Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:6]([C:5]1[C:4]([CH3:11])=[CH:3][C:2]([O:1][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][C:8]=1[CH3:10])=[O:7]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC(=O)N(C)C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (100 mg) and 2-chloro-N,N-dimethylacetamide (89 mg) in DMF (2 mL) was added K2CO3 (185 mg) and the mixture was stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using 30% EtOAc/CH2Cl2 as eluent to give 2-(4-formyl-3,5-dimethylphenoxy)-N,N-dimethylacetamide as a solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+:24].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:24][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [NH4+]
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC=C1C(=O)c2ccccc2OC1c1ccccc1

Procedure:
A solution containing 30.3 g 3-hydroxymethylidene-flavanone, 18.5 g ammonium acetate, and 6 ml glacial acetic acid in 300 ml toluene is refluxed for one hour. After cooling the solution is neutralized with a saturated sodium bicarbonate aqueous solution. The precipitate is filtered off, then dissolved in methylene chloride, washed with water, dried and evaporated. Pure 3-aminomethylidene-flavanone is obtained as pale yellow crystals; m.p. 149°-152° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O.O1CCOCC1>[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:16])[C:1]=1[OH:4]
Reactant: NCCCCCCCC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)NCCCCCCCC(=O)O)c1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A 50% (by weight) solution of potassium carbonate (24 mL, 36 g, 0.127 mol, 1.23 eq), 8-aminocaprylic acid (16.44 g, 0.103 mol, 1.00 eq), and water (20 mL) were added to a 250 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. The white cloudy mixture was treated with a solution of oligo(3-methylsalicylate) (15.90 g, 0.114 mmol 1.11 eq) and dioxane (90 mL), added over five minutes. The addition funnel was replaced with a condenser, and the reaction mixture was heated to 90 degrees C. for 4 hours (at which time the reaction was determined to have finished, by HPLC). The clear orange reaction mixture was cooled to 40 degrees C. and acidified to pH=1 with 3% (by vol.) aqueous hydrochloric acid. All the dioxane and some of the water were stripped (60 degrees C., 50 mm). The water layer from the resulting two-phase mixture was decanted while still warm. The orange oil was crystallized from 65% ethanol-water to give a tan solid upon cooling to -10 degrees C. The solid was recrystallized from 50 mL of 65% ethanol-water. The off-white solid was washed with hot water (30 mL) to remove most of the remaining salicylic acid. The solid was recovered by filtration and was dried over 6 hours in a 50 degrees C. vacuum oven. The N-(3-methylsalicyloyl)-8-aminocaprylic acid was isolated as a light tan solid (12.32 g, 41%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[SH:27][CH2:28][CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:25][CH3:26])[N:4]=[C:3]([CH2:2][S:27][CH2:28][CH2:29][OH:30])[N:12]=[C:11]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CSCCO)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline (4.5 g), 2-mercaptoethanol (1.13 g), potassium carbonate (2.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethylthiomethyl)quinazoline (4.1 g, 82%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-155° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]3[C:22](=[O:25])[NH:23][N:24]=[C:14]3[C:13]3[CH:26]=[CH:27][CH:28]=[N:29][C:12]2=3)=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].[N:32]1([CH2:37][CH2:38][CH2:39]Cl)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:32]1([CH2:37][CH2:38][CH2:39][N:23]2[C:22](=[O:25])[N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:11]([C:9](=[O:10])[CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C:12]4[N:29]=[CH:28][CH:27]=[CH:26][C:13]=4[C:14]3=[N:24]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CN1CCN(CC(=O)N2c3ccccc3-n3c(n[nH]c3=O)-c3cccnc32)CC1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)N2c3ccccc3-n3c(nn(CCCN4CCCC4)c3=O)-c3cccnc32)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (3-pyrrolidinopropyl)chloride in xylene is added. The mixture is kept at 95°-100°C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(3-pyrrolidinopropyl)-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:39]O.Cl.O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[C:19]1[CH:20]=[CH:21][C:22]([OH:39])=[CH:23][CH:24]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CN(C)C(=O)[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g (7.50 mmol) of material from Step A above in 75 mL of tetrahydrofuran at 0° C. was added 1.25 mL of an aqueous solution of 30% hydrogen peroxide. After 1 h, the solution was allowed to warm up to ambient temperature and stirring continued for 2 h. The reaction mixture was acidified with 1N hydrochloric acid to pH 4. Additional water was added, and the aqueous layer was extracted with ethyl acetate (three times). The combined organic extracts were washed with saturated brine, dried (magnesium sulfate) and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (silica gel, methanol/ethyl acetate) to afford the title compound. LC-MS 424.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH2:12])[CH2:7][CH2:6]1)=[O:4].[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(CN)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(CNC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.7 %

Procedure:
To a mixture of 4-aminomethyl-cyclohexanecarboxylic acid methyl ester (1.008 g, 4.758 mmol, Astatech,) in N,N-dimethyl formamide (20.0 mL) was added TEA (617 mg, 6.098 mmol) and 1,1′-carbonyldiimidazole (810.3 mg, 4.997 mmol, Aldrich,). After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-{[(imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (1.184 g, 4.46 mmol, 93%) which was used without further purification.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](O)=[O:12])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([CH2:14][OH:15])=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(CO)c2ccccc12
Yield: 70 %

Procedure:
The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithium Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1N HCl. The product was extracted with ethyl acetate (3×), washed with aqueous sodium bicarbonate (3×), water, brine, and dried over magnesium sulfate. 1,4-Bishydroxymethylnaphthalene (70%) was obtained as a solid after evaporation of the solvent and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[N:17][C:10]=3[NH:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]1([N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[N:17][C:10]=3[N:9]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c2c(=O)n(-c3ccccc3)c(=O)[nH]c2n1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(=O)n(-c3ccccc3)c(=O)n(CCCCBr)c2n1
Yield: 64.9 %

Procedure:
A mixture comprising of 13.36 g 3-phenyl-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 43.18 g of 1,4-dibromobutane, 10.37 g of anhydrous potassium carbonate and 150 ml of N,N-dimethyl-formamide was heated at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was poured into 600 ml of water. The resulting mixture was extracted with ethyl acetate and further with a small amount of dichloromethane. These extracts were combined, dried over anhydrous potassium carbonate and distilled under a reduced pressure to remove the solvent. The obtained residue was dissolved in a small amount of dichloromethane, columnchromatographed over silica gel column and eluted with dichloromethane. The eluate was concentrated under a reduced pressure and the residue was recrystallized from a dichloromethaneisopropyl ether solvent to give 13.06 g of 3-phenyl-5,7-dimethyl-1-(4-bromobutyl)pyrido[2,3-d]-pyrimidin-2,4(1H,3H)-dione having a melting point of 153.5° to 154.5° C., which serves as an intermediate (yield: 65%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)[CH:10]=2)=[O:6].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:21][CH:20]=[CH:19][N:18]=1)[CH:10]=2)=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.17 g. of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester (0.90 g.) in dry N,N-dimethylformamide (50 ml.) and the mixture was stirred at room temperature for 1 hour. Benzyl bromide (0.61 g.) was added and the resulting mixture was stirred for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 1-benzyl-6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester, m.p. 120°-122° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([Br:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:12].[Na+]>O>[Br:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([OH:12])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 140 °C

Procedure:
The title compound was made according to the method described in Org. Proc. Res. rev. 2002, 6, 591-595. To 5-iodo-3-bromo-benzoic acid (500 mg, 1.53 mmol), NaOH (250 mg, 6.1 mmol), Cu2O (240 mg, 1.68 mmol) was added water (4.0 mL)). The mixture was heated for 1.5 h at 140° C. in a sealed tube. The cooled mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified (pH˜2) with TFA and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to yield 3-bromo-5-hydroxy-benzoic acid. 1H NMR (400 MHz, DMSO-d6): 10.30 (s, 1H), 7.46 (m, 1H), 7.31 (m, 1H), 7.17 (m, 1H).
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=O>CO>[O:13]=[C:3]([OH:4])[C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=O
Solvent: CO
Product: O=C(O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 78 %

Procedure:
As a comparative example, it will be noted that Vuorinen et al. (Starke, 43 No. 5, pp. :94-198), in carrying out the oxidation of glucose without methanol, had to use a pressure of pure oxygen of 26 bar in order to obtain an arabinonic acid yield of 78% only with 3.5% and 6.5% impurities consisting of glyceric acid and glycolic acid respectively.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCc1ccccc1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCNC(=O)OCc1ccccc1
Yield: 80.6 %

Procedure:
77.5 g of methacryloyloxyethyl isocyanate (Karenzu MOI, available from Showa Denko K.K.) and 60 g of benzyl alcohol were dissolved in 260 g of dioxane. To the solution were then added 5 drops of di-n-butyltin dilaurate. The reaction mixture was then allowed to undergo reaction at a temperature of 65° C. for 3 hours. The dioxane and excess benzyl alcohol were then distilled off under reduced pressure. The residue was poured into water, extracted with ethyl acetate, and then dried. The solvent was then distilled off to obtain 106 g of benzyloxycarbonylaminoethyl methacrylate in the form of colorless oil.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:28]1(C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.O>[C:28]1([C:2]2[C:14]3[C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[CH:7]=[N:6][C:5]=3[NH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(-c4ccccc4)c23)C1
Temperature: 90 °C
Yield: 52 %

Procedure:
To a solution of tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.540 g, 1.53 mmol) in toluene (8 mL) and ethanol (4 mL) was added phenyl bronic acid (0.371 g, 3.07 mmol) followed by Na2CO3 (0.96 g, 9.18 mmol) as a solution in water (10 mL). The mixture was vortexed and 1,1-Bis(Di-t-butylphosphino)Ferrocene Palladium dichloride (BDtPFPdCl2, CAS#95408-45-0, 0.025 g) was added to the reaction mixture. The reaction was then purged with nitrogen and heated at 90° C. for 16 hours. On completion of the reaction, EtOAc (50 mL) and water (50 mL) was added. The organic layer was separated, washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The crude product was purified using flash column chromatography (SiO2, 50% EtOAc in hexane) to give the pure desired product, tert-butyl 1-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.278 g, 52%) as a white foamy solid. M.p.=>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.72 (s, 1H), 8.38 (s, 1H), 7.73-7.62 (m, 2H), 7.56-7.42 (m, 3H), 4.65 (s, 2H), 3.54-3.45 (m, 2H), 2.88-2.8 (m, 2H), 1.44 (s, 9H); LCMS [M+H]: 351.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:37].N1C=CC=CC=1>O1CCOCC1>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:37])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncnn2c(-c3cccc(CCl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1.5 h
Yield: 24.5 %

Procedure:
{3-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol (254 mg, 0.57 mmol) was suspended in 2 mL of dioxane and SOCl2 (83 μL, 1:1 mmol) was added followed by the dropwise addition of pyridine (0.14 mL, 1.7 mmol). The mixture was stirred for 1.5 hours and carefully quenched by the addition of 2M aqueous Na2CO3. The mixture was diluted with water and extracted with 3×10 mL of 10% MeOH/EtoAc. The combined organic fractions were washed with 1M aqueous H3PO4, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO® Redi-sep 12, 80% to 100% EtOAc/hexanes to provide 65 mg (24%) of the title compound as a crusty solid. 1H-NMR (DMSO-d6) 8.55 (s, 1H), 8.19 (s, 1H), 8.08, (d, 1H) 7.99 (s, 1H) 7.83 (d, 1H) 7.70 (s, 1H), 7.46 (t, 1H), 7.40 (t, 1H), 7.38-7.26 (m, 4H), 7.24 (d, 1H), 7.22 (s, 1H), 5.72 (s, 2H), 4.60 (s, 2H); LC-MS [M+H]+=465.3, 467.2, RT=3.24 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: NC1CC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with cyclopropylamine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=254.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (561 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N:31]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:50])C=1>C(Cl)Cl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N+:31]=3[O-:50])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 174) (7.6 mg, 0.0128 mmol) in CH2Cl2 (1.3 mL) was added m-CPBA (5.8 mg, 77% purity, 0.0256 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (10 mL), washed with aq. NaHSO3, saturated K2CO3, and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (50% Et2O/CH2Cl2) afforded the title compound. Rf=0.23 (50% Et2O/CH2Cl2). LCMS=609.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 5.74 (d, J=8.3 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 4.11-3.96 (m, 1H), 3.88 (d, J=14.9 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 0.65 (d, J=6.6 Hz, 3H).