Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:6]([N:13]1[CH2:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[O:16][CH2:2][C:3]1=[O:4])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: OC(CNCc1ccccc1)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
After addition of chloroacetyl chloride (8.49 g, 75.2 mmol) in toluene (30 ml) to a ice-cooled solution of 2-benzylamino-1-(4-bromo-phenyl)-ethanol (intermediate 31, 21.85 g, 71.4 mmol) in toluene (300 ml), a solution of triethylamine (10.25 g, 101 mmol) in toluene (20 ml) was added to the mixture and stirred for one hour. Sodium methoxide (28% solution in methanol, 45.73 g, 237 mmol) in methanol (30 ml) was then added to the solution and stirred for 2 hours. Reaction was quenched by adding dilute hydrochloric acid to adjust the pH around 7.0, and partitioned between water and ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine and dried over sodium sulfate. Solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to afford 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (intermediate 32, 21.26 g, 86%) as a colorless oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[N:11]1([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: C1CN(C2CCC3(CC2)OCCO3)CCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(N2CCOCC2)CC1
Reaction time: 17 h

Procedure:
To a solution of 7 (4.50 g, 19.8 mmol) in THF (100 mL) was added 7 N aqueous HCl (40 mL). The reaction mixture was stirred for 17 h and the reaction was quenched by pouring onto saturated aqueous NaHCO3 (475 mL). The mixture was extracted with EtOAc (1×) then CH2Cl2 (3×) and the combined organic extracts dried (MgSO4) and concentrated. The resulting oil was purified by Kugelrohr distillation to give (VII-g) (3.17 g, 87%) as a clear oil; 1H NMR (400 MHz, CDCl3) δ 1.80-1.94 (m, 2H), 1.80-2.10 (m, 2H), 2.30 (m, 1H), 2.45-2.65 (m, 8H), 3.74 (t, J=4.7 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Fc1ccc(Cl)cc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-chloro-1-fluorobenzene (4.31 g, 20 mmol) was added dropwise to a −78° C. solution of LDA in THF (prepared from diisopropylamine (3.38 ml, 24 mmol) and n-BuLi (1.6 M, 13.1 ml, 21 mmol)). The mixture was stirred at −78° C. for 1 h, and then was transferred slowly (˜30-60 min) via cannula to a stirred −78° C. mixture of dry ice and THF (40 ml). The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to rt (gas evolution). The mixture was concentrated, and was then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with 1N hydrochloric acid, and then was extracted with chloroform (3×400 ml). The chloroform extract was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound. The product was contaminated with a small amount of the isomeric product 2-bromo-6-chloro-3-fluorobenzoic acid. 1H NMR for title compound 3-Bromo-5-chloro-2-fluorobenzoic acid: (400 MHz, CDCl3) δ 7.93 (dd, 1H, J=2.8, 5.6 Hz), 7.79 (dd, 1H, J=2.8, 5.6 Hz) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1.CO>[ClH:19].[ClH:19].[CH:15]1([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1CC(N2CCCNCC2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 1-L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and a reflux condenser. The flask was charged with a slurry of crude 4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (92.4 g, 363.8 mmol) in a mixture of dioxane/MeOH (100 mL/50 mL). HCl (4 M in dioxane, 250 mL) was added with vigorous mechanical agitation following which the reaction mixture was heated to ca. 55° C. in an oil bath. A pale orange-yellow solution resulted. The reaction mixture was maintained at ca. 55° C. for 16 h. After cooling to rt, the reaction mixture, a thick slurry, was transferred to a 2-L recovery flask and concentrated to a pasty solid. Methyl tert-butyl ether (200 mL) was added, and the slurry agitated at ca. 55° C. in an oil bath for 1 h. The solvent was removed by rotary evaporation under reduced pressure to afford the product as an off-white solid (81.2 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 11.92 (s, 1H), 9.87 (s, 1H), 9.46 (s, 1H), 3.76-3.03 (m, 9H), 2.43-2.33 (m, 2H), 2.17-2.15 (m, 4H), 1.75-1.60 (m, 2H). MS m/z (ESI+): 155.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:18])=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Yield: 84.2 %

Procedure:
A mixture of 4-methyl-2-phenylbenzoic acid methyl ester (2.26 g, 10 mmol), prepared as in Example 227B, N-bromosuccinimide (1.87 g, 10.5 mmol) and 2,2′-azobisisobutyronitrile (25 mg) in carbon tetrachloride (40 mL) was stirred at reflux for 7 hours. The reaction mixture was poured into ethyl acetate and extracted with water (2×), aqueous sodium hydrogen sulfite and brine, dried, filtered, and concentrated in vacuo. Chromatography on silica gel (10% ethyl acetate-hexane) gave 4-bromomethyl-2-phenylbenzoic acid methyl ester (2.57 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CO.ClCCl>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 1.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].N>C1COCC1.CO.O>[F:1][C:2]1[C:3]2[NH:9][C:10](=[O:11])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES−) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].C(O)(=O)C>O>[Cl:20][C:19]1[CH:18]=[CH:17][C:15]([N:16]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:14][C:13]=1[OH:12]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 15.2 g. of 3,4,5,6-tetrahydrophthalic anhydride, 14.4 g. of 3-hydroxy-4-chloroaniline and 50 ml. of glacial acetic acid was refluxed with stirring for 2 hours and then, the reaction mixture was cooled to a room temperature and water was added to precipitate a crystal and the crystal was separated by a filtration and recrystallized from isopropanol to obtain N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 236.5°-238° C.; yellow crystal) (yield: 87.5%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([O:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: OCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
Phenol (0.098 g, 1.04 mmol) and 7-bromo-1-heptanol (0.243 g, 1.246 mmol) were dissolved in acetone (25 mL) in a 50 mL round bottomed flask. Potassium carbonate (0.86 g, 6.23 mmol) was added to this solution and the flask was fitted with a condenser and refluxed using an oil bath at 70° C. for a period of 26 hours. The reaction flask was then cooled to room temperature. The contents of the flask was then filtered through a fluted filter paper and washed with acetone (10 mL). The combined filtrate was then evaporated to dryress under reduced pressure. The residue obtained was dissolved in ethyl acetate (25 mL). The ethyl acetate solution was then washed with 1N. NaOH (3×5 mL), water (2×5 mL) and brine (2×5 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product. The product was then purified by flash chromatography (Si gel, 12×2.5 cm) using ethyl acetate: hexane (1:1) to afford the pure 7-(phenyloxy)-1-heptanol (0.22 g, quantitative yield). The product alcohol from step A was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.31-1.52 (m, 6H), 1.52-1.63 (m, 2H), 1.73-1.89 (m, 2H), 1.97 (bs, 1H), 3.61 (t, 2H, J=6.57 Hz), 3.93 (t, 2H, J=6.50 Hz), 6.80-6.97 (m, 3H) and 7.20-7.28 (m, 2H); 13C-NMR (CDCl3) δ 25.5, 25.8, 29.0, 29.1, 32.4, 62.5, 67.7, 114.3, 120.3, 129.2 and 158.8; IR (neat): 3348 cm−1; MS (ES+): 209 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH:5]=O)=[CH2:4].C([O-])(=O)C.[NH4+:11].Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[CH2:2]([C:3]1[CH:5]=[N:11][C:19]([CH3:21])=[C:13]([CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:1]
Reactant: [NH4+]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C=C(C=O)CC
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC)cnc1C
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of ethacrolein (12.8 g 0.152 mole) and ammonium acetate (24.4 g 0.304 mole) in 50 cc acetonitrile is stirred at room temperature and a solution of ethyl 2-chloroacetoacetate (25 g 0.152 mole) in 30 cc acetonitrile is added dropwise over 15 minutes. The reaction mixture is heated at reflux for 16 hours, cooled, and partitioned between water and ethyl acetate. The organic phase is concentrated in vacuo and chromatographed on silica gel using 9:1 hexane-ethylacetate to afford 12.7 g of the title product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]2[N:11]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:12]=[CH:13][C:5]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 60% sodium hydride in mineral oil (1.390 g, 34.8 mmol) in N,N-dimethylformamide (60 mL) at 0° C. was added a solution of 4,5-dichloro-1H-pyrrolo[2,3-b]pyridine (Adesis, 5.0 g, 26.7 mmol) in N,N-dimethylformamide (20 mL) slowly over 5 minutes. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was cooled to 0° C. and a solution of p-toluenesulfonyl chloride (5.35 g, 28.1 mmol) in N,N-dimethylformamide (20 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. Additional p-toluenesulfonyl chloride (500 mg, 2.62 mmol) was added, and the mixture was stirred another 1 hour at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 40-70% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 341.6 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].IC.[C:15]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 3-hydroxy-4-nitrobenzaldehyde (51.3 g), iodomethane (38.3 ml) and K2CO3 (85 g) in DMF (250 ml) was stirred at 60° C. for 1 h. The reaction mixture was cooled to room temperature and poured into water (600 ml). The solids were collected by filtration and dried in vacuo (50° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Yield: 54.3 %

Procedure:
1,1-Dimethylethyl 4-{[(6-chloro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.80 g, 54%) was prepared as a white solid from 2-chloro-5-hydroxypyridine (0.60 g, 4.51 mmol), N-Boc-4-piperidinemethanol (1.0 g, 4.51 mmol) and Ph3P (1.20 g, 4.51 mmol) in THF (25 mL) followed by diisopropyl azodicarboxylate (0.97 g, 94%, 4.51 mmol) in THF (8 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.25-7.15 (m, 2H), 4.20-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.80-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.85-1.75 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 327 (M+H).
Reaction SMILES: C(CC1SC(S)=NC=1)(O)=O.[C:11]1([O:19][CH3:20])[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:13][CH3:14].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:14][O:13][C:12]1[CH:15]=[C:16]([CH:17]=[CH:18][C:11]=1[O:19][CH3:20])[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:27]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)Cc1cnc(S)s1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC

Procedure:
A 5-carboxymethyl-2-mercaptothiazole derivative can be prepared by reacting veratrole with succinic anhydride in the presence of anhydrous aluminum chloride to obtain 3-(3,4-dimethoxybenzoyl)propionic acid, subjecting the compound to demethylation with hydrobromic acid to obtain 3-(3,4-dihydroxybenzoyl)propionic acid, subjecting the compound to enol-lactonation in the presence of acetic anhydride and sodium acetate, reacting the resulting compound sequentially with N-bromosuccinimide and with diphenyldiazomethane to obtain 3-(3,4-diacetoxybenzoyl)-3-bromopropionate, and further reacting the compound with ammonium dithiocarbamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[CH3:33][O:34][NH:35][CH3:36]>Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:35]([O:34][CH3:33])[CH3:36])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
To a solution of CH2Cl2 (1 L) was added 3-fluoro-4-nitrobenzoic acid (100 g, 540 mmol) and EDCI (155.3 g, 810 mmol) followed by NMM (178 mL, 1.62 mol) and N-methoxymethanamine hydrochloride (79.0 g, 810 mmol). The solution was allowed to stir under N2 at rt for 17 h. The reaction mixture was then diluted with 1N HCl (1 L), transferred to separatory funnel, and separated. The organic phase was washed with 1N NaOH (2×500 mL) and water (250 mL). All aqueous layers were back extracted with EtOAc (2×500 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. to afford 102.3 g of the above compound as a yellow solid (448 mmol, yield 83%). 1H-NMR (DMSO-d6) δ 8.22 to 8.18 (t, J=8.0 Hz, 1H), 7.79 to 7.76 (d, J=11.5 Hz, 1H), 7.60 to 7.58 (d, J=8.3 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H); MS [M+H]+=229.1; LCMS RT=2.27 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24].C(OCC)C>C1COCC1.O>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 25 °C

Procedure:
(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (773 g, 1 mole) is dissolved in THF (1500 ml) with an addition of water (40 ml) under reflux. After gradual cooling down to ambient temperature, diethylether (300 ml) is added drop-wise to the mixture over 6 hours. The precipitated crystals are sucked off and washed with THF. Yield: 232 g (30%). Optical purity: 93% ee (CE).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chlorooxoacetate (2.41 mL, 26.1 mmol) was added dropwise over 2 mins to a stirred solution of ethyl cis-4-(4-aminophenoxy)cyclohexanecarboxylate (6.24 g, 23.7 mmol) and diisopropylethylamine (8.25 mL, 47.4 mmol) in DCM (200 mL) and the reaction mixture was stirred at ambient temperature for 16 h. Water (75 mL) was added and the layers were separated. The organic layer was washed with an aqueous solution of hydrochloric acid (1M, 75 mL) and then a saturated aqueous solution of sodium hydrogen carbonate (75 mL), dried (MgSO4) and concentrated in vacuo to provide the title compound as a white solid (8.23 g, 100%).