Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C[N:51](C)C=O>>[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:51])[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1

Procedure:
1-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]-cyclopropanecarboxylic acid benzyl ester (2 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature, and water (0.481 ml) was added. Iodobenzene diacetate (2.87 g) was added at room temperature with stirring, and the reaction mixture was stirred for 2.5 hours. Water (40 ml) was added to the reaction mixture, and the reaction was quenched by the addition of a 2N aqueous solution of sodium hydroxide until pH became 11and ethyl acetate was added and the layers were separated. The organic layer was washed with water and a 5% aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resultant crude brown oil was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1, then 1:2) to give the title compound (819 mg) as cream crystals.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=O)[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:11](\[CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)/[CH2:12][CH3:13])=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)C1CCC2(CC1)OCCO2
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC2(CC1)OCCO2
Yield: 15.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(1,4-dioxaspiro[4.5]decan-8-yl)propan-1-one (259 mg, 1.3 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (360 mg, 1.3 mmol) to give 90 mg title compound (Z-isomer, 16% yield) and 110 mg E-isomer (19% yield) as well.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([CH3:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([CH3:41])=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3ccccc3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.035 g, 0.148 mmol) in dichloromethane (10 mL) was added oxalyl chloride in dichloromethane (2M, 0.081 mL, 0.163 mmol) with a catalytic (drop) amount of DMF. After stirring at ambient temperature for 30 minutes, 1-benzyl-3-methyl-1H-indazol-4-amine (0.0387 g, 0.163 mmol) was added (as a solution in 1 mL methylene chloride), followed by diisopropylethylamine (0.0310 mL, 0.178 mmol). The mixture was stirred overnight and then partitioned between water and DCM. The combined organic extracts were dried (phase separator silicone treated filter paper), evaporated in vacuum and purified on silica gel (10-50% EtOAc in hexanes) to afford N-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.022 g, 33% yield) as a white solid, 22 mg. MS (APCI) m/z=456 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([C:19]([CH:21]=[CH2:22])=[O:20])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:17][C:19](=[O:20])[CH2:21][CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)CC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 2 (5.0 g, 0.021 mole) was reacted with ethylvinyl ketone (6.3 ml) and triethylamine (1 ml) in methanol (30 ml) by the method of Example 3 to give the title compound, m.p. ca. 76°-79° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:8]([O:7][CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=2)[CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 206 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (1 eq) in dichloromethane (1.6 ml/mmol) was added dropwise to a cooled solution (0° C.) of methyl 2-(piperidin-2-yl)acetate hydrochloride (1.1 eq) in dichloromethane (40 ml/mmol) and triethylamine (2.5 eq). The mixture was stirred for 90 min at 25° C., after which the reaction was completed (thin-layer chromatographic analysis). Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added and the mixture was stirred for 15 min. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 80%
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:14]#[CH:15].CCN(CC)CC>C(#N)C.CCOC(C)=O.[Cu]I.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>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]#[C:14][CH2:13][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1I
Reactant: C#CCN1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1C#CCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
Dissolve 1-iodo-2-methoxy-4-nitro-benzene (618 mg, 2.21 mmol) in acetonitrile (10 mL) and treat sequentially with 1-prop-2-ynyl-pyrrolidine (352 mg, 3.22 mmol), Et3N (2 mL), CuI (77 mg, 0.404 mmol) and Pd(PPh3)4 (360 mg, 0.311 mmol). Stir the mixture at room temperature for 3 h, then dilute with EtOAc (50 mL) and wash with saturated NaHCO3 (30 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 50% EtOAc/hexanes to 100% EtOAc, to give the title compound as an orange oil (292 mg, 51%). MS (ES+) 261.1 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.77 (dd, 1H, J=8.3, 2.2 Hz), 7.70 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=8.3 Hz), 3.95 (s, 3H), 3.72 (s, 2H), 2.75-2.70 (m, 4H), 1.87-1.83 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.Cl.[CH3:15]O>O1CCOCC1>[CH3:15][O:12][C:11]([CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:13]
Reactant: CO
Reactant: O=C(O)C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of (rac)-5-bromo-indan-1-carboxylic acid (1.326 g, 5.5 mmol) in MeOH (55 ml) was treated with 4N HCl in dioxane (15 ml) and the mixture was stirred at reflux for 7 h. The yellow solution was allowed to cool to room temperature and all volatiles were removed. The remaining brown oil was purified by chromatography (silica gel; heptane/EtOAc 95:5) to obtain the title compound as light yellow oil (1.31 g, 93%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:3][OH:4].[CH2:14](I)[CH2:15][CH2:16][CH3:17].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:14]([O:4][CH2:3][CH:2]([CH3:1])[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:15][CH2:16][CH3:17]
Reactant: C[C@H](CO)[C@H](C)OC1CCCCO1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOCC(C)C(C)OC1CCCCO1

Procedure:
1.88 g (10 retool) of the crude (2R,3S)-2-methyl-3-tetrahydropyranyloxy-l-butanol was dissolved in 30 ml of DMF. Thereto was added 18.4 g of n-BuI. Thereto was further added carefully by small portions 4 g of oily sodium hydride (about 60%), with ice cooling. To the reaction mixture was added 300 ml of ethyl acetate. The insoluble materials were removed by filtration. The filtrate was washed with two 100 ml-portions of water, dried and concentrated under reduced pressure to obtain crude 1-butoxy-2-methyl-3-tetrahydropyranyloxybutane as an oily material. This crude product was dissolved in 150 ml of methanol. 5 g of Amberlist 15 was added thereto, and the mixture was stirred for 2 days at room temperature. The Amberlist 15 was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to Kugelrohr distillation to obtain 0.90 g of the title compound as an oily material.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH:7]([C:9]([OH:11])=[O:10])[OH:8].[CH2:12](O)[CH3:13]>>[ClH:3].[CH2:12]([O:10][C:9](=[O:11])[CH:7]([OH:8])[CH2:6][NH2:5])[CH3:13]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: NCC(O)C(=O)O
Product: CCOC(=O)C(O)CN
Product: Cl
Reaction time: 17 h
Yield: 100 %

Procedure:
Dry ethanol (40 mL) was cooled on an ice bath and thionyl chloride (4 mL) was added dropwise maintaining the temperature below 5° C. To this cold solution was added (RS)-isoserine (2.5 g, 23.79 mmol) and stirring was continued until a homogeneous solution was obtained. The ice bath was removed and stirring was continued for 17 hours at room temperature. The solution was concentrated in vacuo to afford 4.0 g (100%) of (RS)-isoserine ethyl ester hydrochloride as an oil.
Reaction SMILES: [CH2:1]=[CH2:2].[CH:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])([CH3:5])[CH3:4]>>[OH:15][C:13]1[CH:2]=[C:1]([C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:7]=2)[O:12][C:10](=[O:11])[C:9]=1[O:8][C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=1[CH:3]([CH3:4])[CH3:5]
Reactant: C=C
Reactant: CC(C)c1ccccc1OC(C(=O)O)C(=O)O
Product: CC(C)c1ccccc1Oc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-trimethylsilyloxy)ethylene (2.62 g, 13.6 mmol) and diethyl ester of 2-(isopropyl)phenoxy propanedioic acid (2.0 g, 6.8 mmol). 1H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.44 (m, 1H), 6.67 (d, 1H), 6.89 (s, 1H), 7.0 (t, 1H), 7.09 (t, 1H), 7.29 (d, 1H), 7.53 (m, 3H), 7.83 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:9]=2[N:10]=1.CS(C)=O.[C:23]1([CH3:33])C=CC(S([O-])(=O)=O)=C[CH:24]=1.[NH+]1C=CC=CC=1.C(O)(=[O:42])C>C(OCC)(OCC)(OCC)CC.C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][O:17][C:24](=[O:42])[CH2:23][CH3:33])[CH2:14][OH:15])[C:9]=2[N:10]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CCOC(CC)(OCC)OCC
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CS(C)=O
Product: CCC(=O)OCC(CO)OCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To 5 g of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir) in 20 ml of triethyl orthopropionate was added 5 ml of dimethylsulfoxide (DMSO) and 0.25 g of pyridinium p-toluenesulfonate (PPTS). The slurry was stirred at room temperature for 4.5 hours. 70% Aqueous acetic acid (10 ml) was added and the mixture was stirred for 2 hours. Then 30 ml of ethanol was added, the mixture was stirred for another 0.5 hour and filtered. The white solid was washed twice with 50 ml each of ethanol and air dried to give 4.77 g of product. 1H-NMR: δ 0.9 (t,3H), 2.05 (q,2H), 3.32 (m,2H), 3.8 (m,1H), 3.85 (dd,1H), 4.0 (dd,1H), 4.8 (t,1H), 5.35 (ad,2H), 6.45 (br s, 2H), 7.75 (s,1H), 10.6 (s,1H).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:4]=1)#[N:2].CC[N:26]([CH2:29]C)CC.[OH2:31].C(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:29]([NH2:26])=[O:31])=[CH:12][CH:13]=2)[N:5]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:4]=1)#[N:2]
Reactant: O
Reactant: CCN(CC)CC
Reactant: COc1ccc(-n2nc(C#N)cc2-c2ccc(CN)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-n2nc(C#N)cc2-c2ccc(CNC(N)=O)cc2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 3-cyano-1-(4-methoxyphenyl)-5-[4-(aminometyl)phenyl]-1H-pyrazole (90 mg) trimethylsilylisocyanate (152 mg) and Et3N (0.18 ml) in CH2Cl2 (5 ml) was stirred at room temperature. After stirring for 5 hours (checked by TLC), water and CHCl3 was added. The organic layer was separated. Aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine. Dried over MgSO4, filtered and evaporated under reduced pressure to give 48 mg (52%) of N-{4-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH2:10])[CH2:6][CH:7]([CH3:9])[CH3:8].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:10]1[CH2:25][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][C:17]=2[C:21]([F:24])([F:22])[F:23])[C:14]1=[O:13])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)c1cccc(C(F)(F)F)c1CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 115 °C
Yield: 55.7 %

Procedure:
A mixture of (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride (Aldrich, 273 mg, 1.5 mmol) and 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (prepared as in Example 1, 445 mg, 1.5 mmol) in acetonitrile (5 mL) and triethylamine (420 μL, 3.0 mmol) was placed in a microwave reaction vessel and sealed. The reaction mixture was then placed in a microwave reactor and heated at 115° C. for 15 min. After this time, the reaction mixture was cooled and concentrated with silica gel (2 g) in vacuo. The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 20% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid methyl ester (275 mg, 56%) as a colorless viscous oil.
Reaction SMILES: NC1C=CC=CC=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O.[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[CH:21]=[C:22]([NH2:38])[C:23]([NH2:37])=[CH:24][C:25]=1[O:26][C:27]1[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1>CO>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[C:25]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[CH:24][C:23]2[NH:37][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)=[N:38][C:22]=2[CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1
Reactant: O=Cc1ccccn1
Solvent: Nc1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.26 ml of 1 M methanol solution of aniline and pyridine-2-carboxaldehyde (1/1) was added to a methanol (1 ml) solution of 35 mg of 4-(2-chlorophenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in (step 1), and the reaction liquid was stirred overnight at 60° C. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and then dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: N#CCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a stirred solution of 3-(4-phenylpiperidin-1-yl)propionitrile (5.1 g, 24 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 83 mL, 83 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 130 mL) was added and stirring was continued for 2 hours at 50°-70° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with EtOAc (100 mL) and CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2 Cl2 (20 mL) and treated with HCl in ether (1.0M, 50 mL). The solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (60 mL) was added to the resulting white solid, the pH was adjusted to 10-11 with 1M NaOH, and the aqueous phase was extracted three times with CH2Cl2. Drying over MgSO4 followed by removal of solvents gave 4.5 g (87%) of pure product (light brown solid), which was characterized spectroscopically.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].[N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[OH:19][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Nc1ccccc1
Reactant: CCCCC=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of pentanal (86 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=1.O.[OH-].[Li+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCC(C)=O)c2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)COc1cccc(COc2ccc(CCC(=O)O)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a solution of ethyl 3-(3-fluoro-4-{[3-(2-oxopropoxy)benzyl]oxy}phenyl)propanoate (0.31 g, 0.82 mmol) in ethanol-water (2 mL-1 mL) was added lithium hydroxide monohydrate (0.052 g, 1.23 mmol), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 2 N hydrochloric acid (0.7 mL), and extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.047 g, yield 17%) as white powders.