Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Reactant: [H][H]
Product: CCCCCC1C(=O)CCC1CC(=O)OC

Procedure:
To a reactor (a volume of 50 ml) was respectively charged 1 g (4.5 mmol) of methyl (2-pentyl-3-keto-1-cyclopentenyl-)acetate (a compound in which R1 represents an n-pentyl group and R2 represents a methyl group in the above formula (1)) and 0.2 g of each catalyst shown in Table 1. Thereto was respectively added 10 ml of a solvent shown in Table 1, and the mixture was held at a temperature shown in Table 1. Pressure reduction and hydrogen introduction were repeated while stirring the mixture, and the air in the reactor was replaced with hydrogen at ordinary pressure. The mixture was continuously stirred in this state for 4 hours. Subsequently, the catalyst was removed from the reaction mixture by filtration, and then thereto were added 30 ml of water and 30 ml of toluene followed by stirring to extract a product into the toluene phase. Toluene was distilled off from this toluene phase, yielding methyl dihydrojasmonate (a compound in which R3 represents an n-pentyl group and R4 represents a methyl group in the above formula (2)). The yield and isomer ratio (cis-isomer/trans-isomer) of the resulting methyl dihydrojasmonate were determined by gas chromatography. The results are shown in Table 1.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1.[Cl:28][C:29]1[S:33][C:32]([CH:34]=[O:35])=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[C:19]([CH:34]([C:32]2[S:33][C:29]([Cl:28])=[CH:30][CH:31]=2)[OH:35])[CH:18]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: Fc1ccc(Br)c2ccccc12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)s1)c1cc(Br)c2ccccc2c1F
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (1.04 g) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.58 M hexane solution, 4.43 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of 1-bromo-4-fluoronaphthalene (1.50 g) in tetrahydrofuran (12 ml) at −78° C. The mixture was stirred at the same temperature for one hour, and thereto was added dropwise a solution of 5-chloro-2-thiophenecarboxaldehyde (1.07 g) in tetrahydrofuran (11 ml) at −78° C. The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by an aminosilane-treated silica gel column chromatography (hexane:ethyl acetate=3:1) to give 4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol (2.00 g) as pale yellow powder. APCI-Mass m/Z 353/355 (M+H—H2O). (2) The above 4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol was treated in a manner similar to Reference Example 1-(2) to give the desired 4-bromo-2-(5-chloro-2-thienylmethyl)-1-fluoronaphthalene as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:22])[O:18][CH:19]([CH3:21])[CH3:20])[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]=1[O:10][CH2:11][CH3:12])([O-:3])=[O:2].I[CH3:24].[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:24][N:16]([C:6]1[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]([O:10][CH2:11][CH3:12])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:17](=[O:22])[O:18][CH:19]([CH3:20])[CH3:21]
Reactant: CI
Reactant: CCOc1cc(NC(=O)OC(C)C)cc([N+](=O)[O-])c1OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(N(C)C(=O)OC(C)C)cc([N+](=O)[O-])c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
Isopropyl N-(3-nitro-4,5-diethoxyphenyl)carbamate (3.12 g) and iodomethane (4.30 g) were dissolved in tetrahydrofuran (10 ml). The resultant solution was dropwise added to a tetrahydrofuran solution containing potassium hydroxide (1.68 g) and tetra-n-butylammonium bromide (1.0 g). After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-methyl-N-(3-nitro-4,5-diethoxyphenyl)carbamate (Compound No. 161) (2.92 g) in a yield of 89.5%. nD20.0 1.5075.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH3:19]>CO>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15](=[N:8][OH:9])[NH2:16])=[CH:13][C:12]=1[CH3:19]
Reactant: NO
Reactant: Cc1cc(C#N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(N)=NO)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Methanol (20 ml) at 5° C. was treated portionwise over 5 min. with stirring with potassium t-butoxide (1.68 g, 0.015 mole), then after a further 5 mins the solution was treated with hydroxylamine hydrochloride (1.11 g, 0.016 mole). The resulting mixture was allowed to warm to room temperature, stirred for 1 h, then treated with a solution of 4-bromo-3-methylbenzonitrile (2.0 g, 0.010 mole) in methanol (10 ml) and heated under reflux for 3 h. The mixture was allowed to cool, then filtered through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a white solid (1.56 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1.CN(C)C=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
To a mixture of chlorobenzene (170 L, 1684 mol), 3-chlorophenylacetic acid (50 Kg, 293 mol), and dimethylformamide (0.7 L, 9 mol) at 0° C. was added thionyl chloride (39.1 Kg, 329 mol) over the course of 30 min. The mixture was warmed to 15° C. and agitated for 6 h. The mixture was cooled to 0° C. and aluminum chloride (43 Kg, 322 mol) was added over the course of 1.5 h. The mixture was warmed to 20° C. and agitated for 15 h. Water (200 L) and ethanol (200 L) were added to the mixture and the biphasic mixture was agitated for 2 h. The phases were separated and the organic phase was washed twice with aqueous ethylenediaminetetraacetic acid tetrasodium salt (3 wt %, 200 L), and once with water (200 L). Heptane (1600 L) was added to the organic phases over the course of 15 minutes. The suspension was agitated for 30 minutes, cooled to −5° C., and filtered. The filtered material was dried at 40° C. for 20 h. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone was isolated in 83.6% yield (67.4 Kg).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:14][N:13]=[C:12]([CH:15]=[O:16])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.CCCCCCC>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:14][N:13]=[C:12]([CH:15]([OH:16])[CH3:19])[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Al](C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)no1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazole-3-carbaldehyde (1.74 g, 7.22 mmol) in CH2Cl2 (72.0 mL) was treated at 0° C. with trimethylaluminum (22.0 mL of a 1M solution in heptane, 22.0 mmol). The reaction mixture was then stirred at 0° C. for 50 min. CH2Cl2 (80.0 mL) followed by sat. aq. NH4Cl (80 mL) were then added. The mixture was then treated with 1N HCl (50 mL) and the aq. layer was extracted with CH2Cl2 (100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil: TLC:rf (7:3 hept-EA)=0.32. LC-MS-conditions 02: tR=1.01 min, [M+H]+=258.41.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(O[CH2:26][CH:27]=[C:28]([C:34]#[N:35])[C:29](OCC)=[O:30])C>CCO>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:29](=[O:30])[C:28]([C:34]#[N:35])=[C:27]([CH3:26])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CCOCC=C(C#N)C(=O)OCC
Solvent: CCO
Product: Cc1nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c(=O)c1C#N
Temperature: 25 °C
Yield: 44 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (14.16 g, 46 mMol) in EtOH (50 mL) was added Ethyl 2-ethoxyethylidene-cyanoacetate (8.4 g, 46 mMol). The reaction was refluxed for 18 h, cooled to RT and concentrated under vacuum. Purification by flash chromatography on silica gel (5% EtOAc, CH2Cl2) followed by crystallization from EtOAc, hexane and Et2O, pet. ether gave the title compound (8.03 g, 44%) as a white solid: MS (ES) m/e 397.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:27][N:8]([C:6]1[C:5]([CH3:28])=[CH:4][N:3]=[C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[N:7]=1)[CH:9]1[CH2:26][CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a suspension of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (211 mg, 0.52 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (160.3 mg, 1.20 mmol) in butan-1-ol (5 mL) was added DIPEA (201.63 mg, 1.56 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a white solid (176.87 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:19][CH3:20])[C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:19][CH3:20])[C@H:14]([C:16](=[O:18])[N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[CH3:22])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CNCCc1cccc(O)c1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]([C@@H](C)C(=O)N(C)CCc1cccc(O)c1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a stirred solution of (2S)-2-[(1R,2S)-2-carboxy-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.70 g, 5.6 mmol) in CH2Cl2 (20 mL) were added N-methyl-3-hydroxyphenethylamine hydrobromide (2.44 g, 11.2 mmol), BOP (3.72 g, 8.4 mmol), HOBT (1.29 g, 8.4 mmol), and diisopropylethylamine (4.88 mL, 28.0 mmol) at room temperature. After being stirred at room temperature for 2 hr, the mixture was quenched with 1N HCl (80 mL×3), extracted with AcOEt, dried (MgSO4) and concentrated in vacuo to give a crude oil (3.83 g), which was then purified by flash column chromatography (hexane:AcOEt=1:1) to give (2S)-2-((1R,2S)-2-{[2-(3-hydroxy-phenyl)-ethyl]-methyl-carbamoyl}-1-methylsulfanyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a gum (1.38 g, 56%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].Cl.C([N:18]=C=NCCCN(C)C)C.N.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:18])=[O:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C(=O)O)n1cc([N+](=O)[O-])cn1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoic acid (1.2 g) obtained in Step A of Example 109 in N,N-dimethylformamide (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 g) and 1-hydroxybenzotriazole ammonia salt (1.4 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16](OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.C([O-])(O)=O.[Na+]>CO.CC(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:16]2[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
A mixture of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.00 g, 11.0 mmol) and 5% Pd/C (400 mg) in MeOH (40 mL) was stirred under hydrogen atmosphere at ambient temperature for 8.5 hr and at 50° C. for 12 hr, filtered through a pad of celite, and concentrated. The precipitate was suspended in hexane and the suspension was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried (3.03 g). A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.00 g, 4.82 mmol) and the above solid (1.65 g, 7.23 mmol) in 2-propanol (10 mL) was stirred at reflux for 5 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (629 mg, 43%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH2:13]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:16]#[CH:17])[CH3:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O.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)I>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:14]#[C:13][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#C[Si](CC)(CC)CC
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[Si](C#Cc1ccc(C(=O)OC)cc1C)(CC)CC
Temperature: 25 °C

Procedure:
A solution of methyl 4-bromo-3-methylbenzoate (1.0 eq.), triethyl(ethynyl)silane (1.0 eq.), bis(triphenyl-phosphine)palladium chloride (10 mol %), copper iodide (10 mol %), and triethylamine (5.0 eq.) in DMF (0.04 M) was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give methyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>CCOCC>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][CH:10]4[C@@H:15]3[CH2:14][CH2:13][C@H:12]([OH:19])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12CCC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3C[C@@H](O)CC[C@@H]3[C@H]1CC2
Reaction time: 1 h

Procedure:
This synthesis is depicted in FIG. 11. A solution of the ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml) was added dropwise at RT. to a slurry of LiAlH4 (38 mg, 1 mmol) in ether (3 ml) (e). After 1 h, the mixture was hydrolyzed with 10% aq. H2SO4. After workup (ether), the crude product (802 mg, 9:1-mixture of 12 and 11) was chromatographed on silica gel with CH2Cl2. A small fraction of 11 (70 mg) was eluted first, followed by the main fraction of 12 (705 mg, 87%). M.p. 113-115°, [a]--+36.3° (C=1.0).--IR. (CHCl3): 3640 m, 3500 br., 1585 w.--1H-NMR. (90 MHz): 0.78 (s, 3 H); 3.60 (m, w1/2 ≈(m, 20, 1 H); 5.71 (m, 1 H), 5.87 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].Cl[CH2:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:20]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:20]=3[CH3:32])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C)c(-c4ccc(Cl)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 1 e], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 5-chloromethyl-3-(4-chloro-phenyl)-1,4-dimethyl-1H-pyrazole in the presence of cesium carbonate and potassium iodide in acetone to give {6-[5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([O:24]C3CCCC3)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:41])[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1
Reactant: CC(C)C[C@H](NC(=O)COc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)COc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
From Example 56. To a solution of cyclopentyl N-({4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenoxy}acetyl)-L-leucinate (35 mg, 0.06 mmol) in THF (1 ml) and water (1 ml) was added LiOH (30 mg, 1.24 mmol, 20 eq). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and water (5 ml) added. The pH was adjusted to 7 using 1M HCl and the aqueous layer extracted with 1-butanol (3×5 ml). The combined organic extracts were concentrated under reduced pressure. The solid residue was triturated with Et2O, filtered and dried under reduced pressure to provide the title compound as a cream solid (11 mg, 36% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13]Br>>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: Fc1ccccc1CCBr
Reactant: CCc1ccncc1
Product: CC(CCc1ccccc1F)c1ccncc1
Yield: 34.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.90 g (9.35 mmol) of 2-fluorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified, to obtain 0.74 g of desired compound (yield: 39.2%).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH:7]([F:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9].C1COCC1.O>CO>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([F:23])[C:6]([OH:24])=[O:5])=[CH:16][CH:15]=1
Reactant: COC(=O)C(F)C(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(F)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
LiOH.H2O (25 mg, 0.59 mmol) was added to a solution of N-biphenyl-4-yl-2-fluoro-malonamic acid methyl ester (114 mg, 0.39 mmol) in a mixture of methanol (0.5 mL), THF (1 mL) and H2O (0.3 mL). The resulting mixture was stirred for 2 hours at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 35 mg (32%) of N-biphenyl-4-yl-2-fluoro-malonamic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O>CCOCC>[CH3:20][N:19]([CH3:21])[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(C2(N(C)C)CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(C2(N(C)C)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound from step 1 (6.80 g, 23 mmol) was dissolved in ether (100 mL), mixed with 5% H2SO4 (100 mL) and the solution vigorously stirred for 2 d at RT. The phases were separated and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted three times with ether, the combined organic phases were then washed with water, dried over Na2SO4 and concentrated to low volume in a vacuum.