Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)([OH:3])=O.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[OH:39][CH2:40][CH2:41][CH2:42][NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CO.C(Cl)(Cl)Cl>[CH:45]1([CH2:44][N:43]([CH2:42][CH2:41][CH2:40][OH:39])[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:3])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: OCCCNCC1CCCCC1
Reactant: O=C(O)CCCCOc1ccc2c(c1)CCC(=O)N2
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(OCCCCC(=O)N(CCCO)CC3CCCCC3)ccc2N1
Reaction time: 0.5 h

Procedure:
Into 400 ml of chloroform, were added 5 g of 6-(4-carboxybutoxy)-3,4-dihydrocarbostyril and 3.2 g of DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, stirring was continued at a room temperature for 30 minutes and 3.9 g of N-(3-hydroxypropyl)-N-cyclohexylmethylamine was added to the reaction mixture and the reaction was continued for 3 hours. After the reaction was completed, the reaction mixture was washed with 1 N-NaOH aqueous solution, 10% HCl and water in this order and was dried with anhydrous Na2SO4. The drying agent was removed by filtration and the thus obtained dried product was concentrated to obtain a residue. The residue was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=40:1). The elute obtained was concentrated and was recrystallized from ethyl acetate-petroleum ether. 4.0 Grams of 6-{4-[N-cyclohexylmethyl-N-(3-hydroxypropyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyril was obtained in the form of colorless needle-like crystals. Melting point: 95°-97° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CC(O)C.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=S1Cc2ccccc2C12CCNCC2
Reaction time: 4 h
Yield: 75.4 %

Procedure:
42.0 g (0.13 mole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine]-2-oxide [prepared as described in step (b) above] were dissolved in 420 ml of 2-propanol, and 150 ml of a 4 N solution of hydrogen chloride in dioxane was added thereto, whilst ice-cooling. The mixture was then stirred for 4 hours. At the end of this time, 200 ml of diethyl ether were added to the mixture, and the mixture was allowed to stand for 1 hour, whilst ice-cooling. The precipitated crystals were then collected by filtration. The crystals were dissolved in 200 ml of a 5% w/v aqueous solution of sodium hydroxide. The product was extracted with methylene chloride, and the organic extract was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 21.7 g of the title compound as a white amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Cl)cc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
Reaction SMILES: CS(C)=O.C(OC(=O)C)(=O)C.[CH3:12][C:13]1([CH3:29])[O:17][C@@H:16]([C@H:18]2[O:22][C@@H:21]3[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:20]3[C@H:19]2[OH:28])[CH2:15][O:14]1.C(OC(=O)C)(=O)C>>[CH3:12][C:13]1([CH3:29])[O:17][C@@H:16]([C@H:18]2[O:22][C@@H:21]3[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:20]3[C@@H:19]2[OH:28])[CH2:15][O:14]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1

Procedure:
Sowa, W. and Thomas, G. H. S., (Can. J. of Chem., 1966, Vol. 44, 836-838) used the DMSO/acetic anhydride oxidation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose in small scale (10 mmole) using a 20 fold excess of acetic anhydride. The ulose was then reduced providing 1,2:5,6-di-O-isopropylidene-α-D-allofuranose of poor quality, thus the product had to be column purified. Overall this procedure is not suitable for large-scale productions due to the large reagent consumption, two step procedure and the column purification step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1.[OH-:16].[Na+].O>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CO>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([OH:16])[CH:3]=[N:4][CH:5]=2)[CH2:11][CH2:12]1
Reactant: Brc1cncc(OCC2CCOCC2)c1
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1cncc(OCC2CCOCC2)c1
Temperature: 210 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
A mixture of 3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (300 mg), copper(II) sulfate pentahydrate (130 mg), bronze (100 mg), sodium hydroxide (700 mg), and water (5 mL) was stirred in an autoclave at 210° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by addition of methanol, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and extracted with chloroform. The aqueous layer was neutralized by addition of 1M hydrochloric acid (3.5 mL), followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-ol (137 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][O:4]1.F[C:16]1[N:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[NH:24][C:23]2=[O:30])=[CH:18][C:17]=1[CH3:31].CN(C=O)C>O>[CH3:28][C:25]1([CH3:29])[NH:24][C:23](=[O:30])[N:22]([C:19]2[CH:20]=[N:21][C:16]([O:12][C:9]3[CH:8]=[CH:7][C:6]4[CH2:5][O:4][CH:3]([C:2]([F:1])([F:13])[F:14])[C:11]=4[CH:10]=3)=[C:17]([CH3:31])[CH:18]=2)[C:26]1=[O:27]
Reactant: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1F
Reactant: Oc1ccc2c(c1)C(C(F)(F)F)OC2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1Oc1ccc2c(c1)C(C(F)(F)F)OC2
Temperature: 110 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
To a solution of 3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (enantiomer 1) (Intermediate 28, 20 mg, 0.098 mmol) and 3-(6-fluoro-5-methyl-3-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 6, 27.9 mg, 0.118 mmol) in DMF (1 mL) dipotassium carbonate (27.1 mg, 0.196 mmol) was added and the reaction mixture was stirred for 48 hours at 110° C. After cooling the mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by reverse phase flash chromatography on C18 column (MEGA BE Varian, 5 g) using water/acetonitrile from 100:0 to 0:100 as eluent affording the title compound (5 mg) as white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>CN(C)C=O>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (3 g, 11.81 mmol) in dimethylformamide (20 mL) was added 3-bromophenol (1 g, 5.78 mmol) and NaOH (500 mg, 12.50 mmol). The resulting solution was stirred at 100° C. for 3 h. The reaction mixture was quenched by the adding H2O (100 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated, and the residue purified by silica gel column chromatography (1:20 EtOAc/petroleum ether) to provide 1.1 g (31%) of 1-bromo-3-(2,2,2-trifluoroethoxy)benzene.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=2[O:20][CH3:21])=[C:9]([CH3:22])[N:8]=[C:7]([NH2:23])[N:6]=1>CS(C)=O.CN(C=O)C.O>[NH2:23][C:7]1[N:6]=[C:5]([Cl:4])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:1]#[N:2])=[CH:14][C:13]=2[O:20][CH3:21])=[C:9]([CH3:22])[N:8]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium cyanide (0.17 g) was added to a stirred solution of the product from step (ii) (0.40 g) in DMSO (5 mL) and DMF (5 mL). The mixture was stirred at rt for 15 h, diluted with water and then extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to give the subtitle compound, 0.20 g.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23](Cl)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C1C[O:36]CC1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)=[O:9])[C:23](=[O:36])[CH2:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:22]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)CNc2ccc(F)cc2)ccc1S(C)(=O)=O
Reactant: O=C(CCl)c1ccccc1
Solvent: O
Product: Cc1cc(C(=O)CN(C(=O)Cc2ccccc2)c2ccc(F)cc2)ccc1S(C)(=O)=O
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 2-(4-fluoroanilino)-1-(3-methyl-4-methylsulfonylphenyl)-1-ethanone (1.5 g, 4.67 mmol) (obtained in preparation 19) in anhydrous THF (15 ml) was added phenacylchloride (0.722 g, 0.62 mmol) very slowly under nitrogen atmosphere at 25° C. The mixture was stirred for 2 h and diluted with water (25 ml). The solid separated was filtered, washed with water (2×15 ml) followed by petroleum ether (2×5 ml) and dried under vacuum to give 1.6 g of the title compound in 78% yield.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1N.OC1C=C([N+]([O-])=O)C=CC=1N.[OH:23][C:24]1C2C(=CC=C(N)C=2)[CH:27]=[C:26]([S:35]([OH:38])(=[O:37])=[O:36])[CH:25]=1.OC1C2C(=CC(N)=CC=2)C=C(S(O)(=O)=O)C=1>>[OH:23][C:24]1[C:3]2[C:4](=[C:5]([NH2:8])[CH:6]=[CH:7][CH:2]=2)[CH:27]=[C:26]([S:35]([OH:38])(=[O:37])=[O:36])[CH:25]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Agent: Nc1ccc([N+](=O)[O-])cc1O
Agent: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1
Product: Nc1cccc2c(O)cc(S(=O)(=O)O)cc12

Procedure:
On account of their easy accessibility and the neutral black shade obtainable therewith, particular interest attaches to the dyes that are derived from 1-hydroxy-2 amino-4-nitrobenzene or 1-hydroxy-2-amino-5-nitrobenzene as diazo components, and from 1-hydroxy-7-aminonaphthalene-3-sulphonic acid or 1-hydroxy-6-aminonaphthalene-3-sulphonic acid as coupling component.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Temperature: 180 °C
Yield: 27 %

Procedure:
A quantity (4.88 g., 0.025 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, Example 1, above) with 20.0 ml. morpholine, and 20.0 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 180° C. for 6 hrs. The aqueous reaction mixture was cooled to 25° C. and then reheated to effect removal of excess morpholine and about one-half the water was removed by evaporation. This concentrate was then diluted with 50 ml. water and extracted with three 50-ml. portions of chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The chloroform was removed from the filtrate by evaporation under reduced pressure and the solid residue was triturated with acetone. The insolubles were collected on a filter. Testing via thin layer chromatography showed that there were three components. The components were separated by chromatography on a column of silica gel using a solvent mixture consisting of 1 part methanol and 9 parts methylene chloride. The fractions having the most rapidly moving component were collected and combined. The solvents were removed by evaporation. Chloroformic extraction of the original water-diluted reaction mixture was repeated followed by drying, treating with charcoal, filtration, and removal of chloroform was effected as before. This residue was combined with the residue from the chromatographic separation, and a crystallization and recrystallization from acetonitrile was effected. There was thus obtained 1.40 g. (27% yield) of 2-amino-6-methyl-4-morpholinopyridine-1-oxide as colorless needles having a melting point at 292° C. (with decomposition).
Reaction SMILES: [C:1]([C:6]1(C)[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[CH:7]1C#N)(OCC)=O.[OH:16]OS([O-])=O.[K+]>O>[CH3:1][C:6]1[CH2:10][C:9]([CH3:11])([OH:16])[C:8](=[O:12])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C1(C)CC(C)C(=O)C1C#N
Agent: [K+]
Solvent: O
Product: CC1=CC(=O)C(C)(O)C1
Yield: 70 %

Procedure:
The same product as that of paragraph (d) of Example 5 can also be obtained by treating 3-carboethoxy-2-cyano-3,5-dimethylcyclopentanone [see paragraph (a) of Example 5] with Caroat, acidifying the resulting mixture to pH 1 and then refluxing the mixture for 24 hours. Working-up as described in paragraph (d) of Example 5 yields 70% of pure crystalline 3,5-dimethylcyclopent-2-en-5-olone of melting point 92°-93° C. (from water).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]1[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]1)=[O:24]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCC(O)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4-hydroxypiperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[NH:10][CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=4)[N:13]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[N:18][CH:19]=4)[N:13]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)c1ccc(-c2c[nH]c(-c3cc(C4CC4)on3)n2)cn1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(C(C)(C)O)nc2)nc1-c1cc(C2CC2)on1
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
To a solution of product from Step 4 (60 mg, 0.193 mmol) in THF (1 ml) was added cesium carbonate (126 mg, 0.387 mmol). After being stirred for 10 min, CH3I (0.013 ml, 0.213 mmol) was added and the reaction was stirred for 4 hrs. The reaction mixture was diluted with EtOAc, washed with NaHCO3 (sat), dried, concentrated, and separated by prep TLC (hex:EtOAc:CH3OH=6:5:1) to give 2-{5-[2-(5-cyclopropylisoxazol-3-yl)-1-methyl-1H-imidazol-4-yl]pyridin-2-yl}propan-2-ol (45 mg) LCMS: [M+H]+=325.3.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH:11](CC)[C:12]3[CH:13]=[N:14][C:15](N)=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4].[I-:24].II.N(OCCC(C)C)=O>[Cu]I.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH2:11][C:12]3[CH:13]=[N:14][C:15]([I:24])=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4]
Reactant: CCC1c2cnc(N)nc2-c2c(c(C(=O)NC)nn2C)C1(C)C
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CNC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(I)nc1-2
Temperature: 70 °C

Procedure:
In a round bottom flask maintained under argon atmosphere, ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (13.00 g, 45.400 mmol) was dissolved into anhydrous dimethoxyethane (800 mL); cesiun iodide (11.795 g, 45.400 mmol), bisublimated iodine (5.761 g, 22.698 mmol), copper(I) iodide (2.594 g, 13.621 mmol), and iso-amyl nitrite (9.107 mL, 68.100 mmol) were added in that order and the mixture was heated to 70° C. for 22 hours.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.322 mmol), ethanol (4 mL), THF (0.8 mL), and sodium hydroxide (0.537 mL, 1.611 mmol). The final product was collected as 88 mg (97%). LCMS E-S (M+H)=283.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.4 Hz, 6 H), 5.40 (m, 1 H), 8.25 (d, J=5.6 Hz, 2 H), 8.32 (s, 1 H), 8.44 (s, 1 H), 8.79 (d, J=5.6 Hz, 2 H), 14.12 (br. s., 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH2:12][NH2:13])[CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34].C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NC[C@H]1CCCN1C1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2C2CCOCC2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A mixture of [(2R)-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl]methylamine (preparation 157) (460 mg, 2.50 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), and triethylamine (870 ml, 6.24 mmol) in ethyl acetate (8 ml) was heated under reflux for 18 hrs, then cooled. Water (1.5 ml) was added, the reaction mixture dried over MgSO4, and filtered through celite, washing the filter pad well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue purified by column chromatography on silica gel using hexane:ethyl acetate (50:50) as eluant to give the desired product as a white solid, (970 mg, 82%).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[Na+].[Na+].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16].[OH:18][C:19]1([CH2:28][OH:29])[CH:24]([OH:25])[CH:23]([OH:26])[CH2:22][O:21]C1=O>CO>[OH:29][CH:28]([CH:19]([OH:18])[CH:24]([OH:25])[CH:23]([OH:26])[CH2:22][OH:21])[C:1]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:2]
Reactant: O=C1OCC(O)C(O)C1(O)CO
Reactant: O=C([O-])[O-]
Reactant: NCCOCCOCC(=O)O
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Temperature: 25 °C

Procedure:
172 mg of sodium carbonate are added to a solution of 450 mg of [2-(2-aminoethoxy)ethoxy]acetic acid and 318 mg of 3,4,5-trihydroxy-hydroxymethyltetrahydropyran-2-one in 10 ml of methanol, and the mixture is stirred at room temperature until the reaction has gone to completion. The reaction solution is filtered and concentrated. The residue is taken up in water and acetonitrile (1/1), resulting in the formation of 2 phases. The aqueous phase is concentrated and contains 20:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10](=[O:27])[CH3:11])[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Yield: 72.5 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoic acid methyl ester (7.11 g, 18.1 mmol), HgSO4 (5.43 g, 18.1 mmol), and conc. H2SO4 (1.92 mL, 36.1 mmol) in acetone-water (150 mL/25 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc-THF, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was triturated with MeOH to afford the desired product (4.46 g, 73%).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>COCCOC>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH:24][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COCCN(C)CCCN
Solvent: COCCOC
Product: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 76.9 %

Procedure:
A solution of chloride 21 (2.0 g, 9.03 mmol) and N1-(2-methoxyethyl)-N1-methylpropane-1,3-diamine (297) (2.0 g, 13.6 mmol) in DME (140 mL) was stirred at 20° C. for 18 h, the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-15%) of MeOH/DCM, to give 1-oxide 52 (2.3 g, 79%) as a yellow solid: mp 59-61° C.; 1H NMR [(CH3)2SO] δ 7.94 (s, 1H, H-9), 7.68 (br s, 1H, NH), 7.38 (s, 1H, H-5), 3.24-3.44 (m, 6H, CH2), 3.23 (s, 3H, OCH3), 2.92-2.99 (m, 4H, H-6, H-8), 2.56 (br t, J=5.8 Hz, 2H, CH2N), 2.24 (s, 3H, NCH3), 2.03-2.07 (m, 2H, H-7), 1.70-1.74 (m, 2H, CH2); HRMS (FAB+): calcd for C17H26N5O2 (MH+) m/z 332.2087, found, 332.2089.