Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15](CCCCN)[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.Cl[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CC(C)(C#N)CCCl
Reactant: NCCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1
Product: CC(C)(CN)CCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
The intermediate 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(4-amino-3,3-dimethylbutyl)piperazine was prepared analogous to the method described for 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(4-aminobutyl)piperazine (Intermediate 11b) using 4-chloro-2,2-dimethylbutyronitrile.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:9](=[O:17])[N:10]([CH3:16])[N:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH3:15][O:14][C:13]1[CH:12]=[N:11][N:10]([CH3:16])[C:9](=[O:17])[C:8]=1[C:20]1[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[CH3:18]
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: COc1cnn(C)c(=O)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnn(C)c(=O)c1-c1c(C)cc(C)cc1C
Yield: 37.7 %

Procedure:
To a mixture of 55 ml of dioxane and 17 ml of water were added 1.38 g of 4-chloro-5-methoxy-2-methyl-3(2H)-pyridazinone, 1.55 g of 2,4,6-trimethylphenylboronic acid, 1.86 g of sodium carbonate, 2.53 g of tetrabutylammonium bromide and 0.38 g of tetrakis(triphenylphosphine)palladium. This mixture was heated under reflux for 32 hours under a nitrogen atmosphere. A part of the reaction mixture was evaporated. To the resultant concentrate, 150 ml of water was added, followed by extraction with ethyl acetate (twice). The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 0.77 g of 5-methoxy-2-methyl-4-(2,4,6-trimethylphenyl)-3(2H)-pyridazinone [compound (V-2-1)] as a white crystal. Melting point: 186 to 192° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine -4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (57.8 mg, 83% yield). 1HNMR (500 MHz, CDCl3) δ: 11.95 (1H, s), 7.97 (1H, t, J=5.50 Hz), 7.41–7.38 (3H, m), 7.16 (1H, dd, J=8.24, 2.14 Hz), 6.63 (2H, d, J=8.24 Hz), 6.50 (2H, d, J=6.40 Hz), 3.76 (6H, s), 3.29 (3H, s). HRMS (ESI) calcd for C21H20Cl2N3O5 (M+H): 464.0780; found: 464.0775.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperidin-4-yl-methanol (Lancaster) to give the title compound. HR-MS (ES, m/z) calculated for C35H43Cl2N4O3 [(M+H)+] 637.2707, observed 637.2708.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[N+:17]([O-])([O-:19])=[O:18].[K+].O1C2C=CC=CC=2C=CC1>S(=O)(=O)(O)O>[N+:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:4]2=[O:11])([O-:19])=[O:18]
Reactant: CCOC(=O)c1cc(=O)c2ccccc2o1
Reactant: O=[N+]([O-])[O-]
Agent: C1=Cc2ccccc2OC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl chromone-2-carboxylate (Example 16) in about 3 mL of sulfuric acid cooled to −10° C. is added about 1 mL potassium nitrate in sulfuric acid. The molar ratio of potassium nitrate to the benzopyran is slightly greater than 1:1. The reaction mixture is stirred at 0° C. for 1 h, the ice bath removed, and the reaction stirred at room temperature until the reaction is complete by HPLC (<3% benzopyran): about 4-6 h. The nitrated benzopyran precipitates as the reaction progresses. The reaction mixture is poured onto ice, and the precipitate is dissolved in ethyl acetate. The ethyl acetate layer is dried, filtered, and evaporated to afford ethyl 6-nitrochromone-2-carboxylate as a light yellow solid (about 90% yield).
Reaction SMILES: [Se].[BH4-].[Na+].[SeH2:4].[Na].[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([Se:4][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [SeH2]
Reactant: ClCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Product: c1ccc(C[Se]Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 250 milliliter 3 necked round bottom flask equipped with an addition funnel and a magnetic stirring bar is placed 4.6 grams (0.058 moles) of selenium powder and 50 milliliters of deoxygenated distilled water. The flask is purged of air with nitrogen and a solution comprising 4.6 grams (0.122 moles) sodium borohydride in 50 milliliters of deoxygenated distilled water slowly added to the solution in the flask from the addition funnel. Upon contacting of these two solutions, vigorous hydrogen evolution occurs and the selenium powder is consumed thereby yielding a solution containing sodium hydrogen selenide. About 14.6 grams (0.166 moles) benzylchloride is now introduced into the flask and the resulting mixture stirred at room temperature for 18 hours. The solid product thus produced is collected by filtration washed with water and recrystallized twice from pentane. Yield 11.81 grams of rod like crystals, (m. p. 45° to 46° C).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([F:20])[CH:7]=2)[CH2:2]1.CO[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[F:20][C:8]1[CH:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:34]([C:32]3[O:33][C:29]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:28][CH:27]=4)=[N:30][N:31]=3)=[O:35])[CH2:2]2)[CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2F)CC1
Yield: 32 %

Procedure:
Using a similar protocol as described in Example 10 employing 29D (0.10 g, 0.36 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.11 g, 0.43 mmol) as starting materials afforded 52 mg (30%) of 29 as a foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[CH3:17][O:18][C:19]([CH3:30])([CH3:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:28][CH2:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([O:18][CH3:17])([CH3:29])[CH3:30])[CH2:26][CH2:25]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: COC(C)(C)CN1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(C)(C)OC)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 6 in EXAMPLE 1, using 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 3, Step 2) and [1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methylamine (EXAMPLE 4, Step 6).
Reaction SMILES: O.CC1C=CC(S(O)(=O)=O)=CC=1.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](O)[C:15]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]1[NH:25][C:26](=[O:36])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:29]=1>C1(C)C(C)=CC=CC=1>[OH:13][C:14]1[C:15]2[N:21]=[C:22]([CH2:23][C:24]3[NH:25][C:26](=[O:36])[CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:29]=3)[O:37][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1c(O)cccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3c(O)cccc3o2)[nH]1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
239 mg of 4-methylbenzenesulphonic acid hydrate are added to a solution of 870 mg of N-(2,6-dihydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in 60 ml of ortho-xylene. The reaction mixture is brought to reflux for 4 hours. After cooling to 0° C., the insoluble material formed is filtered off. The filtrate is concentrated to dryness under reduced pressure and then the residue is chromatographed on a silica gel column, elution being carried out with 90/10 CH2Cl2/MeOH. 654 mg of 2-[(4-hydroxy-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC([N:6]([CH2:13][CH:14]([OH:24])[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=O)C.C[Si](C)(C)Br.C.C1OC1C>C(Cl)Cl.O.Cl.CO>[OH:24][CH:14]([CH2:13][NH:6][OH:7])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)ON(CC(O)CP(=O)(OCC)OCC)C(=O)OCC
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)CC(O)CNO
Reaction time: 2.5 h
Yield: 53.4 %

Procedure:
To a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-hydroxypropylphosphonate (24.0 g.) in methylene chloride (50 ml.) was added dropwise trimethylbromosilane (41 ml.) under ice-cooling, whereafter the mixture was stirred for half an hour at the same temperature and then for additional 2.5 hours at ambient temperature. After the reaction was completed, the chloroform and the excess of the trimethylbromosilane was distilled off from the reaction mixture under reduced pressure to give a residue, which was dissolved in water (125 ml.) and stirred for an hour at an hour at ambient temperature. This aqueous solution was washed three times with chloroform (each 30 ml. portion) and evaporated to dryness under reduced pressure to give a residue, which was dissolved in 1 N hydrochloric acid (240 ml.) and heated to reflux for 15 hours. The resultant aqueous solution was evaporated to dryness under reduced pressure to give a residue, which was dissolved in water (60 ml.), decolorized with activated charcoal (500 mg.) and evaporated to dryness under reduced pressure. The residue thus obtained was dissolved in a mixture of water (20 ml.) and methanol (40 ml.), and adjusted to pH 3-4 with propylene oxide (about 25 ml.) to precipitate oily materials. Furthermore, to this solution was added ethanol (80 ml.) and allowed to stand for a while in order to precipitate said materials completely, and these materials were collected by decantation and dissolved in water (20 ml.). The insoluble materials were removed by filtration, and to the filtrate was added methanol (35 ml.) at 50°-60° C. The resultant solution was allowed to stand for 3.5 hours at ambient temperature, and precipitating crystals were collected by filtration, washed twice with methanol (10 ml.) and dried on phosphorus pentoxide to give 2-hydroxy-3-(N-hydroxyamino)-propylphosphonic acid (5.9 g.).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH2:1]([O:30][C:28](=[O:29])[C@H:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Benzyl bromide (2.34 ml, 19.8 ml) was added to a solution of N-tert-butyloxycarbonyl-4-hydroxy-3-methoxy-D-phenylalanine (3.44 g) and N,N-diisopropylethylamine (3.85 ml) in N,N-dimethylformamide (20 ml). After being stirred at room temperature for 6 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (4:1) to give (2R)-2-(tert-butyloxycarbonylamino)-3-(4-hydroxy-3-methoxyphenyl)propionic acid benzyl ester (2.98 g) as colorless powders.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:21]([O:23]CC)=[O:22].Cl>O1CCCC1.O>[C:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:21]([OH:23])=[O:22])([OH:11])=[O:10]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C(=O)O)c1ccc(O)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
About 0.5 mole of 4-hydroxybenzeneacetic acid is dissolved in about 50 ml of anhydrous tetrahydrofuran at -40° C. To this solution is added 3 equivalents of lithium diisopropylamide. The temperature is maintained at about -40° C. for about 15 minutes. Then 1 equivalent of ethyl chloroformate is added and the temperature is raised from about -40° C. to about 20° C. and the reaction mixture stirred for about 60 minutes. The reaction mixture is poured into water and the monoester of α-carboxy-4-hydroxybenzeneacetic acid is recovered from the aqueous solution. Hydrolysis of the half-ester with sodium hydroxide followed by acidification with hydrochloric acid gives α-carboxy-4-hydroxybenzeneacetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[N+:26]([O-:28])=[O:27].[NH3:29]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O>[Cl:24][C:22]1[CH:23]=[C:18]([C:12]2([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH2:29])=[C:4]([N+:26]([O-:28])=[O:27])[CH:5]=3)[CH2:13]2)[CH:19]=[C:20]([Cl:25])[CH:21]=1
Reactant: N
Reactant: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 3-[4-(bromomethyl)-3-nitrophenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.0 g) in tetrahydrofuran (10 mL) was added dropwise to a solution of 28% ammonia (aqueous solution, 5 mL) and tetrabutyl ammonium iodide (0.05 g) in tetrahydrofuran (10 mL) and methanol (20 mL) under ice cooling, and the mixture was then stirred for 10 hours at room temperature. The reaction solution was diluted with water, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrophenyl}methanamine (0.8 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9].[CH2:15]([O:22][CH2:23][CH:24]1[CH2:26][O:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[CH2:15]([O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:10]([CH2:8][CH3:9])[S:11]([CH3:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: CCNS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCN(CC(O)COCc1ccccc1)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Triethylamine (0.043 ml, 0.1 equiv) was added to a mixture of N-ethylmethanesulfonamide (413 mg, 1.1 equiv) and 2-benzyloxymethyloxirane (500 mg, 3.04 mmol) prepared according to (J. Am. Chem. Soc., 1996, 118, 7094-7100) in anhydrous dioxane (1 ml). The reaction mixture was then heated to 50° C. overnight. As the reaction was not complete, it was heated to 100° C. for another 5 hours (reaction complete according to TLC). The volatiles were then removed in vacuo. Flash chromatography eluting with cyclohexane/Ethyl acetate (6/4 then 1/1) afforded 836 mg (2.91 mmol, 96%). LCMS (Method E) 1.44 min, M+H 288. 1H-NMR (CDCl3, 400 MHz): 7.43-7.27 (m, 5H), 4.57 (s, 2H), 4.11-3.90 (m, 1H), 3.62-3.44 (m, 2H), 3.43-3.20 (m, 4H), 2.90 (s, 3H), 1.14-1.33 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][N:5]2[C:10]=1[C:9]([O:11]C1C=CC=CC=1)=[N:8][CH:7]=[N:6]2.CS(N)(=O)=O>>[OH:11][C:9]1[C:10]2=[C:2]([CH3:1])[C:3]([O:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Agent: CS(N)(=O)=O
Product: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(O)c12
Yield: 64 %

Procedure:
The compound from Step A above was treated with methanesulfonamide by a procedure similar to that described for the preparation of Example 24 to obtain N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide. (64% yield). MS: (M+H)+=301.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:27]5[CH2:28][O:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (28.4 mg, 45.4%), MS (ISP) m/z=459.5 [(M+H)+], was prepared in accordance with the general method of example 1 Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid obtained from saponification of the racemic [1,4]Dioxan-2-yl-acetic acid ethyl ester prepared as reported in Tetrahedron Vol. 45, 1989, pp. 69-76.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14](O)=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14]([Cl:20])=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 99 %

Procedure:
To a suspension of 2-(4-nitrophthalimido)acetic acid (58.6 g) in toluene (250 ml) was added phosphorus pentachloride (48.8 g) and the mixture was refluxed for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. By addition of hexane to the residue, the title compound (62.3 g) was obtained as light yellow sharp-pointed needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13](Br)[S:14][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2].[Cu][C:18]#[N:19]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2cc(C#N)sc2c1O
Temperature: 140 °C
Yield: 19.3 %

Procedure:
A mixture of 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.d, 150 mg, 0.5 mmol) and copper(I) cyanide (90 mg, 1.0 mmol) suspended in 2 mL DMF was heated at 140° C. for 30 minutes in a CEM microwave reactor. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to a crude residue. The desired product was purified by column chromatography eluting from silica gel with a gradient of 20-70% ethyl acetate in hexanes to give 24 mg of a white solid; MS: (+) m/z 248.9 (M+1)