Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].[CH2:19](O)[CH3:20].C(I)C.[C:25](=[S:27])=[S:26]>>[CH2:19]([S:27][C:25]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:26])[CH3:20]
Reactant: S=C=S
Reactant: CCO
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Agent: [K+]
Agent: [OH-]
Solvent: CCI
Product: CCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a mixture of (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), KOH (96%, 2.34 g) and 50% ethanol (80 ml) is added dropwise carbon disulfide (1.8 ml) at room temperature, and the mixture is stirred at the same temperature for 30 minutes. To the mixture is added dropwise ethyl iodide (4.68 g), and the mixture is further stirred at room temperature for 48 hours and distilled to remove the solvent. To the residue is added water, and the mixture is washed with ether. The aqueous layer is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from chloroform to give the title compound (4.45 g, 69%) as colorless needles, m.p. 177°-178° C., NMR (CDCl3 --DMSO--d6, δ): 1.38 (t, J=7.0 Hz, 3H, N--CSSCH2CH3), 3.34 (q, J=7.0 Hz, 2H, N--CSSCH2CH3), Mass (m/e): 320 (M+), 258 (M+ --CH3CH2SH)
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(COCCOS(C)(=O)=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 19.0 g of 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane and 95.0 ml of methylene chloride containing 9.1 ml of methanesulfonyl chloride was dropwise added 16.4 ml of triethylamine with ice cooling over 1 hour. The resulting mixture was stirred for 10 minutes at the same temperature and further for 1 hour at room temperature. The reaction mixture was added to a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 24.5 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([N:17]1[CH2:21][C:20](=O)[N:19]=[CH:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:9]([N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C1CN(C(=O)c2ccccc2)C=N1
Product: Cc1cc(NC2=NCCN2C(=O)c2ccccc2)n(C)n1

Procedure:
5-amino-1,3-dimethylpyrazole (20.0 g.) and 1-benzoyl-2-imidazolinone (British patent 1,392,849) (28.4 g.) were reacted as described in Example I to give 22.02 g. product. mp 147°-149°
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2].C(O)(C)C>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCC2(CC1)OCCO2
Reaction time: 24 h
Yield: 94.6 %

Procedure:
Second Step: 267.3 g of the compound (11), 5.0 g of Pd/C, 500 mL of isopropyl alcohol (IPA) and 500 mL of toluene were added to a reactor, and stirred under hydrogen atmosphere for 24 hours. After confirming that the reaction had been completed by GC analysis, the Pd/C was filtered off, and the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and the solvent was distilled off under reduced pressure to obtain 255.2 g of (1,4-dioxaspiro[4,5]dec-8-yl)acetic acid ethyl ester (12) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A stirred mixture of 4-ethoxybenzoic acid (0.33 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.67 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 18 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated. The residue was triturated in Et2O, then EtOAc and isolated by filtration followed by drying in vacuo to give 4-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.27 g, 30% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.73 min (97.04%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 1.34 (t, J=7.0 Hz, 3H), 1.81-1.95 (m, 3H), 1.97-2.12 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.78 (m, 1H), 4.09 (q, J=6.9 Hz, 3H), 4.60 (d, J=5.9 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 7.44-8.44 (m, 5H), 9.06 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.53, 21.02, 28.57, 29.11, 42.52, 58.76, 63.31, 113.99, 121.56, 123.16, 125.97, 129.09, 129.55, 131.37, 133.35, 147.73, 161.02, 165.89, 167.75, 167.89, 172.13, 172.19; LCMS: MH=450; Anal Calcd for C24H23N3O6+0.75H2O: C, 62.26; H, 5.33; N, 9.08. Found: C, 62.25; H, 5.13; N, 9.17.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.500 g, 1.73 mmol) and 1-benzyl-piperidin-4-one were mixed with acetic acid (0.200 mL) in MeOH (8 mL). The reaction was cooled to 0° C. and stirred for one hour before sodium cyanoborohydride (0.108 g, 1.74 mmol) was added. The reaction was allowed to warm to room temperature and was monitored by analytical LCMS. When complete, the reaction was quenched with aqueous sodium bicarbonate then submitted to standard workup procedures. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH2:12]=O.[CH3:14][NH:15][CH3:16]>CC(O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH2:14][N:15]([CH3:12])[CH3:16])[C:3]=12
Reactant: C=O
Reactant: CNC
Reactant: Clc1ncc(Br)c2cc[nH]c12
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2c(Cl)ncc(Br)c12
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (Zhang et al., J. Org. Chem., 2002, 67, 2345-2347) (200 mg, 0.864 mmol), formaldehyde (37 wt. % in H2O, 0.500 mL, 6.17 mmol), and dimethylamine (40 wt. % in H2O, 1.00 mL, 8.88 mmol) in AcOH (6 mL) was heated in a microwave reactor at 100° C. for 40 min. The solvent was removed under reduced pressure. The crude product was partitioned between CH2Cl2 (15 mL) and saturated NaHCO3 (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, gave the title compound. MS: m/z=290 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CO.O.[CH3:21][N:22]1[CH2:27][CH2:26]N[CH2:24][CH2:23]1>CS(C)=O>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:4]=2[CH:16]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride (50 g) was stirred in a mixture of N-Methylpiperazine (113 g) and Dimethylsulfoxide (300 mL) at 120° C. for 20 h under nitrogen atmosphere. The reaction mass was cooled to 20° C., followed by addition of methanol (500 mL) and the reaction mass was stirred for 30 min. Water (150 mL) was added at 20° C. in 25 min, and the reaction mass was cooled to 5° C. The reaction mass was stirred for 30 min at 0-5° C. The product was filtered and was washed with chilled methanol (50 mL, 5° C.). Dried the product at 50° C. under reduced pressure to give technical 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine or Olanzapine.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:32][Si](C)(C)C>CN(C)C=O.C(Cl)Cl.CO>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH2:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (300 mg, 0.88 mmol) and 1 drop of N,N-dimethylformamide in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with oxalyl chloride (84 μL, 0.97 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (560 μL, 2.64 mmol) and subsequently stirred at 25° C. for 15 h. The resulting reaction mixture was diluted with methylene chloride (20 mL) and methanol (15 mL) and then washed with a 5% aqueous sulfuric acid solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionamide (140 mg, 47%) as a yellow foam: mp 72-76° C. (foam to gel); FAB-HRMS m/e calcd for C15H20N2O5S (M+H)+341.1172, found 341.1181.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[H][H]>C(O)C.[Pd]>[O:14]1[CH2:19][CH2:18][CH:17]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCOCC2)C1

Procedure:
tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate was added to a solution of tetrahydro-4H-pyran-4-one and 10% Pd/C (300 mg) in ethanol and the reaction mixture left under about 415 kPa (about 60 psi) of hydrogen gas for 18 hours. The reaction mixture was filtered through Arbocel®, washing through thoroughly with ethyl acetate. The filtrate was concentrated in vacuo and the crude product purified by column chromatography on silica gel to yield the desired product, 6.7 g (61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([O-])([O-])=O.[K+].[K+].C([O:20][C:21](=[O:24])[CH2:22]Cl)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:22][C:21]([OH:24])=[O:20]
Reactant: CCOC(=O)CCl
Reactant: COc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2CC(=O)O
Reaction time: 0.17 h

Procedure:
To a solution of 4-methoxyindole (294 mg) in DMF (10 mL) was added K2CO3 (829 mg). After 10 min stirring, ethylchloroacetate (0.426 mL) was added. The reaction mixture was stirred overnight at 120° C., was allowed to cool down and was filtered off. The solid was washed with DCM and the filtrate was concentrated in vacuo. After CC (silica gel, EA/MeOH 9/1) followed by preparative HPLC (I), the resulting material was dissolved in 1M NaOH/THF (20 mL, 1/1). The mixture was stirred at RT overnight, neutralized with 1M HCl (8 mL) and concentrated to dryness. The residue was taken up in DCM and the resulting suspension was filtered off. The filtrate was evaporated in vacuo to afford 340 mg of beige powder. LC-MS (D): tR=0.76 min; [M+H]+: 206.1.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:31](=[O:33])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1
Reaction time: 0.5 h
Yield: 144 %

Procedure:
To a solution of 2-methyl-N1-(4-{[3-(methyloxy)phenyl]oxy}phenyl)alaninamide (Intermediate 72, 1.33 g) and triethylamine (3.70 mL, 26.6 mmol) in dry dichloromethane (80 mL) at 0° C. was added dropwise a solution of triphosgene (600 mg, 2.022 mmol) in dry dichloromethane (20 mL) and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with a saturated solution of ammonium chloride (100 mL) and two phases were separated. Aqueous layer was extracted with dichloromethane (100 mL) and the two organic phases were collected, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP cartridge) using as eluent a gradient and cyclohexane/ethyl acetate from 80/20 to 40/60 to afford the title compound as a white solid (950 mg).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:53])[C:36]([CH3:52])([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:52])([O:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:35]([OH:34])=[O:53])=[CH:43][CH:42]=3)[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 25 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by massirected HPLC to produce the product as a white solid (25%). MS [EI+] 534 (M+H)+, 566 (M+Na)+, [EI−] 532 (M−H)+; HPLC: T=3.26 min, purity 97%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1>C1(C)C=CC=CC=1.CCOCC>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:36]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(CBr)cc2)cc1
Reactant: Cc1cncs1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(C[n+]3csc(C)c3)cc2)cc1
Product: [Br-]
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A mixture of 3.5 g of N-[4-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 2.69 g of 5-methylthiazole in 45 ml of toluene is refluxed under argon for 6 hours, then allowed to stand at ambient temperature overnight. The mixture is diluted with ether then evaporated to a residue which is dissolved in hot tetrahydrofuran and again diluted with ether. The solid is collected by centrifugation and washed with ether several times then dried under vacuum to give 1.9 g of the product as a white powder, m.p. 120°-125° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH3:19])(O)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-:21].[K+].[K+].[C:26](#[N:28])[CH3:27]>>[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([NH:28][C:26](=[O:21])[CH3:27])([CH3:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1(O)CCN(Cc2ccccc2)C1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Add concentrated sulphuric acid (16 mL) dropwise to 1-benzyl-3-methyl-pyrrolidin-3-ol (4.4 g, 23 mmol) in acetonitrile (12 mL) at 0° C. Stir and allow the resulting solution to warm up gradually to room temperature overnight. Pour onto crushed ice and add saturated aqueous potassium carbonate and extract with dichloromethane. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give N-(1-benzyl-3-methylpyrrolidin-3-yl)-acetamide which may be used in the next step without further purification (4.89 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.34 (5H, m), 5.62 (1H, s), 3.57-3.66 (2H, m), 2.76-2.84 (2H, m), 2.54 (1H, td, J=8.80, 5.87 Hz), 2.47 (1H, d, J=9.78 Hz), 2.13 (1H, m), 1.90-1.93 (3H, m), 1.84-1.90 (1H, m), 1.49 (3H, s), MS (ES): m/z=233 [M+H].
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][OH:19]>>[CH3:18][O:19][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CO
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Product: COc1c(C(F)(F)F)cc(C#N)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed methanol (10 mL) and cooled to 0° C. Na (337 mg, 14.65 mmol, 2.00 equiv) was added. When the Na was reacted completely, 4-chloro-3,5-bis(trifluoromethyl)benzonitrile (2.0 g, 7.31 mmol, 1.00 equiv) was added at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue could been used for the next step directly. This resulted in 1.33 g of 4-methoxy-3,5-bis(trifluoromethyl)benzonitrile as yellow oil. Mass spectrum (GC, m/z): Calcd. for C10H5F6NO, 269.0 (M). found 269.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH2:7].[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=O)[CH:12]=[CH:13][C:14]=1[Cl:15]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:17]=[C:5]([C:4](=[O:7])[NH2:3])[N:6]=[C:2]2[CH3:1])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: Cc1ncc[nH]1
Reactant: O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1nc(C(N)=O)cn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of 8.61 g. (0.105 mol.) of 2-methylimidazole in 60 ml. of water is added dropwise to the stirred solution of 18.8 g. (0.1 mol.) of 3,4-dichlorophenyl-isocyanate in 120 ml. of toluene at 10° to 12° C. under cooling. The reaction mixture is stirred at room temperature for one hour. The separated product is filtered off, washed and dried. 22.0 g. (81.5%) of 1-(3,4-dichlorophenyl)-carbamoyl-2-methylimidazole are obtained; m.p.: 140° C.