Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[Cl:29]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:29])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(3-methyl-benzyloxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A (218 mg, 0.58 mmol) in isopropanol (2 mL) was added N-chlorosuccinimide (84 mg, 0.63 mmol) and 2 drops of dichloroacetic acid. The solution was heated at 60° C. for two hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as a light yellow oil (230 mg, 78%). MS (M+H): 413
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]>[Fe].CC(O)=O.CCOC(C)=O>[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1C#N
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additonal 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(NC(=O)CCl)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCCCCC
Product: COc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methoxy-phenyl)-acetamide [J. Heterocycl. Chem., 32, 1429. (1995)] and 4-benzyl-piperidine according to the method described in Example 143b. Melting Point: 81-83° C. (hexane)
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([NH:26][C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of benzyl (2R)-2-carboxymethyl-4-methylvalerate (527 mg) and cyclohexylamine (238 mg) in methylene chloride (10 ml) was added WSCD·HCl (460 mg) at room temperature. After being stirred overnight, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 5% HCl, water, saturated sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane to give benzyl (2R)-2-(cyclohexylcarbamoylmethyl)-4-methylvalerate (410 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[NH:16][C:17]3=[O:26])=[N:12]2)=[CH:2]1.N12C[CH2:41][CH2:40][N:39]=[C:38]1[CH2:37][CH2:36][CH2:35]CC2.Cl.N1C=CC=CC=1CCl>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[N:16]([CH2:41][C:40]4[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=4)[C:17]3=[O:26])=[N:12]2)=[CH:2]1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Agent: ClCc1ccccn1
Solvent: CS(C)=O
Product: CC(C)Cn1c(=O)n(Cc2ccccn2)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 80 °C

Procedure:
2-(1-benzothien-3-ylmethyl)-7-isobutyl-3-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in anhydrous dimethylsulfoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene was added. 2-picolyl chloride hydrochloride was added and the mixture was heated at 80° C. for 18 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trifluoroacetic acid mixtures. 525 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[NH2:12])[CH3:2]
Reactant: CCOC(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccncc1N
Yield: 111.8 %

Procedure:
To a 250-ml Parr flask was added 0.30 g (1.4 mmol) of 3-nitro-4-pyridineacetic acid ethyl ester, 50 mg of 10% palladium on charcoal and 100 mL of ethanol. The mixture was subjected to hydrogenation using a Parr hydrogenator at 40 PSI for 15 min. The mixture was filtered through celite, and the filtrate was concentrated to give an oil which crystallised under a high vacuum to afford 0.282 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ1.15 (t, J=7.2 Hz, 3H), 3.52 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 5.11 (s, 2H), 6.89 (d, J=4.8 Hz, 1H), 7.67 (d, J=4.8 Hz, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:5]1[N:6]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 25.3 %

Procedure:
The title compound (1.1 g, 25%) was prepared from 2-butyl-4-methyl-1,6-dihydro-6-pyrimidone (2.3 g, 13.85 mmol), 4-[2-bromoethoxy]benzaldehyde (3.17 g, 13.85 mmol) in the presence of K2CO3 (3.82 g, 27.7 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:10]=2[O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)[CH3:2].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CN1Cc2ccc(OC)cc2Oc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)CN1Cc2ccc(O)cc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (400 mg, 1.27 mmol) in dichloromethane (5 mL) was cooled to −5° C. and treated with ethanethiol (419 mg, 6.75 mmol) and aluminum chloride (815 mg, 6.11 mmol). After 30 min, the reaction was quenched with aqueous ammonium chloride solution. The solvent was removed in vacuo and the residue dissolved in 1M HCl. The aqueous layer was extracted with three portions of dichloromethane and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal chromatography (SiO2, 4 mm, 10% EtOH; 90% CH2C2) afforded 1-6.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N:17]1[CH2:48][CH2:47][C:20]2([N:25]([CH2:26][C:27]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:28]=3[CH:29]=[CH:30][N:31]4S(C3C=CC(C)=CC=3)(=O)=O)[C:24](=[O:46])[CH2:23][CH2:22][CH2:21]2)[CH2:19][CH2:18]1>CO>[NH:31]1[C:32]2[C:28](=[C:27]([CH2:26][N:25]3[C:20]4([CH2:19][CH2:18][N:17]([C:8]5[CH:9]=[N:10][C:11]6[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:7]=5)[CH2:48][CH2:47]4)[CH2:21][CH2:22][CH2:23][C:24]3=[O:46])[CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:30]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4cnc6ccccc6n4)CC5)cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1Cc1cccc2[nH]ccc12
Reaction time: 16 h
Yield: 25 %

Procedure:
Cs2CO3 (0.201 g, 0.621 mmol) was added to a stirred solution of 9-(quinoxalin-2-yl)-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (0.12 g, 0.207 mmol) in methanol (8.0 mL) and stirring was continued for 16 h at 80° C. under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×125 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC under neutral conditions to yield the title compound as a yellow solid (0.022 g, 25%). [1H-NMR (CDCl3, 300 MHz): δ 8.5 (s, 1H), 8.21 (brs, 1H), 7.88 (d, 1H), 7.91-7.55 (m, 2H), 7.42 (t, 1H), 7.19-7.08 (m, 2H), 6.85 (d, 1H), 6.49-6.42 (m, 1H), 4.99 (s, 2H), 4.49-4.36 (m, 2H), 3.12 (t, 2H), 2.69 (t, 2H), 2.25-2.10 (m, 4H), 2.03-1.90 (m, 2H), 1.78 (d, 2H); HPLC RtA=4.393 min (98%); LCMS RtE=1.753, [M+H]+=426.1].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[C:7]([CH3:13])[CH:6]=1)[CH:2]=[CH2:3].[N:14]1([CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:18]=[CH:17][N:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:20][CH2:19][N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)=[C:7]([CH3:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CS)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CSCCn2ccnn2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
To a mixture of 1.98 g (10.2 mmol) (4-allyloxy-2-methyl-phenyl)-methanethiol and 2.72 g (10.2 mmol) toluene-4-sulfonic acid 2-[1,2,3]triazol-1-yl-ethyl ester in 25 ml N,N-dimethylformamide was added under argon at −50° C. 515 mg (20.4 mmol) sodium hydride. The mixture was allowed to warm up to room temperature and was stirred under argon for 12 hours. 80% of the DMF was stilled off in vacuo, ethyl acetate and water given to the mixture. The aqueous phase was reextracted with ethyl acetate and the combined organic extracts dried and evaporated to yield 2.8 g of 1-[2-(4-allyloxy-2-methyl-benzylsulfanyl)ethyl]-1H-[1,2,3]triazole as brown oil. The raw material (73% purity) was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C=O)C>[CH2:22]([C:8]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:23]
Reactant: CCI
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
A solution of 1C (10 g, 38.16 mmol) in DMF (60 mL) was added over a period of 30 min to an ice cold solution of NaH (2.29 g, 95.41 mmol) in DMF (40 mL), and the mixture was stirred for 10 min. Ethyl iodide (17.86 g, 114.48 mmol) was then added, and the mixture was stirred for 2 h at room temperature. The reaction was then brought to 0° C., excess NaH was quenched with ice water and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (7.0 g, 64%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J=9.0 Hz, 1H), 6.82 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 6.6 (d, J=2.1 Hz, 1H), 4.1 (q, J=7.2 Hz, 2H), 3.8 (s, 3H), 3.12-2.9 (m, 3H), 2.47 (d, J=15.9 Hz, 1H), 2.42 (m, 1H), 2.03 (dt, J1=13.5 Hz, J2=4.5 Hz, 1H), 1.8-1.6 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.9 (t, J=7.5 Hz, 3H). ESI-MS m/z=291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CCNCC
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(CC)CC)cc1)c1ccc2oc(Cl)cc2c1
Yield: 81 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with diethylamine (3 mL) in MeOH (8 mL) under reflux to give the desired product (61 mg, 81%, Z/E=1/1.25) as a brown solid. 1HNMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 & 7.09 (d, J=8.8 Hz, 2H), 7.00 & 6.99 (d, J=8.4 Hz, 1H), 6.83 & 6.80 (d, J=8.8 Hz, 2H), 6.71 & 6.69 (d, J=8.4 Hz, 2H), 6.45 (s, 1H), 6.43 (d, J=8.8 Hz, 2H), 4.08 & 3.90 (t, J=5.8 Hz, 2H), 2.92 & 2.80 (t, J=5.8 Hz, 2H), 2.69 & 2.62 (q, J=7.0 Hz, 4H), 2.50 (q, J=7.6 Hz, 2H), 1.10 & 1.04 (q, J=7.2 Hz, 6H), 0.91 (t, J=7.6 Hz, 3H); m/z=490[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.BrBr.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.C(OCC)C.CC(C)=O.O>[C:14]([CH:16]([CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(C(C)=O)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C#N)CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
4′-Methoxyacetophenone (15.0 g) was dissolved in chloroform (70 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After dropwise addition, the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 1-bromo-1-(4-methoxyphenyl)ethanone (yield 22.05 g) as crystals. To ethyl cyanoacetate (79.20 g) was added potassium carbonate (27.65 g), and the mixture was stirred at 45° C. for 1 hr. A solution (100 mL) of crude 1-bromo-1-(4-methoxyphenyl)ethanone (22.0 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. An excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as an oil (yield 30.25 g, about 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH:12](O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:36]#[N:37])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:20])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:36]#[N:37])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-(4-pyridyl)propionate (0.60 g, 2.0 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.50 g, 2.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (4 ml), and trimethylsilyl cyanide (0.39 g, 3.9 mmol) and N,N-dimethylcarbamoyl chloride (0.38 g, 3.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 50 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (20 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.54 g, 85%).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(=O)(=O)(O)O>S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)c1ccc2oc3ccccc3c(=O)c2c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCCCCCCOC(=O)c1ccc2oc3ccccc3c(=O)c2c1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 12.01 g (50 mmol) of the above 9-oxo-9H-xanthene-2-carboxylic acid, 77.4 g (420 mmol) of n-dodecanol and 0.2 g (2 mmol) of concentrated sulfuric acid is kept at 140° C. for 6 hours. The sulfuric acid is neutralized with 0.33 g (4 mmol) of sodium acetate and the excess n-dodecancl is removed by distillation (98° C./0.1 mbar). The brown residue is taken up in isopropanol and the product which has precipitated is filtered off and dried under a high vacuum. 16.7 g(82%) of n-dodecyl 9-oxo-9H-xanthene-2-carboxylate, melting point 79°-81° C., result s a beige powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36]C(OC(C)(C)C)=O)[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(OCC)(=O)C.C(OCC)C>[ClH:44].[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH2:36])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)pentanoyl]oxyhexadecanamide (4.90 g) in 4N hydrogen chloride in ethyl acetate (10 ml) was stirred at room temperature for an hour, and then at 0° C. for an additional one hour. This solution was diluted with diethyl ether (25 ml). The resulting precipitate was collected by filtration, and washed with diethyl ether (30 ml). This crystalline solid was dried over potassium hydroxide under vacuum to yield (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl)oxyhexadecanamide hydrochloride (4.35 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>C(Cl)Cl>[O:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]3[C:43]4[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=4[C:37]([C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=4)=[N:36]3)[CH2:13][CH2:12]2)=[N:16]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2noc3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of 176 mg (0.55 mmol) of 4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2(2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in methanol and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 202 mg (0.55 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%) of a white solid. MS (electrospray): exact mass calculated for C30H32F3N5O4, 583.24; m/z found, 584.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23 (m, 1H), 4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H), 4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H), 3.02-2.85 (m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H), 2.51-2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20 (s, 1.5H), 2.16 (s, 1.5H), 2.02-1.86 (m, 2H).