Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[S:9][C:5]=2[CH:4]=1.CO.[Li+].[OH-].O>C1COCC1>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 1 h

Procedure:
To ethyl 6-(trifluoromethyl)-1-benzothiophene-2-carboxylate dissolved in THF and MeOH was added a solution of LiOH in H2O (1.5 equiv). The reaction media became cloudy so H2O, MeOH and THF were added until a clear solution ensued (Final composition of media=2 THF:1 MeOH:1 H2O) (0.2 M). After 1 h, analysis showed consumption of all the starting material. A large proportion of the volatiles were removed under reduced pressure. The remaining solution was treated with 1N HCl. The precipitate was filtered off and dissolved in a mixture of THF, MeOH and EtOAc. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a solid. The latter was ground with a mortar and pestle and let dry overnight under high vacuum.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([F:39])=[C:35]([CH:38]=1)[CH:36]=O.[Cl-].[NH4+]>C1COCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([F:39])=[C:35]([CH:36]=[CH:8][O:9][CH3:10])[CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1cc(Br)ccc1F
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Potassium tert-butoxide (1.2 molar equivalents) was added portionwise, over 30 minutes, to a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (1.3 molar equivalents) in THF (2.5 volumes) at −3° C. (+ or −2° C.). A deep red colour developed. The temperature was ramped to 18° C. over 0.5 hour and the reaction stirred for a further 1.5 hours. 5-Bromo-2-fluorobenzaldehyde (limiting reagent) as a solution in THF (5 volumes) was then added over 90 minutes, such that the temperature of the reaction did not exceed 24° C. The reaction was then stirred for 2 hours at room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 volumes) and extracted with t-BME (2×2.5 volumes). The combined extracts were washed with brine (3×2 volumes), dried (Na2SO4), filtered and evaporated in vacuo. The oily residue was extracted with iso-hexane (8×0.5 volumes). Combined iso-hexane extracts were filtered, then washed with glacial acetic acid (2 volumes) and 50% glacial acetic acid in water (2 volumes). After drying (Na2SO4) and filtering, the solvent was removed on a rotary evaporator to give a pale orange oil. Yield was 90% of theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][C:21]([NH2:23])=[O:22]>>[C:21]([CH2:20][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])(=[O:22])[NH2:23]
Reactant: NC(=O)CI
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])c(OCC(N)=O)c1

Procedure:
Reaction of 0.84 g of 5-methoxy-2-nitrophenol, 1.66 g of potassium carbonate and 1.84 g of iodoacetamide by the process described in Example 55) gives 2-carbamoylmethoxy-4-methoxynitrobenzene: mp 185°-7° C.; Rf (O)=0.58.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].C(OCC)C.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:23])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:12]=1)[CH3:29]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-(2-Diethylaminoethyl)-4'-(1-oxo-2-phenylbutyl)methanesulfonanilide (24.0 g., 0.0576 mole) is dissolved in 500 ml. ethyl ether and added dropwise during 1/2 hr. to a solution of phenylmagnesium bromide (0.145 mole) in 500 ml. ethyl ether. The mixture is heated at reflux for 16 hrs. After cooling to room temperature, 100 g. of ammonium chloride in 400 ml. water is added and the solution is stirred for 15 min. The ether layer is separated and the aqueous layer is extracted with ethyl ether and the combined ether solutions are washed with water followed by 1N HCl. The acidic aqueous wash is washed with ethyl ether and basified with 50% NaOH to pH 11. The product is extracted with ethyl ether and the ether solution is washed with water and dried (MgSO4). Evaporation of the ethyl ether yields 28 g. of product as an oil (100% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][N:16]([C@H:25]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:26]([O:28]CC4C=CC(OC)=CC=4)=[O:27])[CH2:15]3)[CH2:9][CH2:8]2)[C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C@@H:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][N:16]([C@H:25]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:26]([OH:28])=[O:27])[CH2:15]3)[CH2:11][CH2:12]2)[C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[N:3]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4c(C)nc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1nc2ccccc2n1C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 103.9 %

Procedure:
The title compound was prepared from 57 mg of α-(R)-(3-(S)-((4-(2-methyl-benzoimidazol-1-yl)piperidin-1-yl)methyl)-4-(S)-phenyl-pyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (from Step C), 4 mL of TFA and 0.3 mL of anisole, using a procedure analogous to that described in Example 95, Step E to provide 48 mg of the title compound as a white solid. ESI-MS 515 (M+H); HPLC A: 1.81 min.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][S:6][CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CNN>>[NH2:9][CH:8]1[CH2:7][S:6][CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][N:3]([CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Product: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O

Procedure:
1.2 g of diastereomer A of t-butyl α-[5-oxo-2-phenyl-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] were subjected to dephthaloylization with methylhydrazine in the same manner as described in Example 1(g), to give 0.66 g of the title compound as an amorphous solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[CH:10]=[N:9][CH:8]=1.[Li]CCCC.[I:18]I>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([I:18])=[N:9][CH:8]=1
Reactant: II
Reactant: Cn1cncc1C1OCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2OCCCO2)cnc1I
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
To a solution of 38 (295 g, 1.754 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (0.772 mL, 1.929 mmol, 2.5 M solution in hexanes) and the reaction mixture was stirred for 20 min. Iodine (445 mg, 1.754 mmol) in THF (2 mL) was slowly added dropwise while maintaining the temperature at −78° C. and the reaction mixture was stirred for a further 30 min, and was quenched by the addition of water and then extracted with EtOAc. The organic phase was, washed with sodium thiosulfate solution, separated, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (20% EtOAc/Hexane) afforded 39 (305 mg, 59% yield) as a white solid. MS (m/z): 294.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-isonicotinoylpiperazin-1-yl)quinolin-7-yl]ethanone (0.030 g, 0.076 mmol) and ammonium acetate (0.0586 g, 0.760 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.19 mL, 0.19 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN5O (M+H)+: m/z=396.2; Found: 396.2.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:13]=3)[CH:8]=2)C(=O)C2=CC=CC=C12>CN.CO>[NH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:8]=1
Reactant: CCCN(CCC)CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCc1ccc2cc(CN)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.6 %

Procedure:
The compound (439 mg) obtained in Example 121-10 was dissolved in a 40% methylamine/methanol solution (45 ml) and stirred at room temperature for 3 days. After completion of the reaction, the solvent was distilled off. Then, a 1 mol/l sodium hydroxide aqueous solution was added to the residue, and the whole was stirred. The solution was extracted with chloroform and the extract was washed with saturated saline solution. After that, the organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off, thereby obtaining the subject compound (283 mg) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH:3]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([C:19]2[CH:34]=[CH:33][C:22]([CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:25][CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][C:6]2[C:5]([O:4][CH:3]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:2]([F:41])([F:1])[F:42])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)(=[O:17])=[O:18])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2OC(c2cccnc2)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2OC(c2cccnc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
4-(N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoxalin-2-yl}sulfamoyl)phenethylcarbamate (Compound 208) was dissolved in dichloromethane (2 mL). To this, trifluoroacetic acid (2 mL) was added at room temperature and the mixture was stirred at room temperature for 24 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and purification by silica gel column chromatography (ethyl acetate/methanol=1/0 to 5/1) was performed to give 4-(2-aminoethyl)-N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)-ethoxy]quinoxalin-2-yl}benzenesulfonamide (Compound 209) (48 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:6]=1
Reactant: Cc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A −78° C. solution of 2-methylthiazole (2 g, 20.17 mmol) in THF (50 mL) was treated drop-wise with n-butyllithium (2.5 M in Hex, 10.49 mL, 26.2 mmol), stirred for 1 h, treated drop-wise with a solution of tributyltin chloride (7.11 mL, 26.2 mmol) in THF (25 mL) and stirred for an additional 1 h at −78° C. The mixture was allowed to warm to RT, stirred for 1 h, treated slowly with ice-cold satd. NaHCO3 (20 mL) and quickly extracted with Et2O (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 2-methyl-5-(tributylstannyl)thiazole (6.67 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 7.55 (s, 1 H), 2.67 (s, 3 H), 1.54-1.45 (m, 6 H), 1.30-1.23 (m, 6 H), 1.09-1.04 (m, 6 H), 0.83 (t, J=7.3 Hz, 9 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 26 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2,3-dimethyl-phenylboronic acid (38 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (14 mg, 27%). LC-MS m/e 415.35 (M+H+)
Reaction SMILES: [CH3:1][O:2]C1C=CC(O)=CC=1.[C:10]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](C(C)(C)C)=[CH:31][CH:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])[CH3:11]>>[C:10]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:39])[CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([O:2][CH3:1])=[CH:33][CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])[CH3:11]
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Product: COc1ccc(OCC(O)CCCC(CCCCCCC(=O)O)C(C)=O)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of 4-methoxyphenol is substituted for the 4-tert-butylphenol of Example 10. The title compound is obtained as a viscous oil after purification by silica gel column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].CO>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CCN(C)C

Procedure:
Method I was used with ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (124 mg, 0.632 mmol), caesium carbonate (624 mg, 1.915 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (96.8 mg, 0.672 mmol). 48 hours reaction time. Column eluent: 50→100% EtOAc in CH2Cl2, followed by 0→10% MeOH in EtOAc. Yield: 103 mg (61%) of a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH3:24])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)CCCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(O)cc(C)c1C1C(=O)CCCC1=O

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dimethylphenyl)cyclohexane-1,3-dione (0.57 g, 0.0018 mol) in ethyl acetate (30 ml) and methanol (530 ml) is added 5% palladium on carbon (0.100 g), and the suspension is then stirred under 4 bar hydrogen pressure for 5 hours. The suspension is filtered through diatomaceous earth and the filtrate evaporated under reduced pressure to afford 2-(4-hydroxy-2,6-dimethylphenyl)cyclohexane-1,3-dione as a grey solid.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]([CH3:10])[CH3:9].ClC1C=C(SC2NC(C)=NC=2C(C)C)C=C(Cl)C=1>>[CH:8]([C:3]1[N:4]=[C:5]([CH3:7])[NH:6][CH:2]=1)([CH3:10])[CH3:9]
Reactant: Cc1nc(C(C)C)c(I)[nH]1
Agent: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)[nH]1
Product: Cc1nc(C(C)C)c[nH]1

Procedure:
4-Isopropyl-2-methylimidazole (3a) was synthesized in accordance with the procedure described in EP-A 585014, while 5-iodo-4-isopropyl-2-methylimidazole (4a) and 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1H-imidazole (5a) were synthesized in accordance with the procedure described in Japanese Kokai Hei-5-255270.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 2-(3-nitrophenyl)ethanol (9 g, 53.8 mmol) in DCM (100 mL) was cooled to 0° C., then pyridine (22.7 g, 287 mmol) was dropwise added to the reaction solution. Then methylsulfonylchloride was added slowly dropwise, followed by stirring at room temperature for one hour. Water was added to terminate the reaction. The aqueous layer was extracted by ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 3-nitrophenethyl methanesulfonate (13 g, yield 98%). 1H NMR: 400 MHz CDCl3 δ 8.13-8.10 (m, 2H), 7.60-7.53 (m, 1H), 7.53-7.47 (m, 1H), 4.48-4.45 (m, 2H), 3.19-3.15 (m, 2H), 2.95 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]2=[O:24])[S:5][CH:6]=1.C(N(CC)CC)C>CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([C:4]2[S:5][CH:6]=[C:2]([C:17]([O:19][CH3:20])=[O:18])[N:3]=2)[C:8]1=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1

Procedure:
To a suspension of tert-butyl [3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (250 mg, 0.609 mmol) and triethylamine (0.850 mL, 6.09 mmol) in MeOH (5 mL) was added bis(triphenylphosphine)palladium (II) chloride (86.0 mg, 0.122 mmol). The reaction mixture was heated at reflux under an atmosphere of carbon monoxide (ca. 1 atm) for 48 h, then partitioned between CHCl3 (20 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=412 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:21])[CH3:20].C(Cl)Cl.C(N(CC)CC)C>>[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (3 g, 0.01 mol), 4-isopropoxyphenylboronic acid (5 g, 0.03 mol), and cupric acetate (2.55 g, 0.0140 mol) were placed in a vial followed by methylene chloride (100 mL, 2 mol) and finally triethylamine (9.78 mL, 0.0702 mol) at 23° C. The flask was then purged with nitrogen, sealed and stirred at room temperature overnight. The reaction was allowed to stir for 16 hours. Reaction was then heated to 50° C. for two hours. The reaction mixture was then cooled to RT and filtrated and the crude material was then purified via chromatography (SiO2, 40 g, 0-75% EtOAC/Hexane) to give 2.4 g of the desired product as a colorless solid. Material was used without additional purification. ESI-MS: 378 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](N)[CH2:12][CH2:13]C>>[CH2:9]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: Cc1c(O)c(=O)ccn1C
Product: CCCCn1ccc(=O)c(O)c1C

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed, starting with butylamine (5.3 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (4.5 g). Proton NMR (D20): 7.84 (d, 1H), 6.80 (d, 1H), 4.15 (q, 2H), 2.39 (s, 3H), 1.61 (m, 2H), 1.16 (m, 2H), 0.72 (t, 3H).