography (EtOAc/Hex-gradient) to give 188 mg of the subtitle compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:22][C:13]([F:12])([F:23])[S:14][C:15]1[CH:16]=[CH:17][C:18]([N:19]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:20][CH:21]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(SC(F)(F)F)cc1
Yield: 70.3 %

Procedure:
In a manner similar to above, 1.6 g (0.01 mole) of 3,4,5,6-tetrahydrophthalic anhydride and 2.0 g (0.01 mole) of p-trifluoromethylthioaniline were treated to obtain 2.3 g of N-(p-trifluoromethylthiophenyl)-3,4,5,6-tetrahydrophthalimide (melting point, 112°-114° C.; 70% yield).
Reaction SMILES: O1CCOCC1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[O:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N+:25]([C:21]1[C:20]([O:28][CH3:29])=[C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C=O)cc2)cccc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To a solution of 60 mL of 1,4-dioxane and 10 mL of water was added 4-formylphenylboronic acid (3.0 g, 0.02 mol), followed by 1-bromo-2-methoxy-3-nitro-benzene 1c (4.64 g, 0.02 mol), tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and sodium carbonate (4.24 g, 0.04 mol). Upon completion of the addition, the mixture was heated to reflux for 5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 3′-nitro-2′-methoxy-biphenyl-4-carbaldehyde 32a (4.1 g, 80.4%) as a yellow solid.