Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[S:9][C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23](Br)([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.[Ag-]=O>[C:23]([O:1][CH:2]([C:8]1[S:9][C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)Br
Reactant: CCOC(=O)C(O)c1sc2ccccc2c1-c1ccccc1
Agent: O=[Ag-]
Solvent: C1CCCCC1
Product: CCOC(=O)C(OC(C)(C)C)c1sc2ccccc2c1-c1ccccc1
Reaction time: 48 h
Yield: 11 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(3-phenyl-1-benzothiophen-2-yl)acetate (3b) (340 mg, 1.09 mmol), silver (I) oxide (758 mg, 3.27 mmol) and tertbutylbromide (612 μL, 5.45 mmol) in cyclohexane (20 mL) was vigorously stirred for 48 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (3c) as a white solid (45 mg, 0.12 mmol, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1ccc2c(c1)CCNC2
Product: COc1ccc2c(c1)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (CA [42923-77-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17][O:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][CH2:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:21]=[CH2:22])[C:3]1=[O:20]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O

Procedure:
94 g (277 mmol) of the compound from Example 28A are dissolved in 1.2 l of anhydrous dioxane, and 8 g (6.9 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. At room temperature, 105 g (333 mmol) of tributylvinyltin are added slowly, and after the addition has ended, the mixture is heated at reflux for 21 h. The reaction solution is allowed to cool and filtered through kieselguhr. The filter cake is washed with ethyl acetate and the combined organic filtrates are concentrated to dryness under reduced pressure. The residue that remains is dissolved in dichloromethane and applied to kieselguhr. The product is chromatographed on 1.2 kg of silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 23 g (29% of theory) of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH2:25][CH3:26].CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][C:19]=1[CH2:25][CH3:26]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Cl
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-3-ethylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[NH2:19][C:20]([NH2:22])=[S:21].O>C(O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:19]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 65.7 %

Procedure:
A solution of 31.1 g (0.096 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide in 130 ml of absolute ethanol was carefully mixed with 8.4 g (0.11 mole) of thiourea. As the thiourea dissolved, the temperature of the solution increased from 23° to 38°. After the exothermic reaction had subsided, the solution was refluxed for four hours and poured into 130 ml of water. A small quantity of insoluble material was removed by filtration and the filtrate was made basic (pH 9) with ammonium hydroxide. Stirring and cooling yielded a crystalline solid which was collected. There was obtained 19 g (65.7%) of dry product, m.p. 116°-18°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 3.4 (CH2), 6.3 hetero-aromatic), 6.8 (NH2), 7.3-8.0 (aromatic), 10.3 (HNC=O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[O:20][CH3:21])[C:9]#[N:10])=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])=[C:12]([O:20][CH3:21])[CH:13]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1C(C#N)c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: COc1cc(N)ccc1C(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of 8.1 parts of α-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile. 2 parts of a solution of thiophene in methanol 4% and 200 parts of methanol is hydroqenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is stirred in a small amount of 2-propanol. The product is filtered off and dried, yielding 4-amino-α-(4-chlorophenyl)-2-methoxybenzeneacetonitrile.
Reaction SMILES: CI.[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[S:10].[CH3:11]CO>CC(C)=O>[CH3:11][S:10][C:4]1[NH:3][CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1
Reactant: CCO
Reactant: S=C1NCCCCN1
Solvent: CI
Solvent: CC(C)=O
Product: CSC1=NCCCCN1
Temperature: 25 °C
Yield: 86 %

Procedure:
Methyl iodide (0.55 ml, 1.15 mmol) was added to a solution of 1,3-diazepane-2-thione (1.00 g, 7.68 mmol) in acetone (8 ml). The reaction mixture was refluxed for 15 min. EtOH was added to the hot solution to dissolve the solids. After cooling to r.t. hex. was added and the precipitate was collected by filtration, washed with hex. and dried to give 1.79 g (86%) crude title compound which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>CN1CCCC1=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: CCCCN
Reactant: Fc1cc(Br)ccn1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCCCNc1cc(Br)ccn1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of 4-bromo-2-fluoropyridine (2.0 g, 11.3 mmol) and n-butan-1-amine (752 mg, 10.3 mmol) in N-methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at 100° C. for 1 hr. The reaction was allowed to cool to room temperature and diluted with DCM (50 mL), washed with water (10 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-20% EtOAc-petroleum ether gradient elution) to afford the desired product (1.4 g, 45%). 1H NMR (300 MHz, CDCl3): 7.88 (d, J=5.4 Hz, 1H), 6.70 (d, J=5.4 Hz, 1H), 6.54 (s, 1H), 4.60 (br s, 1H), 3.26-3.19 (m, 2H), 1.63-1.56 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t, J=7.2 Hz, 3H). (R)-tert-butyl 1-(2-(butylamino)pyridin-4-yl)pyrrolidin-3-ylcarbamate. To a solution of 4-bromo-N-butylpyridin-2-amine (458 mg, 2 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (410 mg, 2.2 mmol) in anhydrous dioxane (12 mL) was added Pd2(dba)3 (200 mg, 0.22 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xant-phos) (200 mg, 0.24 mmol) and t-BuONa (576 mg, 6 mmol) under atmosphere of argen. The resulting reaction was stirred at 100° C. for 2 hrs and diluted with water (40 mL), extracted with DCM, The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH-DCM gradient elution) to afford the crude product (purity>70%). (R)-4-(3-aminopyrrolidin-1-yl)-N-butylpyridin-2-amine dihydrochloride. Crude product obtained above was dissolved in MeOH (6 mL) and ether solution of HCl gas (ca. 4N, 10 mL) was added. The resulting reaction was stirred at ambient temperature for 20 hrs. The reaction was concentrated under reduced pressure and purified by prep-HPLC to afford the desired product (50 mg, 6.7% yield in two steps). 1H NMR (300 MHz, CD3OD): 7.59 (d, J=7.5 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H), 5.79 (s, 1H), 4.89 (m, 1H), 4.15 (m, 1H), 3.74-3.66 (m, 3H), 3.38-3.29 (m, 2H), 2.60-2.53 (m, 1H), 2.34-2.30 (m, 1H), 1.73-1.64 (m, 2H), 1.56-1.46 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); LC-MS: m/z=235.2 [M+H]+, tR=0.92 min; HPLC: 100% (214 nm), 97% (254 nm), tR=4.84 min. The compounds in Example 255 through Example 297 were prepared using methods analogous to those described in Example 254.
Reaction SMILES: [OH:1][C:2]([P:13]([OH:16])([OH:15])=[O:14])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:3]([OH:5])=[O:4]>[Pd].O>[OH:1][C:2]([P:13]([OH:15])([OH:16])=[O:14])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(O)(Cc1ccccn1)P(=O)(O)O
Agent: [Pd]
Solvent: O
Product: O=C(O)C(O)(CC1CCCCN1)P(=O)(O)O
Reaction time: 48 h

Procedure:
A mixture of 1 g of 2-hydroxy-2-phosphono-3-(2-pyridinyl)propanoic acid and 0.5 g of palladium on charcoal catalyst in 50 ml of distilled water is hydrogenated on a Parr apparatus at 40 PSI for about 2 days. The catalyst is removed by filtration, and the filtrate is concentrated to a few mls. Ethanol is added slowly to precipitate a solid, which is recrystallized from water/ethanol to afford 2-hydroxy-3-(2-piperidinyl)-2-phosphonopropanoic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=C)=[CH:7][CH:6]=1.[OH:13]C1C=CC(C=O)=CC=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:13])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OCCO)cc1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCCO)cc1

Procedure:
Woods et al. (U.S. Pat. No. 5,019,629) describe a two-step procedure for preparing p-(2-hydroxyethoxy)styrene starting with p-hydroxybenzaldehyde. In the first step, p-(2-hydroxyethoxy)benzaldehyde is formed by reacting p-hydroxybenzaldehyde with ethylene carbonate in the presence of potassium carbonate. In the second step, p-(2-hydroxyethoxy)styrene is formed by reacting the isolated p-(2-hydroxyethoxy)benzaldehyde with methyltriphenylphosphonium bromide in the presence of sodium amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:19][C:18]1[C:10]([NH:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NCc1ccccc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1cccc(C(=O)O)c1NCc1ccccc1Cl
Yield: 85 %

Procedure:
2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid (22 g, 72 mmol) was reduced with sodium hydrosulfite by the method described in Example 2(ii) to provide 3-amino-2-[(2-chlorophenyl)methyl]aminobenzoic acid in 85% yield; mp 203°-204° C. This amine was acylated with excess valeryl chloride in the presence of excess 10% sodium hydroxide solution and toluene. The resulting valeryl derivative was heated in acetic acid and hydrochloric acid according to the procedure described in Method A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([Cl:24])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Cc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
4-chloro-4'-ethane sulfonylmethylbenzhydrol (6.0 g), thionyl chloride (5.4 g), toluene (200 ml) and a catalytic amount of N,N-dimethylformamide were mixed and gradually heated with stirring to a refluxing temperature. The mixture was stirred for 4 hours under reflux and then left to cool. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as a slight yellow viscous substance (4.6 g, nD20 : 1.6044, yield: 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:16][Si:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[C:26](B(O)O)=[CH:25][CH:24]=[N:23]1.O.CCOC(C)=O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][Si:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[C:26]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:25][CH:24]=[N:23]1
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: Oc1ccc(Oc2ccc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc(O)cc2)nc1
Temperature: 100 °C

Procedure:
A suspension of Intermediate E (6.0 g, 23 mmol) and 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-5-boronic acid (SM-2) (6.6 g, 27 mmol) in a mixture of DME (60 mL) and 2N aqueous Na2CO3 (33 mL) is sparged with Argon for 30 minutes. The mixture is treated with tetrakis(triphenylphosphine)palladium(0) (2.6 g, 2 mmol) and heated to 100° C. for 16 hours. The solution is cooled, poured into water/EtOAc, and the organic layer is collected. The aqueous layer is extracted twice with EtOAc, and the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified on SiO2 (EtOAc/heptanes) to provide F.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[NH:23][N:22]=1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:8][CH:9]=2)[N:22]=1)=[O:20])[CH3:17]
Reactant: CCCc1cc(C(=O)OCC)n[nH]1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the recovered intermediate (19a) (1.4 g, 5 mmol, 1.0 eq) dissolved into 15 mL DMF, was added 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (910 mg, 5.0 mmol, 1.0 eq) and potassium carbonate (0.8 g, 5.5 mmol, 1.1 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was then added to 50 mL of 10% aq. LiCi solution and extracted with 50 mL EtOAc. The organic was dried over MgSO4, and concentrated under reduced pressure to yield intermediate (19b) and its regioisomer in a 1:1 ratio. The recovered regioisomers were dissolved into 25 mL MeOH. To this was added 10 mL of 1M NaOH and the mixture was stirred at room temperature over night. The mixture was acidified with acetic acid and concentrated under reduced pressure. The recovered oil was purified by preparatory HPLC, producing the desired regioisomer of the title compound as a white solid TFA salt after lyophilization (230 mg). 1H NMR (DMSO) 0.89 (t, 3H), 1.52 (s, 9H), 5.71 (s, 2H), 6.71 (s, 1H), 7.15 (d, 2H), 7.83 (d, 2H), 13.28 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: Cn1cc(C=O)c2ccc(F)cc21
Yield: 94 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 6-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethyl indole-2-carboxylate, the title compound (0.3 g, 94%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:13]=2[OH:26])=O)=[CH:7][CH:6]=1)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[OH:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]2[O:26][C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][C:12]=3[N:11]=2)=[CH:7][CH:6]=1
Reactant: CCCCCCCCc1ccc(O)c(NC(=O)c2ccc(OC(C)=O)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCc1ccc2oc(-c3ccc(O)cc3)nc2c1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 200 ml-round-bottomed flask, 4.00 g (10.4 mM) of 2-(4-acetoxybenzoylamino)-4-octylphenol, 0.40 g of p-toluenesulfonic acid monohydrate and 40 ml of o-dichlorobenzene were placed, followed by stirring for 1 hour at 188°-192° C. After the reaction, odichlorobenzene in the reaction mixture was distilled off under reduced pressure. To the residue, 1.98 g (30.0 mM) of potassium hydroxide and 60 ml of ethanol was added and stirred for 1 hour on a water bath kept at about 75° C. After the reaction, ethanol in the reaction mixture was distilled off under reduced pressure. Water was added to the resultant residue, followed by addition of 6.0 ml (34.0 mM) of concentrated hydrochloric acid under stirring on an ice bath to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from ethanol to obtain 2.70 g of 2-(4-hydroxyphenyl)-5-octylbenzoxazole (Yield: 80.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=3)[C:10](=[O:22])[C:9]=2[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)=[O:32].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH:31]=[O:32])=[CH:17][CH:16]=3)[C:10](=[O:22])[C:9]=2[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3C=O)cc1)C2=O
Reaction time: 1 h
Yield: 84 %

Procedure:
Method A. A suspension 1-(4-methoxy-phenyl)-6-(4-iodo-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (55, 2.0 g, 3.87 mmol), 2-formylphenylboronic acid (13, 870 mg, 5.81 mmol, 1.5 equiv), and K2CO3 (1.60 g, 11.6 mmol, 3.0 equiv) in toluene (18 mL), ethanol (6 mL) and H2O (6 mL) at room temperature was degassed three times under a steady nitrogen stream before being treated with Pd(PPh3)4 (22 mg, 0.02 mmol, 5% equiv) at room temperature under N2. The reaction mixture was subsequently degassed three times again before being warmed to reflux for 12 h. When HPLC showed the Suzuki coupling reaction was complete, the reaction mixture was cooled down to 5–10° C. before being treated with water (20 mL) at 5–10° C. with good stirring. The mixture was stirred for an additional 1 h at 5–10° C. before the solids were collected by filtration. The wet cake was then thoroughly washed with water (2×30 mL) and 30% EtOAc/hexane (2×20 mL), dried in vacuo at 40–45° C. for 12 h to afford the crude desired 6-(2′-formyl-biphenyl-4-yl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (56, 1.61 g, 1.915 g theoretical, 84%) as off-white solids, which was found to be pure enough to do the following reaction without further purification. For 56, CIMS m/z 496 (M++H, C29H25N3O5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O>C(O)(=O)C.[Pd]>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH3:6])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C)cc(OC)c1OC

Procedure:
Synthesis, Volume 8 (1993), page 799 discloses hydrogenating 3,4,5-trimethoxybenzaldehyde, dissolved in acetic acid, in the presence of 10% palladium on activated carbon to give 3,4,5-trimethoxytoluene.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.BrC1C=CC=CC=1O>CCOCC.CCCCCC.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:4]1[C:3]2[C:8](=[CH:9][C:10]3[C:15]([CH:2]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Oc1ccccc1Br
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc2cc3ccccc3cc2c1
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
A solution of 9-bromoanthracene (0.67 g, 2.6 mmol, 1.2 eq) in dry Et2O (13 mL) under N2 was cooled to −30° C. and nBuli (1.6 M in hexane, 1.6 mL, 2.6 mmol, 1.2 eq) was added dropwise. The solution was stirred for 20 min. at −30° C. followed by dropwise addition of ZnCl2 (0.50 M in THF, 5.2 mL, 2.6 mmol, 1.2 eq). The reaction was stirred and warmed to RT over 30 min. The volatiles were removed under N2 purge and the residue was redissolved in 3:1 THF/NMP (11 mL). The MOM-protected bromophenol (2.2 mmol, 1.0 eq) and Pd(PtBu3)2 (22 mg, 44 μmol, 4 mol %) were added and the reaction was heated to 100° C. for 2 h. The reaction was cooled to RT and the THF was removed. The residue was diluted with CH2Cl2, washed with 1 M HCl, and dried over Na2SO4. The crude material was purified by flash chromatography.