Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(C)=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)C(C)=O.[ClH:23]>CO>[ClH:23].[ClH:23].[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]=[N:11][C:8]2[CH:9]=[CH:10][C:5]([NH2:1])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(N=Nc2ccc(NC(C)=O)cc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Reaction time: 1.5 h

Procedure:
A suspension of 35 parts of 4,4'-diacetamino-azobenzene in 315 parts by volume of methanol and 315 parts by volume of 2 N hydrochloric acid is heated to 74°, stirred for 90 minutes at this temperature and cooled to 18°, and the product is filtered off. The 4,4'-diaminoazobenzene dihydrochloride thus obtained is pressed out well and is suspended, without being washed, in 1,000 parts of water. The new suspension is stirred for 15 minutes at room temperature, about 300 parts by volume of 2.5 N sodium hydroxide solution are added dropwise (pH = 7) and the mixture is filtered. The residue is washed free from salt and is dried in vacuo at 60°. 24.6 parts (98.5% of theory) of an ochre-yellow powder are obtained. Melting point: 236°-238°, with decomposition.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[SH:10].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Cl>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][S:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:4]
Reactant: Cc1cc(S)c(C)o1
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SCc2ccccn2)c(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 ml 3 neck round bottom flask equipped with magnetic stirrer, pot thermometer, Y tube, nitrogen inlet tube, reflux condenser and heating mantle, is placed a solution of 0.54 g (0.01 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The reaction mass is maintained at 25°-30° C and a solution of 0.64 g (0.005 moles) of 2,5-dimethyl-3-furan thiol in 3 ml absolute methanol is added to the reaction mass. While maintaining the reaction at 25° C, picolyl chloride hydrochloride (0.82 g; 0.005 moles) dissolved in 2 ml absolute methanol is added to the reaction mass. The reaction being exothermic, the reaction mass warms up to 42° C and a white solid precipitate forms. The reaction mass is allowed to cool to 25° C with stirring over a period of 30 minutes. The reaction mass is then heated to reflux (60° - 65° C) under nitrogen and reflux is continued for a period of 1 hour. The reaction mass is cooled to 30° C and flushed with nitrogen. After remaining at room temperature for a period of 20 hours, 10 ml. of water is added to the reaction mass with stirring, causing the reaction mass to now exist in two phases; an aqueous phase and an organic phase. The pH of the reaction mixture is 5. 7 ml of n-hexane is then added to the reaction mass with stirring and transferred into a separatory funnel. The aqueous layer is separated from the organic phase and extracted with 8 ml n-hexane after first diluting the aqueous phase with another 10 ml of water. The hexane extracts are combined, washed with 7 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, gravity filtered, and concentrated on a rotary evaporator using water-aspirator vacuum.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[C:15]([O:14][C:12]([N:11]1[CH:10]([CH3:19])[C:9](=[O:8])[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]1[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=C(/C=C/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1C(=O)C(C(=O)OCc2ccccc2)C(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.59 g (20.0 mmol) of (R)—N-tert-butoxycarbonylalanine benzyl ester and 5.92 g (20.0 mmol) of dibenzyl fumarate in 60 mL of toluene was added 1.60 g (40 mmol) of 60% NaH in mineral oil. The reaction was stirred at ambient temperature under N2 for 24 h, then diluted with 300 mL of diethyl ether. The solution was extracted with 1M HCl(aq.)(1×50 mL), saturated NaHCO3(aq) (3×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated to provide the titled compound as an oil.
Reaction SMILES: NCCC[Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(O)(=O)C>O>[CH2:7]([O:6][SiH:5]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:8]
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCO[SiH](OCC)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Aminopropyltriethoxysilane (1 ml) and 1.8 ml of 0.1% acetic acid were made up to 10 ml with water and added to 0.4 g sedimented yeast cells, which had been produced as described in Example 1. The mixture was stirred at room temperature for 24 hours and the cells were then separated and washed thoroughly with water. A 1% suspension of the treated cells in PBS, containing 5% glutaraldehyde was added to 2.5 mg of horseradish peroxidase in 2.5 ml PBS and kept at 21° C. for one hour. The cells were then separated and washed with PBS by centrifugation.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:10]=1)[CH2:2][C:3]#[CH:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25](I)=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:4]#[C:3][CH2:2][CH2:1][C:5]3[CH:6]=[CH:7][C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:10]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Reactant: C#CCCc1ccc(NC(C)C)nc1
Product: CC(C)Nc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1

Procedure:
The product was prepared analogously to Example 50.5d from 100 mg (0.53 mmol) of (5-but-3-ynylpyridin-2-yl)isopropylamine and 168 mg (0.53 mmol) of 5-(4-chlorophenyl)-2-iodopyridine (purification by preparative HPLC-MS). Yield: 520 mg (54% of theoretical); C23H22ClN3 (M=375.894); calc.: molpeak (M+H)+:376/378; found: molpeak (M+H)+:376/378; HPLC-MS: 5.33 minutes (method G).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4]#[C:5][CH3:6].[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH2:11]>C(O)C>[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH:11][C:5]([CH3:6])=[CH:4][C:3]([O:2][CH3:1])=[O:7]
Reactant: NCC(O)CO
Reactant: CC#CC(=O)OC
Solvent: CCO
Product: COC(=O)C=C(C)NCC(O)CO

Procedure:
To 5.0 g (0.051 m) methyl-2-butynoate in 25 ml absolute ethanol is added 5.0 g (0.055 m) 2,3-dihydroxypropylamine. This solution is heated at 75°-80° for 18 hours and the solvent is then removed at reduced pressure. The residue oil is chromatographed on silica gel, eluting with 10% methanol/chloroform to afford the desired product as a white solid. m.p. 109°-111°. The yield is 5.6 g (59%). ##STR4##
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(#N)C>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Solvent: CC#N
Product: Cc1ccn2c(C)c(-c3ccc4sc(=O)n(C)c4c3)nc2c1
Yield: 63.4 %

Procedure:
A solution of 5-(2-bromopropionyl)-3-methyl-2-benzothiazolinone (3.0 g) and 2-amino-4-methylpyridine (3.24 g) in acetonitrile (100 ml) was refluxed for 8 hours. The reaction mixture was concentrated to about a half volume and poured into a mixture of water and ethyl acetate. The resulitng mixture was acidified to PHO.5 with 10% hydrochloric acid. The precipitate was collected by filtration and washed successively with water and ethyl acetate. The resulting precipitate was added to a mixture of ethyl acetate, tetrahydrofuran and water, and the mixture was adjust to pH 7.0 with 20% aqueous potassium carbonate solution. The separated organic alyer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford a crystalline residue. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 5-(3,7-dimethylimidazo-[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (1.96 g).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>CO.C[O-].[Na+]>[C@@H:11]1([N:34]2[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(=O)n([C@@H]2O[C@@H](CO)[C@H](O)[C@H]2O)cc1F
Yield: 92.1 %

Procedure:
To a solution of compound 3 (11.7 g, 20.37 mmol) in MeOH (300 ml), NaOMe (4.2 ml of a methanolic 25% w/v solution) was added and the solution was stirred until the reaction was complete. The solvent was then evaporated and the residue was dissolved in H2O (200 ml), washed with ether and neutralized with Dowex 50 ion exchange resin. After filtration of the resin, the aqueous solution was evaporated to give compound 4(4.92 g, 92% yield) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([C:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(-c2ncnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ncnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)cc1F
Yield: 72.9 %

Procedure:
0.82 g ethyl 2-fluoro-4-[6-(1-trityl-1H-pyrazol-4-yl)-quinazolin-4-yl]benzoate (compound in Example 752) was dissolved in 30 mL solvent mixture of ethanol and water (2:1), then 0.11 g lithium hydroxide was added thereto, and the mixture was heated for 5 hours under reflux. The reaction solution was neutralized under ice-cooling. The solution was extracted with dichloromethane and recrystallized from ethanol/ether, to give 570 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[C:4]([N+:15]([O-])=O)[C:5]([I:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[NH4+].[Cl-]>CO.[Fe]>[Br:1][C:2]1[C:3]([F:18])=[C:4]([C:5]([I:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)[NH2:15]
Reactant: O=[N+]([O-])c1c(F)c(Br)cc(-c2ccccn2)c1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1c(F)c(Br)cc(-c2ccccn2)c1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 2-(5-bromo-4-fluoro-2-iodo-3-nitrophenyl)pyridine (1.0 g, 2.36 mmol) in MeOH (25 mL) was added Fe powder (0.66 mL, 11.82 mmol) at 0° C. The mixture was stirred at rt for 10 min followed by addition of aqueous solution of NH4Cl (0.63 g, 11.82 mmol). The mixture was then heated up to 80° C. for 2 h. After completion of reaction (by TLC), the mixture was poured onto 100 mL of ice cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and solvent evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 6% EtOAc:hexane to obtain the desired product as a white solid (0.90 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:16]>CO>[NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: N
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Solvent: CO
Product: NC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4.0 g (18.7 mmol) of methyl 2-amino-5-fluoro-4-nitro-benzoate were dissolved in 250 ml of methanol and saturated with ammonia at -40° C. Subsequently, the mixture was stirred at room temperature overnight. The solution was concentrated and ther residue was triturated with methylene chloride. The precipitate was filtered off under suction and dried. 3.17 g (85%) of 2-amino-5-fluoro-4-nitro-benzamide were obtained as yellow crystals;
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:16]=[C:17]([CH3:18])[C:5]=12)=[N+]=[N-]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:16]=[C:17]([CH3:18])[C:5]=12
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of ethyl 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.0 g, 3.2 mmol) and sodium azide (0.23 g, 3.5 mmol) in N,N-dimethylformamide (5 mL) was heated and stirred at 100° C. for 30 minutes. The solution was cooled to room temperature, and poured into water, and the resulting solution was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. To a solution of the ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in ethanol (150 mL) was added 10% palladium-carbon (1.2 g, 50% hydrate), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (basic silica gel, ethyl acetate:methanol=93:7) gave the title compound (900 mg, 96% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
1-(4-Piperidyl)indol-2-one (53 mg, 0.245 mmole), 2,4-dimethoxybenzoyl chloride (54 mg, 0.27 mmole), and 38 mL (0.27 mmole) triethylamine were mixed in 4 ml of chloroform at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and then at 23° C. for 15 minutes during which time the pH was adjusted to 7.5 with triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative thick layer chromatography (CHCl3 --CH3OH--NH4OH; 95:5:0.5) to yield 42 mg of the title compound: m.p. 88°-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:13][CH:7]1[CH2:8][C:9](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10]2)=[O:5])[CH3:2]>[Pt]>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:13][CH:7]1[CH2:8][CH:9]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CC(=Cc3ccccc3)CC1C(OC1CCCCO1)C2
Agent: [Pt]
Product: CCOC(=O)N1C2CC(Cc3ccccc3)CC1C(OC1CCCCO1)C2

Procedure:
Hydrogenation of the 3-benzylidene-6-(tetrahydro-pyran-2-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester similarly to the procedure described in Step 4 of Example 1 over 5% platinum on carbon gave 0.3 g of a resin.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:11]1[CH:10]=[CH:9][C:8]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[S:1](=[O:3])(=[O:2])[O:6][C:7]=2[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2c3ccc(C)cc3OS2(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol) in CH2Cl2 (10 ml) is slowly added dropwise to a solution of N-(2-hydroxy-4-methylphenyl)-4-methylbenzenesulfonamide (1.5 g, 5.41 mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C. for one hour. After thawing to RT, the solvent is distilled off under reduced pressure and the residue is purified by RP chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NC1CCCCC1
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(NC1CCCCC1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 91 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and cyclohexylamine (100 mg, 1.0 mmol) to give 340 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.14 (s, 1H), 8.03 (d, 1H, J=7.9 Hz), 7.16 (bs, 1H), 7.14 (bs, 1H), 5.08~5.13 (m, 1H), 3.42~3.59 (m, 1H), 2.79 (dm, 1H, J=16.8 Hz), 2.45~2.63 (m, 1H), 2.36 (dm, 1H, J=13.5 Hz), 1.85~2.02 (m, 1H), 1.63~1.74 (m, 4H), 1.05~1.33 (m, 6H).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:22][O:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1>C(O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:22][O:23][NH2:24])[N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Hydrazine hydrate (9 mL) was added to a suspension of 2-{[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}isoindole-1,3-dione (3.9 g) in ethanol (90 mL). The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was filtered to remove a precipitate and the filter cake was washed with ethanol and dichloromethane. The filtrate was concentrated under reduced pressure, diluted with aqueous 1N hydrochloric acid (100 mL), and then washed sequentially with dichloromethane (2×50 mL) and ethyl acetate (1×50 mL). Analysis of the organic washes by LCMS indicated that they did not contain product. The aqueous acidic layer was made basic (˜pH 9) with solid sodium carbonate and then extracted sequentially with dichloromethane (1×100 mL), ethyl acetate (1×100 mL), and dichloromethane (1×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 2.07 g of O-{[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}hydroxylamine as a tan foam.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:9]=1[CH2:10]Br.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:10][C:9]1[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:8]=1[F:7])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCOCc1cc(Br)ccc1F
Temperature: -40 °C

Procedure:
In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The solution was cooled to −40° C. and potassium tert-butoxide (1M in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at −40° C. for thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0° C. and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography.
Reaction SMILES: C([S:14][C:15]1[N:16]=[N:17][N:18]([CH2:20][C:21]#[CH:22])[N:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:20]([N:18]1[N:17]=[N:16][C:15]([SH:14])=[N:19]1)[C:21]#[CH:22]
Reactant: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C#CCn1nnc(S)n1
Temperature: 50 °C
Reaction time: 1.7 h
Yield: 62.5 %

Procedure:
A mixture of 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (1.05 g), anisole (1.79 g) and trifluoroacetic acid (9.7 ml) was stirred at 22° C. for 1.5 hours, at 35° C. for an hour, at 50° C. for 1.7 hours and then at room temperature for a further 14 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (10 ml) and the mixture was adjusted to pH 8.5 with 2N aqueous solution of sodium hydroxide. The aqueous layer was separated, washed with ethyl acetate (20 ml×2) and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to give an oil of 2-(2-propynyl)-2H-tetrazole-5-thiol (0.3 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:13])[F:12])[N+:5]=1[O-:15].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[N+:18]([C:8]1[CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:12])[F:13])[N+:5]([O-:15])=[C:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[CH:9]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(CC(F)(F)F)cccc1CC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Temperature: 0 °C

Procedure:
2,6-Bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.65 g, 10.22 mmol) was dissolved in H2SO4 (4 mL) and cooled to 0° C. HNO3 (3.2 mL) was added slowly and after the addition was complete the reaction mixture was heated to 90° C. for 2 hours. The mixture was poured into ice, made basic with 15% NaOH and extracted with CH2Cl2. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil (2.72 g, 81%). 1H NMR (400 MHz, CDCl3): δ 3.95 (t, J=10.1 Hz, 4H), 8.31 (s, 2H).