Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH2:11][O:12][CH3:13])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+].B(O)O>O1CCOCC1>[CH3:13][O:12][CH2:11][C:10]([NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=1)=[O:14]
Reactant: COCC(=O)NCc1ccc(Br)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Product: COCC(=O)NCc1ccc(B(O)O)cn1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture N-((5-bromopyridin-2-yl)methyl)-2-methoxyacetamide (387 mg, 1.494 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (493 mg, 1.942 mmol), PdCl2(dppf)-CH2Cl2Adduct (122 mg, 0.149 mmol) and potassium acetate (366 mg, 3.73 mmol) in dioxane (10 mL) was heated to 70° C. for 3 hr. LCMS indicated that the major product was boronic acid. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated to afford (6-((2-methoxyacetamido)methyl)-pyridin-3-yl)boronic acid (335 mg, 1.495 mmol, 100% yield) as a brown oil. The material was used as is in the next step. MS (ES+) m/z: 225.0 (M+H); LC retention time: 0.38 min (analytical LCMS Method B).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[C:29]([N:24]1[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C(C)(C)C)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid which was used in the next step without further purification. MS (ESI): m/z=458.1 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12]C(=O)C)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[ClH:16]>>[ClH:16].[NH2:12][CH:3]([CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)[CH2:2][OH:1]
Reactant: CC(=O)NC(CO)CN1CCN(C)CC1
Agent: Cl
Product: CN1CCN(CC(N)CO)CC1
Temperature: 100 °C

Procedure:
A suspension of 0.89 g of N-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl] acetamide in 10.3 mL of an aqueous acid solution of 6N hydrochloric acid is heated at a temperature of about 100° C. for 3 hours. After cooling at a temperature of about 60° C., the reaction medium is filtered and the filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 60° C. About 1 g of 2-amino-3-(4-methyl-piperazinyl)-1-propanol, hydrochloride is obtained in the form of a tacky beige-colored paste. [Infrared spectrum (KBr) 3337; 2955; 2637; 2522; 1617; 1457; 1062; 1009 and 962 cm−1].
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:14]>C1(C)C=CC=CC=1.O>[C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CC#N)Nc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](CC(N)=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-phenylamino-butyronitrile (6.06 g, 0.0378 mol) in toluene (150 mL) was added a cooled solution of conc. sulfuric acid in H2O (20.12 mL H2SO4/3 mL)—(The ratio of toluene to acid/H2O is very important and should be followed strictly). Stir the biphasic mixture at room temperature for 0.5 h and warm to 35° C. and stir for 22 h. The reaction was cooled to room temperature and quenched with 13 g of Na2CO3 in water (add slowly some foaming). Separate the organic and extract 2×EtOAc. Combine all the organics and wash the organics with brine, dry over MgSO4, filter and concentrate to give the desired product in 2.11 g (90%)
Reaction SMILES: [OH:1][NH:2][C:3]([CH2:5][C:6]1([CH3:24])[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[N:8]2[C:7]1=[O:23])=[O:4]>FC(F)(F)C(O)=O>[OH:1][NH:2][C:3]([CH2:5][C:6]1([CH3:24])[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:23])=[O:4]
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)C(C)(CC(=O)NO)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC(=O)NO)C(=O)N2CCCC(C(=O)O)N2C1=O
Yield: 31.4 %

Procedure:
0.8 g of tert.butyl hexahydro-2-[(N-hydroxycarbamoyl)-methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate was treated with 10 ml of trifluoroacetic acid for 1 hour and the mixture was then evaporated. The residue was treated with 5 ml of ethyl acetate and the mixture was evaporated. Trituration of the residue with 1,2-dimethoxy-ethane and recrystallization from methanol/water yielded 0.21 g of hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid having a melting point of 254° C. (decomposition).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C@@:17]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]2=3)[C:14]([OH:16])=[O:15])[N:6]=1.[C:36](O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH3:36][O:15][C:14](=[O:16])[C@@H:13]([O:12][C:7]1[N:6]=[C:5]([CH3:4])[CH:10]=[C:9]([CH3:11])[N:8]=1)[C@@:17]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](Oc1nc(C)cc(C)n1)[C@@]1(c2ccccc2)NCC(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Sodium methylate (10.14 g, 186 mmol) is added at 0° C. to a solution of (±)-(1S*, 9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (5.0 g, 12 mmol, Example 49) in methanol (250 ml). The solution is stirred at rt for 3 h, poured into a solution of citric acid (12.6 g, mono hydrate) in water (600 ml) and extracted three times with EA. The organic phase is washed with brine, dried over MgSO4 and evaporated to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid methyl ester (5.04 g) as a white foam. LC-MS1: tR=0.94 min, [M+1]+=447.07.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(O)cc1

Procedure:
To a solution of 2.76 g (20 mmol) of 4-hydroxybenzoic acid and 800 mg (200 mmol) of sodium hydroxide in 12 ml of water was added 250 mg of methyl tricaprylammonium chloride and 4.67 g (17 mmol) of n-tetradecylbromide. The mixture was heated at reflux for 4 h and then diluted with 30 ml of water. The mixture was extracted with 2×30 ml ether. The ether extracts were combined and washed with water and saturated NaCl solution. The solvent was removed in-vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22]C)[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].Cl>O.CO>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Shake 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.49 g.) with concentrated hydrochloric acid (1.2 cc.) in water (0.8 cc.) and methanol (18 cc.) until solution is complete. Allow to stand 2 hours at room temperature, pour the mixture into water and extract the product with ether. Evaporate the washed and dried ether extracts and recrystallize the solid from a mixture of ethyl acetate and ether to obtain the title compound (0.32 g.), m.p. 169°-70°; ultraviolet absorption peak at 240 mμ (ε17,000); infrared absorption peaks at 2.92, 6.01 μ.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.O.[NH2:21][NH2:22]>CCCCO>[F:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4]([CH:6]3[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]3)=[N:21][NH:22]2)=[CH:15][CH:16]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 36 %

Procedure:
A solution of 1-[4-(2,4-difluoro-benzoyl)-piperidin-1-yl]-ethanone (1.7 g, 6.4 mmol), 6 mL of hydrazine hydrate and 13 mL of n-BuOH was refluxed for 48 hours. The reaction mixture was concentrated in vacuo, the residue was diluted with water (30 mL) and then extracted with ethyl acetate (50 mL). The solvent was removed in vacuo to yield the crude product as an oil. It was washed with heptane and the solvent was filtered to yield the title product (0.60 g, 2.3 mmol, 36% yield) as a white solid. MS (ESI) m/z 261.6 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.44 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](OCC3C=CC=CC=3)=[O:28])=[CH:22][N:21]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:25]=[C:24]([CH3:26])[C:23]([CH2:27][OH:28])=[CH:22][N:21]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1CO
Temperature: 10 °C
Yield: 32.5 %

Procedure:
Lithium aluminium hydride (646 mg) was portionwise added to a solution of benzyl 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (4.56 g) in THF (60 ml) with stirring at 5-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 2 hours. The reaction mixture was cooled at 5° C. and H2O (0.7 ml), 15% NaOH solution (0.7 ml) and H2O (2.1 ml) was added and the resultant mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}methanol (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(Cl)cccc4Cl)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(Cl)cccc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80.2 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,6-dichlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (156 mg, yield 80%).
Reaction SMILES: C(OC(C1C(=O)C2C=CC=CC(=O)C=2NC=1)=O)C.C([O:21][C:22]([C:24]1[C:25](=[O:37])[C:26]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:30](=[O:36])[C:27]=2[NH:28][CH:29]=1)=[O:23])C>>[Br:35][C:31]1[C:30](=[O:36])[C:27]2[NH:28][CH:29]=[C:24]([C:22]([OH:23])=[O:21])[C:25](=[O:37])[C:26]=2[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1c[nH]c2c(=O)c(Br)cccc2c1=O
Agent: CCOC(=O)c1c[nH]c2c(=O)ccccc2c1=O
Product: O=C(O)c1c[nH]c2c(=O)c(Br)cccc2c1=O

Procedure:
In the same manner, but replacing 4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester with an equivalent amount of 8-bromo-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester, described in example 2, 8-bromo-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Cl[CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27]
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 0.5 g (1.73 mmol) of 2-chloro-4-(3-trifluoromethylphenoxy)phenol in 20 ml of N,N-dimethylfomamide, there are added 0.29 g (1.90 mmol) of ethyl 2-chloroethylcarbamate and 0.53 g (3.81 mmol) of potassium carbonate with stirring, and the resultant mixture is heated at 50° C. for 7 hours. The reaction mixture is poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give ethyl 2-[2-chloro-4-(3-trifluoromethylphenoxy)phenoxy]ethylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:3]=1.I[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:3]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1cccc(-n2nc(C)cc2N)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc(C)cc2Nc2ccccc2C(=O)O)n1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-ylamine (7.03 g, 37.3 mmol), 2-iodobenzoic acid (10.2 g, 41.0 mmol), copper acetate (II) (0.745 g, 4.10 mmol) and potassium carbonate (5.67 g, 41.0 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux under an argon atmosphere for 2 hours. The reaction solution was allowed to cool to room temperature, and the reaction mixture was poured into water. The solution was made weakly acidic by the addition of 1N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give crude 2-[[3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (10.6 g, 92% yield). A solution of the compound (9.5 g, 30.8 mmol) in phosphorous oxychloride (15 mL, 161 mmol) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (2.37 g, 25% yield).
Reaction SMILES: [CH3:1][N:2]1[C:31](=[O:32])[CH:5]2[CH:6](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=4)=[CH:17][N:16]=3)[N:7]3[CH:12]([CH:4]2[C:3]1=[O:33])[CH2:11][CH2:10][CH2:9][CH2:8]3.BrC1C=CC(/C=C/C2N3C(CCCC3)C3C(=O)N(C)[C:54](=[O:55])C23)=NC=1.COC1C=CC=CC=1B(O)O>>[CH3:54][O:55][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[CH:6]2[N:7]3[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:4]3[C:3](=[O:33])[N:2]([CH3:1])[C:31](=[O:32])[CH:5]23)=[N:16][CH:17]=1
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Agent: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(/C=C/C2C3C(=O)N(C)C(=O)C3C3CCCCN23)nc1

Procedure:
The title compound is prepared analogously to the compound from Example 17 from 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]-indolizine-1,3-dione (from Example 6, racemic mixture 3) and 18 mg of 2-methoxyphenylboronic acid.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[N:10]=[CH:9][NH:8][C:7]2=[O:17]>CC(O)=O>[N+:14]([C:13]1[CH:12]=[C:11]2[C:6]([C:7]([OH:17])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:3])([O-:16])=[O:15]
Reactant: COc1cc2c(=O)[nH]cnc2cc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2ncnc(O)c2cc1O

Procedure:
To a solution containing 20 ml of 48% aqueous HBr and 20 ml of AcOH was added 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-one (1.4 g, 6.3 mmol) and the mixture was refluxed overnight. The resulting solution was evaporated to afford the crude phenol as a residue and was used without further purification (1.2 g, 5.8 mmol) (M+1, 208).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:13][CH:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[O:26])=[CH:23][N:22]=1
Reactant: O=C(O)c1ccc(-c2ccccc2O)nc1
Reactant: NC1CCN(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2O)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1-pyrimidin-2-ylpiperidin-4-amine (45 mg, 0.25 mmol) was added to a solution of 6-(2-hydroxyphenyl)nicotinic acid (50 mg, 0.23 mmol) in DMF (0.25 ml) and triethylamine (0.176 ml, 1.26 mmol). O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mgs, 0.33 mmol) in DMF (0.5 ml) was then added and the reaction sealed. The reaction was shaken at 50° C. for 16 hours. The reaction was then evaporated to dryness in vacuo. Dichloromethane (2 ml) and saturated aqueous sodium hydrogen carbonate (0.5 ml) were added, the sealed reaction was shaken vigorously for 2 h. After this time the plates were opened and the biphasic mixture filtered through an Isolute SPE phase separation tube. The organic layer (filtrate) was evaporated to dryness in vacuo. DMSO (1 ml) was then added and the plate sealed and shaken at 50° C. until all the residue had dissolved then purified by reverse phase preparative HPLC using method B as defined below. R.T. 3.06 MS ES m/z 376 [M+H]+. This gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Cl:19][C:20]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].O>C(OCC)C.O1CCCC1>[Cl:19][C:20]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:21]=1[CH:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:23]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C(O)c2ccccn2)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-bromopyridine (0.68 ml) was dissolved in diethylether (20 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (4.5 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 2-chloro-4-nitrobenzaldehyde (1.1 g) in diethylether (20 ml) and tetrahydrofuran (30 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and 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 (2-chloro-4-nitrophenyl)(pyridin-2-yl)methanol (0.47 g) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:23]([C:24]([O:26]C)=[O:25])=[C:5]2[CH:6]=[C:7]([C:10](=[O:22])[N:11]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:9][N:4]2[N:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[C:23]([C:24]([OH:26])=[O:25])=[C:5]2[CH:6]=[C:7]([C:10](=[O:22])[N:11]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COC(=O)c1c(Br)nn2ccc(C(=O)N(CCC(C)C)CCC(C)C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(Br)c(C(=O)O)c2c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a stirred solution of methyl 2-bromo-5-(diisopentylcarbamoyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.47 g, 1.072 mmol) in THF (15 ml) and MeOH (15 ml) was added 2M aqueous LiOH solution (10.00 ml, 20 mmol). The mixture was stirred at 30° C. for 4 h then concentrated partially, acidified with 1N HCl and extracted with ethyl acetate (3×40 ml). The combined organics were dried over anhydrous sodium sulphate, filtered and concentrated. The orange solid was triturated with methyl tert-butyl ether (10 ml) to afford 2-bromo-5-(diisopentylcarbamoyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.291 g, 0.679 mmol, 63.3% yield) LCMS m/z 424.1, 426.1 (M+H)+, ret. time=2.21 min.