Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[O:24]1[CH:25]=[CH:26][C:22]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:27]=[C:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:29]=[CH:30][C:7]=3[OH:6])[CH:21]=2)=[CH:23]1
Reactant: COC(=O)c1ccc(-c2ccoc2)cc1NC(=O)c1cc(-c2cccnc2)ccc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccoc2)ccc1C(=O)O)c1cc(-c2cccnc2)ccc1O
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Dioxane (5.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.31 mL) were added to the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-3-yl)benzoate (0.11 g), followed by stirring at 50 to 55° C. for 1 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid (6 mL) was added thereto. The solid substance was collected by filtration to obtain 0.081 g of 4-(furan-3-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-benzoic acid as a yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CC(C)=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimide, potassium salt (20.5 g, 0.11 mol) was suspended in dry DMF (100 mL). To the suspension was added 1-bromo-3-methyl-2-butene (14.8 g, 0.1 mol) with stirring. The reaction mixture was stirred under N2 at 45° C. for 24 h. TLC (silica gel, 30% ethyl acetate-hexane) showed one major UV-visible spot with Rf =0.65. DMF was removed under vacuum and the residue was taken up with water (200 mL) and extracted with ethyl acetate (3×150 mL). The extracts were combined and dried over Na2SO4. Evaporation of solvent gave the title product as a white solid. Yield: 21.0 g (98%). mp: 95°-97° C. MS: 233 (M+NH4)+, 216 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:29](=[O:39])[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[Cl:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:31]([C:33]4[S:34][CH:35]=[CH:36][C:37]=4[Cl:38])[CH2:30][C:29](=[O:39])[NH:28][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccc(OCc4ccccc4)nc3)cc2N1
Yield: 27.5 %

Procedure:
Prepared from {4-(6-benzyloxy-pyridin-3-yl)-2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K26) (172 mg, 0.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (38 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([I:1])=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)C=C(C)c1ccc2nccn2c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C=C(C)c1ccc2ncc(I)n2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
N-iodosuccinimide (252 mg, 1.12 mmol) was added to a mixture of 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester (220 mg, 1.02 mmol) in acetonitrile (10 mL) which had been cooled to 0° C. under nitrogen atmosphere. The mixture was stirred for 1 h, then diluted with ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (2×10 mL), and brine (1×15 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 50% ethyl acetate in hexanes) to yield 3-(3-iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid methyl ester as a pale yellow solid (168.1 mg, 48%). 1H NMR (250 MHz, CDCl3): δ 8.27 (bs, 1H), 7.77 (s, 1H), 7.64 (d, 1H, J=9.4), 7.41 (dd, 1H, J=9.4, J=1.6), 6.27 (d, 1H, J=0.62), 3.84 (s, 3H), 2.68 (d, 3H, J=0.62). MS [EI+] 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 2.78 mmol) in MC (9 mL) were added TsCl (556 mg, 2.91 mmol) and DMAP (509 mg, 4.17 mmol). The reaction mixture stirred for 8 hours at room temperature. The produced precipitated was filtered, washed with water and dried with nitrogen gas flow. The title product (810 mg, 87% yield) was used without further purification. MS m/z: 335 [M+1].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[CH:2].ClCCl.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:9][C:6]1[C:5]([O:11][CH3:12])=[CH:4][C:3]([C:1]#[C:2][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:8][N:7]=1
Reactant: C#Cc1cnc(OC)c(OC)c1
Reactant: Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2ccccc2C)cnc1OC
Reaction time: 16 h
Yield: 55.7 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (50 mg, 0.07 mmol), copper (I) iodide (25 mg, 0.13 mmol) and 5-ethynyl-2,3-dimethoxypyridine (Intermediate 32) (500 mg, 3.1 mmol) were suspended in degassed triethylamine (5 ml) and dichloromethane (5 ml) to give a brown suspension. To this was added 1-iodo-2-methylbenzene (670 mg, 3.1 mmol) by syringe and the reaction was allowed to stir for 16 hours before being diluted with ethyl acetate and washed with brine. The crude material was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) to afford 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (437 mg, 56% yield).
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C1(CCCCOCCC=O)C=CC=CC=1>>[F:1][C:2]([F:11])([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:3]=[O:4]
Reactant: OCC(F)(F)c1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: O=CC(F)(F)c1ccccc1

Procedure:
Obtained from Intermediate 6 (1.0 g, 6.3 mmol) by the procedure described for the Intermediate 13. The title compound was obtained (0.88 g, 86%) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][C@H:19]([CH3:23])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:26])[C@H:19]([CH3:23])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 108d (300 mg, 0.8 mmol) in methanol (8 mL) was added two drops of acetic acid, 30% formaldehyde solution (0.5 mL), and sodium triacetoxyborohydride (354 mg, 1.6 mmol) at room temperature. Then the mixture was stirred at room temperature for 1 h. At the end of reaction, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 108e as a brown solid (280 mg, 90%). LCMS: [M+H]+ 392
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[CH2:21][CH2:20][CH2:19]2>CCOCC.Cl>[F:8][CH:2]([F:1])[C:3](=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=2)[C:22]1=[O:26])[OH:5]
Reactant: CCOC(=O)C(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(=C(O)C(F)F)C2=O
Temperature: 25 °C

Procedure:
A 500 mL one neck round bottomed flask equipped with a nitrogen inlet and provisions for magnetic stirring was charged with ethyl difluoroacetate (6.2 g, 50 mmol) and 75 mL of ether. To this solution was added 12 mL of 25% sodium methoxide in methanol (52.5 mmol). A solution of 6-methoxy-1-tetralone (8.81 g, 50 mmol) in 125 mL of ether was added over about 1 minute. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 150 mL of 1N HCl. The phases were separated and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-[2,2-difluoro-1-hydroxyethylidene]-3,4-dihydro-6-methoxy-1(2H)-naphthalenone (also known as 6-methoxy-2-difluoroacetyl-1-tetralone) formed which were isolated by filtration and air dried (10.8 g, 85%): mp 52°-54° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH3:25])([CH3:22])[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:26]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[CH3:25][O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:26]=[C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2
Reactant: COCC1(C)CCCOc2cc(C#Cc3ccc(C(=O)OC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCC1(C)CCCOc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 42 h
Yield: 98 %

Procedure:
20.06 g (55.04 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 100 ml of THF/ethanol (1/1) and treated with 8.81 g (4 eq.) of NaOH, dissolved in 50 ml of water. The reaction flask was kept in the dark and stirring continued for 42 h at room temperature. The mixture was then poured onto crushed ice/60 ml of 25% HCl, extracted twice with ethylacetate; the organic phase was washed with a small amount of water, dried over sodium sulfate, filtrated, and evaporated to dryness. Crystallization from hexane/ethylacetate yielded 18.90 g of the title product as pale yellow crystals of m.p. 205-206° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)[S:9][CH:10]=1)=O)C.C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[N:21]1
Reactant: CCOC(=O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Reaction time: 19 h
Yield: 45.9 %

Procedure:
Compound 169 (0.04 g, 0.10 mmol) was dissolved in THF (1.0 mL) and methylene chloride (1.0 mL) and after cooling to −78° C., diisobutylaluminum hydride (0.95 mol/L toluene solution, 0.65 mL, 0.62 mmol) was added and stirred in a temperature between −78° C. to room temperature for 19 hours. Saturated aqueous Rochelle salt solution was added to the mixture and the organic layer was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1). Then, the mixture was triturated in ethanol to obtain Compound 173 (16 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCc1c(Cl)cccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCCc2c(Cl)cccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Using the extreme-dilution technique described by Hedden and Brown, J. Am. Chem. Soc., 75, 3744-48 (1953), 4-(3-chloro-[1,1'-biphenyl]-2-yl)butanoic acid chloride (18.9 g, 0.069 mole) was diluted in carbon disulfide (100 ml) and placed in the dropping funnel. The dilution flask was filled with carbon disulfide (approximately 700 ml). Aluminum chloride (19.8 g, 0.15 mole) in carbon disulfide (700 ml) was placed in the reaction flask and heated at reflux. The contents of the dropping funnel were added to the reaction during an eight day period. After complete addition the contents of the dilution flask were added to the reaction flask and the mixture allowed to stir at room temperature for approximately 18 hours. One liter of 2 N hydrochloric acid was added to the mixture and the total stirred for 0.5 hour. The mixture was poured into a separatory funnel and the organic phase separated. The remaining aqueous phase was saturated with sodium chloride and extracted with methylene chloride (3×250 ml). The organic phase and extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield an oil. The oil was subjected to column chromatography on silica gel eluted with toluene:methylene chloride (1:1). The fractions which contained the desired product were combined and evaporated under reduced pressure to give a solid. The solid was recrystallized from methylcyclohexane:n-heptane (30:70) to yield 9-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-5-one (m.p. 117.5°-118.5°). The solvent was evaporated from the mother liquor to give an oil. This oil was subjected to column chromatography on silica gel eluted with n-heptane:ethyl acetate (40:1). The fractions which contained the desired product were combined and evaporated under reduced pressure to give additional product.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:23][CH:24]([CH3:29])[C:25](=[O:28])[NH:26][N:27]=3)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:30][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][NH:8][C:3](=[O:4])[CH3:2])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][C@@H:24]([CH3:29])[C:25](=[O:28])[NH:26][N:27]=1
Reactant: CC1SC(c2ccc(N3CC(CN)OC3=O)cc2F)=NNC1=O
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)[C@H](C)S3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
2-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-6-methyl-4H-[1,3,4]thiadiazin-5-one, trifluoroacetate salt is dissolved in pyridine (2 ml) and acetic anhydride (0.0163 ml, 0.173 mmol) is added. The reaction is stirred at room temperature for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give pure product as a white solid (0.046 g, 76%); 1HNMR (300 MHz, DMSO-d6) δ 1.34 (d, J=7.1 Hz, 3H), 1.82 (s, 3H), 3.41 (t, J=5.5, 2H), 3.71-3.82 (m, 2H), 4.14 (t, J=9.3 Hz, 1H), 4.71-4.79 (m, 1H), 7.41 (dd, J=1.9, 8.8 Hz, 1H), 7.58 (dd, J=1.7, 14, 1H), 7.68 (t, J=8.5, 1H), 8.25 (t, J=5.5 Hz, 1H), 11.7 (s, 1H); mp 200-2; MS (m/z): [M+H]+=381.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([CH:11]([OH:14])[C:12]#[CH:13])=[C:4]2[CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([C:11](=[O:14])[C:12]#[CH:13])=[C:4]2[CH:3]=1
Reactant: C#CC(O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Yield: 101.5 %

Procedure:
1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (1.05 g, 3.14 mmol) in chloroform (100 mL) was treated with manganese dioxide (6.82 g, 78.5 mmol) as described in Example 12 to give 1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.99 g, 100%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.50 (d, 1H), 8.46 (d, 1H), 7.64 (d, 2H), 7.04 (dd, 1H), 6.98 (d, 2H), 3.87 (s, 3H), 2.99 (s, 1H); MS m/z 295 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])=[O:16].[K+].C(=O)(O)[O-].[Na+]>CCO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][OH:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: O=C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)CO)cc1
Temperature: 38 °C
Reaction time: 22 h
Yield: 95.2 %

Procedure:
To a suspension of 4′-acetamido-2-bromoacetophenone 3 (10.0 g, 39 mmol) in EtOH (800 mL), aqueous potassium formate (35.4 g in 200 mL) was added then followed by sodium bicarbonate (3.68 g). The mixture was stirred at 38° C. (inner temp.) for 22 h. The mixture was evaporated in vacuo until the total volume reached to ca. 300 mL The mixture was diluted with ethyl acetate (1200 mL), washed with water (200 mL), then brine (2×400 mL). Aqueous layers were extracted with ethyl acetate (800 mL then 400 mL). Combined organic layer was dried over anhydrous sodium sulfate and then evaporated in vacuo to give crude 4 as a solid (7.17 g, 95%) which was used to the next step without any purification. MS(ES) m/e 194 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.Cl.[CH2:21](O)[CH3:22]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([O:18][CH2:21][CH3:22])=[O:17])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(N)cc2c(=O)n2nc(C(=O)O)cc12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc2n(C)c3ccc(N)cc3c(=O)n2n1
Yield: 81 %

Procedure:
A mixture of 7-amino-4,9-dihydro-4-methyl-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid (8.03 g, 31.10 mmol, Example 1) in 600 mL of ethanol was saturated with hydrogen chloride gas for 20 minutes. The mixture was then refluxed for 12 hours, cooled, concentrated (to remove most of the ethanol), and partitioned between saturated sodium bicarbonate solution and chloroform (500 mL of each). Some solid would not dissolve into either phase. The mixture was filtered, giving 7.19 g (81%) of the title compound as a yellow solid, mp 258°-260° C., dec. The chloroform extract did contain more product, although not as clean.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([O:31][CH:32]([CH3:34])[CH3:33])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:35])[CH:5]([O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][C:8]1[CH:9]=[C:10]([CH3:30])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[O:21][C:22]=2[CH3:23])=[C:12]([CH3:14])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(OC(C)C)C(O)c1cc(C)c(OCCc2nc(C3CCCCC3)oc2C)c(C)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(C3CCCCC3)oc2C)c(C)c1)OC(C)C
Reaction time: 32 h
Yield: 99.5 %

Procedure:
0.189 g of the above prepared 3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dimethyl-phenyl}-3-hydroxy-2-isopropoxy-propionic acid ethyl ester (0.388 mmol) was dissolved in 1.5 ml of trifluoroacetic acid, treated at 0° with 0.620 ml of triethylsilane (10 eq.) and then kept for 32 h at RT under vigorous stirring. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water (pH of aq. Phase ˜9), dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) produced 0.182 g of the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 85.3 %

Procedure:
1 g of bis-(triphenylphosphine)-palladium(II) chloride, 3.8 g of copper(I) iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. This mixture was refluxed, after which 43.4 g of 3-butynol were added dropwise at this temperature (about 100° C.) in the course of 20 minutes. The mixture was stirred for a further 5 hours at this temperature. After the mixture had cooled, the triethylamine was distilled off. The residue was taken up in methyl tert-butyl ether and water. The aqueous phase was extracted twice with methyl tert-butyl ether, and the combined organic extracts were washed in succession with 1N hydrochloric acid and with 10% strength sodium bicarbonate solution, dried over sodium sulfate and evaporated down in a rotary evaporator. Distillation under greatly reduced pressure gave 80 g (86%) of the desired compound. 5-Aminooxy-1-(4-fluorophenyl)-1-pentyne (Example 2.6) N-(5-(4-Fluorophenyl)-4-pentynyloxy)-phthalimide (Example 1.10)