Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](Cl)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N2CCC(O)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 5-((tert-butyldimethylsilyloxy)methyl)-2-chloropyridine (650 mg, 2.5 mmol) in toluene (20 mL) was degassed with argon for 5 min, followed by adding piperidin-4-ol (303 mg, 3 mmol), t-BuOK (426 mg, 3.8 mmol), Pd2(dba)3 (23 mg, 0.0025 mmol) and BINAP (31 mg, 0.05 mmol). The resulting mixture was stirred at 90□ overnight under argon atmosphere. After cooling to rt, solid was removed by filtration and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc (50 mL) and the mixture was washed with brine (50 mL), dried and concentrated to yield the desired product as dark oil (620 mg, 76%). [LCMS: RtA=1.59 min, m/z 323.2 [M+H]+].
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C.S(Cl)([Cl:33])(=O)=O>C(Cl)Cl>[Cl:33][C:19]1[CH:18]=[C:17]([O:16][C:15]([F:24])([F:25])[F:14])[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
0.05 part by weight of diphenyl sulfide is added to a solution of 8.9 parts by weight of 4-trifluoromethoxyphenol in 30 parts by weight of glacial acetic acid, and 6.8 parts by weight of sulfuryl chloride are then added dropwise, without cooling. The mixture is subsequently stirred at room temperature for 3 hours, the solvent is stripped off and the residue is taken up in 50 parts by weight of methylene chloride. This solution is twice washed with 50 parts by weight of saturated bicarbonate solution, and is dried and concentrated. Distillation of the residue under reduced pressure gives 9.8 parts by weight (92% of theory) of 2-chloro-4-trifluoromethoxyphenol of boiling point 70° C./13 mbar.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CN1C(=O)CCC1>[C:13]([C:12]1[C:11]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[N:18][CH:17]=[CH:16][CH:15]=1)#[N:14]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1cccnc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncccc3C#N)CC2)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
50 μL (0.29 mmol) DIPEA are added to a mixture of 14 mg (0.10 mmol) 2-chloronicotinnitrile and 29 mg (0.11 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 1.45 mL NMP. The mixture is stirred at 130° C. overnight. Subsequently the solvent is removed in vacuo, the residue is taken up in DMF and the mixture is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][C:24]=1[Cl:25].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:16][CH:17]=1)=[O:3]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C1NC(=O)C(=Cc2ccc(C(=O)O)cc2)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2ccc(C(=O)Oc3ccc(Cl)c(Cl)c3)cc2)S1
Reaction time: 16 h

Procedure:
5-(4-Carboxybenzylidene)thiazolidine-2,4-dione (from Example 8, Step A) was dissolved in SO2Cl2 followed by addition of 1-2 drops of DMF. This resulting mixture was heated to ˜80° C. for 15-30 min at which time the reaction was concentrated under reduced pressure. The residue was dissolved in THF and added drop wise to a solution of 3,4-dichlorophenol (1.5 eq) and TEA (2 eq). This resulting mixture was stirred for additional 1-2 h at which time the solid in the reaction mixture was filtered off. The filtrate was concentrated under reduced pressure to yield solid that was washed with water and ether to afford pure ester. Alternatively, to a solution of 5-(4-carboxybenzylidene)thiazolidine-2,4-dione (1 eq) and 3,4-dichlorophenol (1 eq) in CH2Cl2 was added DCC (1 eq). The resulting reaction mixture was stirred for 16 h at which time the reaction was filtered, the filtrate was washed with water and concentrated under reduced pressure to provide crude product that was purified by recystallization.
Reaction SMILES: BrC1C(NC(=O)C(=O)CC(C)(C2C=CC=CC=2)C)=CC=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:33](=[O:34])[O:32][CH2:31]2.[I:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[CH2:46][C:47](=[O:51])[C:48](O)=[O:49])=[C:41]([O:54][CH3:55])[CH:40]=1>>[I:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[CH2:46][C:47](=[O:51])[C:48]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:33](=[O:34])[O:32][CH2:31]3)=[O:49])=[C:41]([O:54][CH3:55])[CH:40]=1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Agent: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Product: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid as a foam.
Reaction SMILES: [CH:1]([NH:5][CH:6]1[CH:11]([N+:12]([O-])=O)[C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])=[CH:9][CH:8]=[N:7]1)([CH2:3][CH3:4])[CH3:2].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>C1(C)C=CC=CC=1>[CH:1]([N:5]1[C:26](=[O:30])[C:27]([CH3:29])=[N:12][C:11]2[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=3[Cl:25])=[CH:9][CH:8]=[N:7][C:6]1=2)([CH2:3][CH3:4])[CH3:2]
Reactant: COC(=O)C(C)=O
Reactant: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
Sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine (0.145 g, 0.43 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (77 μL, 0.86 mmol) and heated to reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC giving 4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 113): 1H NMR (300 MHz, CDCl3) δ 8.53–8.52 (d, 1H, J=4.8 Hz), 7.35–7.32 (m, 2H), 7.19–7.13 (m, 2H), 6.85–6.36 (t, 1H, J=73.2 Hz), 2.47 (s, 3H), 2.40–2.20 (m, 1H), 2.10–2.07 (m,1H), 1.65–1.63 (d, 3H, J=6.9 Hz), 0.89–0.84 (t, 3H, J=3.7). MS(AP) m/z 394.2 [(M+H)+, 100], 435.3 [(M+H+CH3CN)+, 10].
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.B.[Na]>C(O)C.CO.O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: OC1CCOc2ccccc21

Procedure:
The compound 3 is reduced using a reducing agent such as sodium boron hydride in a solvent such as methanol, ethanol and tetrahydrofuran, preferably in an alcohol solvent such as methanol and ethanol, under cooling to room temperature to give 4-chromanol (compound 4 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1I)(=[O:8])[CH3:7].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].C([O-])(=O)C.[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[O:21])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(Cl)cc1I
Reactant: C=CC(=O)OC
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1cc(Cl)ccc1NC(C)=O
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a 200-ml flask were successively charged 40 ml of N,N-dimethylformamide (hereinafter abbreviated as DMF), 20 g (0.0677 mole) of 2-acetylamino-5-chloroiodobenzene, 5.94 g (0.069 mole) of methyl acrylate, 6.94 g (0.0846 mole) of anhydrous sodium acetate, 10 mg of palladium chloride and 30 mg of triphenylphosphine in this order. This mixture was stirred at 130° to 135° C. for 3 hours and poured into 200 ml of water, and then a large amount of crystal precipitated. This crystal was filtered off, thoroughly washed with water and dried in vacuo to obtain 14.1 g of methyl 2-acetylamino-5-chlorocinnamate. The yield was 82.2% of the theoretical value, and the melting point was 172° to 174° C. The nuclear magnetic resonance spectrum (1H-NMR) and infrared absorption spectrum (IR) of this compound were as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: ClCc1ccccn1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccn2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (35.0 mg, 0.074 mmol), 2-(chloromethyl)pyridine (13.3 mg, 0.082 mmol, 1.05 equiv), and cesium carbonate (72.3 mg, 0.22 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 35.2 mg (77%). Mass spec.: 563.3 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH3:26].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:26])[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: COCCN(C)C(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
(E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.18 g, 0.67 mmol) obtained in Step 6 of Example 1 was dissolved in THF (4 mL), and the solution was added with N-(2-methoxyethyl)methylamine (0.11 mL, 1.00 mmol), 1-hydroxybenzotriazole monohydrate (0.12 g, 0.85 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g, 0.92 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with a saturated aqueous sodium hydrogencarbonate solution, was extracted with ethyl acetate, the organic layer was sequentially washed with water and saturated brine, was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=25/1) to obtain Compound 5 (0.22 g, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[OH-].[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[C:22]1([CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH:11]=[CH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccn1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
A sample of a 42.4 g (0.4 mole) of pyridine-2-carboxaldehyde was added to a solution of 83.6 mL of 10% sodium hydroxide and 100 mL of DMF at 10° C. Then a solution of 47.2 g (0.21 mole) of 4-benzyloxyacetophenone in 300 mL of DMF was added slowly over a period of 1 hr to the mixture keeping the temperature of the reaction mixture at 5°-13° C. After 1.5 hr, the reaction mixture was allowed to warm to room temperature. Water was added, and the product precipitated out as a solid. The solid was crystallized from 95% ethanol to give 48.2 g (73% yield) of the title compound as a yellow solid, mp=131°-134° C. An additional 3.3 g (5% yield) of the product was obtained from the mother liquor, mp=131°-134° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[N:22]1([C:2]2[CH:3]=[C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: c1cc[nH]c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-n3cccc3)c2)cc1
Temperature: 100 °C
Yield: 7.3 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (0.80 g, 2.3 mmol), pyrrole (0.17 g, 2.5 mmol), tri-tert-butylphosphine (19 mg, 0.092 mmol) and cesium carbonate (1.3 g, 3.9 mmol) were dissolved in toluene (25 mL) and, after argon substitution, tris(dibenzylidenacetone)dipalladium(0) (84 mg, 0.092 mmol) was added. The reaction mixture was heated under an argon atmosphere at 100° C. for 18 hrs. The reaction mixture was cooled, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15:1) to give the title compound (56 mg, yield 7%) as a yellow powder.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cc(F)ccn2)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cc(F)ccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(4-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 78) (36 mg, 0.069 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 2.5 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.06 mmol, 0.09 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(4-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (23 mg, 0.043 mmol, 62%) as a pale brown solid.
Reaction SMILES: NCC1C=C(O)C(C2C=CC=CC=2)=CC=1.[N:16]([CH2:19][C:20]1[CH:21]=[C:22]([OH:33])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[N+]=[N-]>>[NH2:16][CH2:19][C:20]1[CH:21]=[C:22]([OH:33])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccc(F)cc2)c(O)c1
Agent: NCc1ccc(-c2ccccc2)c(O)c1
Product: NCc1ccc(-c2ccc(F)cc2)c(O)c1
Yield: 54 %

Procedure:
Following the same procedure for the preparation of 4-Aminomethyl-biphenyl-2-ol, the title compound is prepared from 4-Azidomethyl-4′-fluoro-biphenyl-2-ol (crude material from the previous step) in 54% yield (over 4 steps). MS (ESI): 218 (M+1)+1.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[H-].[Na+].CN(C)C=O.Cl[CH2:38][C:39](=[O:41])[CH3:40]>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:38][C:39](=[O:41])[CH3:40])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (3 g), sodium hydride (0.47 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-chloropropan-2-one (0.75 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 14%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[O:10][CH:11]=[CH:12][C:13]=1[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16].O1CCOCC1.[C:25](Cl)([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26]>C([O-])([O-])=O.[Na+].[Na+].O>[C:25]([NH:8][C:9]1[O:10][CH:11]=[CH:12][C:13]=1[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16])([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](C(=O)O)c1ccoc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](C(=O)O)c1ccoc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-2-amino-3-furylpropionic acid trifluoroacetic acid salt (0.47 g) was dissolved in 30 mL of 10% Na2CO3 and 5 mL of dioxane and was cooled to 0 C. A solution of FMOC-Cl (0.53 g) in 10 mL was added dropwise. The mixture was then stirred for 15 min. at 0° C. and 2 hr at room temperature. The mixture was diluted with H2O, extracted with diethyl ether, and acidified with citric acid. The mixture was filtered and washed with H2O until neutral. The solid was then dissolved in ethylacetate, dried over Na2SO4, concentrated in vacuo to give the product as a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1.[F-].[K+]>C(Cl)Cl>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][C:14]=1[CH3:19])([O-:10])=[O:9]
Reactant: Cc1cc(Br)ccc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
A mixture of 2.9 ml (27.5 mmol) of 2-fluoro-nitrobenzene, 10.55 g (55 mmol) of 4-bromo-2-methyl-aniline and 1.60 g (27.5 mmol) of spray-dried potassium fluoride is heated to 180° C. After cooling the reaction mixture is taken up in methylene chloride, washed with H2O, with 10% hydrochloric acid and again with H2O, dried with Na2SO4, concentrated and purified by flash chromatography (silica gel; petroleum ether/ethyl acetate=75:25).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)O1.CCOCC>O.C1COCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[F:9]
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Reactant: Fc1cc(I)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1ccc(-c2ccc(Br)c(F)c2)cc1

Procedure:
18 g (65 mmol) of sodium metaborate octahydrate and 2.8 g (3.9 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 200 ml of water and 100 ml of THF, 1-bromo-2-fluoro-4-iodobenzene are added, and a solution of 21.5 g (0.082 mol) of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-1-ol in 100 ml THF is subsequently added dropwise. The batch is heated under reflux overnight, taken up in MTB ether and washed three times with water. The org. phase is dried over sodium sulfate, and the solvent is removed in vacuo. Chromatography of the crude product on silica gel with toluene/ethyl acetate (7:1) gives 3-(4′-bromo-3′-fluorobiphenyl-4-yl)propan-1-ol as a colourless oil.
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>O>[CH3:13][CH:14]1[CH2:18][CH2:17][C:16](=[CH:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[C:15]1=[O:19]
Reactant: CC1CCCC1=O
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C=C2CCC(C)C2=O)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 2.8 g of 85% strength potassium hydroxide and 250 ml of water was charged to a stirred 3-necked flask apparatus with reflux condenser, 68 g of p-anisaldehyde and 49 g of 2-methylcyclopentanone were added, and the mixture was boiled under reflux for 3 hours. It was subsequently cooled to room temperature and the yellow solid which had crystallized out was filtered off with suction, washed to neutrality with water and dried in a vacuum oven at 60° C. In this way 98.3 g of 2-methyl-5-(4-methoxybenzylidene)-cyclopentanone (93.2% pure) were obtained. This corresponds to a yield of 85% of theory.