Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C@@H:9]1[CH2:13][C@H:12]([S:14]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][N:10]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:35].SCCO>FC(F)(F)C(O)=O.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C@@H:9]1[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1)=[O:35]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Agent: OCCS
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To a solution of (2S,4S)-2-[(2S)-2-(hydroxymethyl)-pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.74 g) in trifluoroacetic acid (30 ml) was added 2-mercaptoethanol (0.95 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in toluene (30 ml) and the solution was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed in turn with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.77 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C(OCC)(=O)C>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCCCN
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCCCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-diaminobutane (8.8 g) in ethanol (100 ml) at room temperature was added a solution of 4-chloro-3-nitropyridine in ethanol (50 ml). The mixture was stirred at room temperature for 30 minutes, poured into ethyl acetate (400 ml), and then washed with water (3×150 ml). The aqueous phases were back-extracted with methylene chloride (3×120 ml) and all the organic phases were combined, dried over Na2SO4, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol containing 1% ammonium hydroxide. The fractions containing the product were combined and evaporated under vacuum to give the title compound, (4.2 g), which was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])=[O:4].OCC([C@H]([C@@H](CO)O)O)=O.O=C[C@@H]([C@H]([C@@H](CO)O)O)O>>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The xylulose fraction was used in isomerisation to produce xylose and the ribulose fraction was sent back to epimerisation (for xylulose production). The xylose fraction was used in hydrogenation to produce xylitol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C@@H:13]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:14]([N:16]1[CH2:20][C@@H:19]([NH2:21])[CH2:18][C@H:17]1[C:22](=[O:31])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:40](OC(N(C)[C@@H](C)C(N[C@@H](C1CCCCC1)C(N1C[C@@H](NC(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)C[C@H]1C(O)=O)=O)=O)=O)(C)([CH3:42])[CH3:41].[C@@H]1(N)C2C(=CC=CC=2)CCC1>>[C:1]([O:5][C:6](=[O:39])[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C@@H:13]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:14]([N:16]1[CH2:20][C@@H:19]([NH2:21])[CH2:18][C@H:17]1[C:22](=[O:31])[NH:23][C@@H:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:42][CH2:40][CH2:41]1)=[O:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: N[C@H]1CCCc2ccccc21
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C

Procedure:
In a similar manner to that described for {(S)-1-[(S)-2-((2S,4S)-4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 28), (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid (Intermediate 27) (150 mg, 0.22 mmol) and (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Aldrich) (33 mg, 0.22 mmol) were converted to the title compound (48 mg, foam).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13]([OH:15])=[O:14]>C1(C)C=CC=CC=1.CO>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:11]=[C:10]([C:9]([F:23])([F:24])[F:8])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil. A solution of 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodium hydride (60% suspension in mineral oil—0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 hrs, then it was partitioned between saturated ammonium chloride solution and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (1.6 g) as a beige oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[O-]Cl.[Na+].[N:12]1([CH2:18][CH2:19][CH:20]=[N:21][OH:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[N:12]1([CH2:18][CH2:19][C:20]2[CH2:2][CH:1]([N:3]3[CH2:7][CH2:6][CH2:5][C:4]3=[O:8])[O:22][N:21]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: ON=CCCN1CCCCC1
Reactant: C=CN1CCCC1=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1C1CC(CCN2CCCCC2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 646 μL (1.5 equivalent) of N-vinyl-pyrrolidin-2-one in 5 mL of chloroform, a biphasic solution of 7.4 mL (3.2 equivalents) of 13% Clorax (NaOCl) and a solution of 629.3 mg (4.03 mmol) of 3-piperidin-1-yl-propionaldehyde oxime compound prepared in Example 2 in 5 mL of chloroform were added slowly over 15 minutes with cooling to 0° C. and stirring vigorously. After reacting at room temperature overnight, the reaction mixture was extracted with chloroform three times, washed with a saturated aqueous solution of sodium carbonate twice following water once, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by separation with silica gel column chromatography using chloroform/methanol (30:1) as eluent to obtain 477.4 mg (45% yield) of 1-[3-(2-piperidin-1-yl-ethyl)-4,5-dihydro-isoxazol-5-yl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: COc1ccc(CCN)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Methoxy-phenyl)-ethylamine. MS (ESI): 463.4 (MH+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])#[N:2].N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>CO>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])[C@@H:12]2[OH:13])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:42][CH:41]=1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
2′-O-(2-Cyanoethoxymethyl)uridine (14 g, 43 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 300 mL of THF, and 68 g of pyridine (856 mmol), and 20 g of molecular sieve 4 A was added under an argon atmosphere, and the mixture was stirred for 10 minutes. To the solution was added 19.6 g of 4,4′-dimethoxytritylchloride (57.8 mmol) by 3 portions every 1 hour, and the mixture was further stirred for 1 hour. After 10 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in ethyl acetate, and was washed with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (26.5 g, yield 98%).
Reaction SMILES: [OH-].[K+].Cl.Cl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][CH2:21][CH:22]2[O:27][C:26]3[C:28]([O:32]S(C4C=CC(C)=CC=4)(=O)=O)=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)[CH2:15][CH2:14]1.C(O)(=O)C>O.C(O)C>[OH:32][C:28]1[C:26]2[O:27][CH:22]([CH2:21][NH:20][CH2:19][CH:16]3[CH2:15][CH2:14][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:18][CH2:17]3)[CH2:23][O:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccccc1N1CCC(CNCC2COc3cccc(OS(=O)(=O)c4ccc(C)cc4)c3O2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1N1CCC(CNCC2COc3cccc(O)c3O2)CC1
Reaction time: 16 h
Yield: 212.1 %

Procedure:
A solution of potassium hydroxide (1. 0 g) in water (19.7 ml) and ethanol (19.7 ml) was added in portions (~10 ml) at 15 minute intervals to [2-({[1-(2-methoxyphenyl)piperid-4-yl]methylamino}methyl)-1,4-benzodioxan-8-yl]toluene-4-sulphonate dihydrochloride (0.15 g). The mixture was heated under reflux for 21/2 hours, cooled and neutralised with glacial acetic acid. The product was extracted into ether (3×100 ml) and the combined extracts allowed to stand for 16 hours. The precipitate which had then formed was collected by filtration and dried to give N-(8-hydroxy-1,4-benzodioxan-2-ylmethyl) -1-[1-(2-methoxyphenyl) piperid-4-yl]methylamine as a colourless solid (0.2 g), m.p. 116°-119° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([O:51][CH3:52])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=5)=[C:38]([O:51][CH3:52])[CH:37]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(N)ccc1C(O)c1cc(C)ccn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.7 g), (4-amino-2-methoxyphenyl)(4-methylpyridin-2-yl)methanol (0.5 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N,N-dimethylformamide (15 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g), triethylamine (0.61 ml) and 4-dimethylaminopyridine (catalytic amout) at room temperature under ice-cooling, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) as pale brown amorphous.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)O)[CH2:2][CH3:3].[CH3:12][C:13]([CH3:15])=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:14][C:13]([CH3:15])([CH3:12])[O:11][C:6]=2[CH:7]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCc1cccc2c1OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using a mixture of 7.61 g (50 mM) of 4-n-propylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of benzene. 5 n-Propyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 9.13 g (47 mM) as colorless transparent liquid having a boiling point of 82°-87° C./3 mmHg.
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]=C)[N:10]=[C:9]([O:19][CH2:20]C)[CH:8]=1)(C)(C)C.F[C:24](F)(F)[C:25](O)=O>>[CH2:24]([CH:14]([NH:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([O:19][CH3:20])[N:10]=1)[C:6]([OH:5])=[O:22])[CH2:15][CH:16]=[CH2:17])[CH3:25]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCCCNc1cc(C(=O)OC(C)(C)C)cc(OCC)n1
Product: C=CCC(CC)Nc1cc(C(=O)O)cc(OC)n1

Procedure:
The title compound is prepared by stirring 2-ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl ester 18 h in neat trifluoroacetic acid. Evaporation of the TFA gives the title compound that is used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C([O-])([O-])=O.[K+].[K+].[N+](C1C=C(S(O[CH2:31][CH:32]2[CH2:34][O:33]2)(=O)=O)C=CC=1)([O-])=O>CC#N>[O:33]1[CH2:34][CH:32]1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(O)cc1C#N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)cc1C#N

Procedure:
A stirred suspension of 4-hydroxyphthalonitrile (3.5 g; 24.3 mmol), K2CO3 (4.03 g; 29.2 mmol) and 2-{[(3-nitrophenyl)sulfonyloxy]methyl}-oxirane (6.50 g; 25.0 mmol; see Example B above) in MeCN (170 mL) was refluxed for 1.5 h. The cooled reaction mixture was filtered, the filtrate concentrated and the solid residue recrystallized from IPA to give the sub-title compound.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[CH3:32][Mg]Br.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([CH3:32])([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O

Procedure:
A solution of 1.72 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 9.7 ml. of 3 M methyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.26 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.45, 5.80 (shoulder), 5.85, 6.45, 7.25, 10.30 μ. NMR: δ 1.32 (S, 15-methyl), 4.01 (S, 4, ketal), 4.40 (M, 2, CH2NO2), 5.22 (M, 2, 5 and 6--H), 5.63 (M, 2, 13 and 14--H) ppm. Mass spectrum: M+ at m/e 453), (theory 453), M+--H2O at m/e 435.2571 (theory 435.2620).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:5]1[S:4][C:3]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:2]([Cl:1])[CH:6]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3Cl)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine. (1.15 g, 3.44 mmol) and CH2Cl2 (12 mL) is added NBS (0.64 g, 3.62 mmol). The solution is stirred at ambient temperature overnight, washed with water (2×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to furnish the title compound (1.36 g, 3.29 mmol, 96%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.49 (s, 3H), 2.53 (s, 3H), 3.26-3.36 (m, 1H), 6.70 (s, 1H), 7.07 (s, 1H). LC/MS (m/z): calcd. for C17H19BrClN3S (M+H)+: 412.1; found: 412.0.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[NH2:32][C:33]([CH3:54])([CH3:53])[C:34]([N:36]1[CH2:48][C:47]2NC3C=CC=C4C(=O)[NH:50][N:51]=[C:38]([C:39]=2C=34)[CH2:37]1)=[O:35]>>[NH2:32][C:33]([CH3:54])([CH3:53])[C:34]([N:36]1[CH2:48][C:47]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:50][N:51]=[C:38]([C:39]=2[C:2]=34)[CH2:37]1)=[O:35]
Reactant: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 65 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the same procedures similar to those for Compound 62. 1H NMR (DMSO-d6) δ 12.1 (s, 1H), 10.2 (s, 1H), 7.40 (dd, 1H, J=1.8, 10.2 Hz), 7.20 (dd, 1H, J=1.8, 10.2 Hz), 5.25 (s, 2H), 4.75 (s, 1H), and 1.32 (s, 6H). MS (ESI) m/e [M+1]+330.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]2[C:12]([NH:13][C:14]3[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][CH:17]=[C:18](Cl)[C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.CS(C)=O.O>[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH:33][C:18]1[C:19]2[C:20](=[O:23])[C:21]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:22]=3)[NH:13][C:14]=2[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][CH:17]=1)[CH3:29]
Reactant: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CCN(CC)CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])c2[nH]c3ccc(OCc4ccccc4)cc3c(=O)c12
Temperature: 60 °C
Yield: 93.8 %

Procedure:
A mixture of 7-benzyloxy-1-chloro-4-nitroacridin-9(10H)-one (IV-P) (9.52 g, 25 mmol), 2-diethylaminoethylamine (4.3 ml, 30 mmol) and triethylamine (3.5 ml, 25 mmol) in dimethylformamide or dimethyl sulphoxide (150 ml) was stirred and heated at 60° C. for 1 hour. Next water (500 ml) and a concentrated solution of sodium carbonate (40 ml) were added and the precipitate was filtered, washed with water and dried to give 10.8 g (94%) of crude product. Crystallisation from dimethylformamide (100 ml) gave analytically pure product, yield 10 g (87%).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)C.[OH-].[Li+].Cl>O1CCOCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]([OH:13])=[O:3])[CH:8]=1
Reactant: CCOC(=O)COc1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from preparation 295, (pyridin-3-yloxy)-acetic acid ethyl ester, 300 mg (1.68 mmol) in 15 mL of dioxane was added a solution of 400 mg (16.8 mmol) of lithium hydroxide in 15 mL of water. The solution was stirred for three hours at rt. then acidified to pH=1.0 with 5 N HCl and concentrated to dryness to give a quantitative yield of the crude desired product. MS (ion spray) 154.1 (M+). Crude product was carried on without further purification.