Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.O>C1(C)C=CC=CC=1>[CH3:12][N:2]([CH3:1])[C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: CN(C)CCCl
Reactant: CN(C)C(=O)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCC(C(=O)N(C)C)c1ccccc1
Yield: 76.8 %

Procedure:
To a mechanically-stirred, refluxing suspension of 5.85 g (0.15 mol) of NaNH2 in 150 ml of toluene, was added dropwise under N2, 50 ml of a toluene solution consisting of 16.3 g (0.1 mol) of N,N-dimethyl-phenylacetamide (prepared by reaction of phenylacetyl chloride and N,N-dimethylamine in CH2Cl2 solvent) in toluene, and the mixture was stirred at reflux for 4 hr. Then, 16.5g (0.15 mol) of 2-(dimethylamino)ethyl chloride in 100 ml of toluene was added dropwise. The mixture was refluxed for 6 hr and then stirred at RT for 16 hr. Water (150 ml) was added to the mixture, and then the organic layer was separated and extracted with 1N HCl. The acid extract was basified in the cold with 2.5N NaOH and the basic solution extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and distilled to afford 18 g (76.8%) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide as a colorless oil, bp 108°-110°/0.2 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.O.O.Cl[Sn]Cl>CCO>[CH2:12]([O:11][C:9](=[O:10])[CH:8]=[CH:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([NH2:1])[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1cccc(N)c1

Procedure:
Ethyl 3-nitrocinnamate (1) (2.0 g, 9.04 mmol) was reduced using method A, except that SnCl2.2H2O (10.2 g, 45.20 mmol) in EtOH (20 mL) was used and after the reaction the solvent was concentrated in vacuo, Rochelle's salt and saturated NaHCO3 (1:1, 80 mL) were added, and the aqueous basified with 1N NaOH. The aqueous was extracted with EtOAc (3×40 mL), washed with Rochelle's salt/saturated NaHCO3 solution (2×40 mL), dried (MgSO4) and the solvent was concentrated in vacuo to give the title compound. Yield: 1.77 g, >100%; LC/MS tr 0.89 min; MS (ES+) m/z 192 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:17])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 4-benzyloxy-2-bromophenol (20 g, 71.6 mmol) in N,N-dimethylformamide (65 ml) was added potassium carbonate (12.4 g, 89.6 mmol) and methyl iodide (12.7 g, 89.6 mmol). The mixture was stirred at room temperature for 18 hours, poured into water (250 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (20.15 g, 96%), δH (250 MHz, CDCl3) 3.84 (3H, s, ArOCH3), 4.99 (2H, s, OCH2), 6.80-6.94 (2H, m ArH), 7.21 (1H, d, J 2.75Hz, ArH), 7.28-7.43 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][N:30]1[CH2:31][C:27]([F:35])([F:26])[CH2:28][C@H:29]1[C:32]([OH:34])=[O:33])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CN2CC(F)(F)C[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.049 g, 0.11 mmol) and (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid (0.044 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4Cl solution and brine. The organic layer was separated and dried over Na2SO4. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give 6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[F:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)cc3)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Yield: 101.1 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-(propane-2-sulfonyl)-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (175 mg, 0.26 mmol), 4-fluoro-phenylboronic acid (73 mg, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.039 mmol), and cesium carbonate (172 mg, 0.52 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (180 mg, 99%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H49FO8S (M+Na)+ 707.3024, found 707.3020.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37]>C1COCC1.CC(C)=O>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 78.5 %

Procedure:
4.98 g (20 mmol) N-carbobenzoxy-L-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 2.73 g (26.5 mmol) L-valinol were contacted and reacted in THF, using a mixed anhydride procedure substantially as described in Example 1. The crude product, 5.93 g, was recrystallized from a mixture of 150 mL ethyl acetate and 250 mL n-hexane to give 5.24 g (15.7 mmol, 78%) of colorless N-carbobenzoxy-L-prolyl-L-valinol, m.p. 109.3°-110.7°, α25D -65.3°, (C=1.01 g/100 mL in acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:11])[S-:10])=[N:6][CH:7]=1.C([NH+](CC)CC)C.[CH2:19]=[CH:20][C:21](=[O:24])[CH2:22][CH3:23]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:10])[S:11][CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH3:23])=[N:6][CH:7]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC(=O)CC
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
The procedure of Example 6 is followed but triethylammonium 5-chloropyrid-2-yldithiocarbamate (91.5 g) and pent-1-en-3-one (28.0 g) in anhydrous chloroform (600 cc) are used as the starting materials at a maximum temperature of 5° C. The reaction is allowed to proceed for 2 hours at a maximum temperature of 5° C. The crude product (90.0 g) is dissolved in methylene chloride (400 cc). The solution is chromatographed on a column of diameter 6.5 cm, containing silica (0.063-0.2 mm; 750 g). Elution is carried out with methylene chloride (1,500 cc), this eluate being discarded, and then with methylene chloride (6 liters), this eluate being collected and evaporated to dryness. The product obtained (59.1 g) is purified by recrystallisation from a mixture of acetonitrile (60 cc) and diisopropyl ether (120 cc). 3-Oxopentyl 5-chloropyrid-2-yldithiocarbamate (49.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 80° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][C:22]1[N:26]=[C:25](S(C2C=CC(C)=CC=2)(=O)=O)[S:24][N:23]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][C:22]1[N:26]=[C:25]([O:9][C:7]2[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[S:24][N:23]=1
Reactant: Cc1ccc(S(=O)(=O)c2nc(Cc3cccc(Cl)c3)ns2)cc1
Reactant: Cc1cc(O)c(C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(Cc3cccc(Cl)c3)ns2)c(C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
3.86 g (28.1 mmol) of 2,5-dimethyl-4-hydroxyaniline are placed in 50 ml of acetonitrile, 4.66 g (33.8 mmol) of potassium carbonate are added at ambient temperature and the mixture is stirred for 30 min at ambient temperature. Subsequently, 11.0 g (28.1 mmol) of 3-(3-chlorobenzyl)-5-[(4-methylphenyl)sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated using a rotary evaporator and the residue is taken in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 6.86 g of product are obtained (96.4% purity, 68.0% yield, log P (pH 2.3)=3.68).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1)=[O:68]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cn(-c2ccccn2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cn(-c2ccccn2)nn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 83.1 %

Procedure:
DIPEA (166 mg, 0.23 mL, 1.28 mmol) was added to a stirred solution of 1-Pyridin-2-yl-1H-[1,2,3]triazole-4-carboxylic acid (61 mg, 0.25 mmol)(prepared by the method as described above) in DMF (4 mL). HOBT (38 mg, 0.28 mmol) and EDCI (123 mg, 0.64 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (104 mg, 0.28 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 105 mg (80.7% yield) of 1-pyridin-2-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.70%. 1H NMR (DMSO-d6): δ 9.2 (s, 1H), 8.7 (m, 2H), 8.22 (d, 2H), 8.0 (t, 1H), 7.66-7.5 (m, 3H), 4.3-4.16 (dd, 2H), 3.84 (bs, 1H), 3.66-3.4 (m, 5H), 3.26 (d, 2H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([NH2:10])=[C:8]([CH2:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>O.Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:9](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:12]=1)[NH:10][N:1]=[C:20]2[S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2N)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2cc(Cl)cc3c(S(=O)(=O)c4ccc(F)cc4)n[nH]c23)CC1
Temperature: 25 °C

Procedure:
A solution of NaNO2 (22.0 mg) in water at 0° C. is treated dropwise with a solution of 4-chloro-2-{[(4-fluorophenyl)sulfonyl]methyl}-6-(4-methylpiperazin-1-yl)aniline (102.2 mg, 0.25 mmol) in 1M HCl, allowed to warm to room temperature over a 2 h period, treated with saturated Na2CO3 to pH>10 and filtered. The filtercake is washed with water and dried in vacuo to give the title compound, identified by mass spectral and NMR analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.CS(O[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:17]([O-:19])=[O:18])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: COCCCCOS(C)(=O)=O
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCCCN(C(=O)OC(C)(C)C)c1cccc(OC)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
tert-Butyl (3-methoxy-2-nitrophenyl)carbamate (3.00 g) and 4-methoxybutyl methanesulfonate (3.06 g) were dissolved in dimethylformamide (40 ml), cesium carbonate (7.30 g) was added, and the mixture was stirred at 65° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-7:3) was concentrated under reduced pressure to give the object product (2.11 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:4].CCOCC.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:12][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.2 h

Procedure:
25.2 g (154 mmol) of methyl terephthalaldehydate was dissolved in 200 ml of tetrahydrofuran. 51.2 ml(154 mmol) of a 2M ether solution of phenyl magnesium bromide was added dropwise thereto under cooling in a sodium chloride-ice bath with stirring for 12 minutes and the mixture was stirred for further 20 minutes. Dilute hydrochloric acid was added to the resulting reaction mixture, then the obtained mixture was extracted twice with ethyl acetate. After the organic phase was washed with brine and dried (MgSO4), the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1 (v/v)) to obtain 31.7 g (131 mmol) of methyl α-hydroxy-α-phenyl-p-toluate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[N:1]1([C:11]([C@@H:7]2[CH2:8][CH2:9][CH2:10][O:6]2)=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cl)[C@@H]1CCCO1
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: O=C([C@@H]1CCCO1)n1ccnc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
21.8 g (32.0 mmol) imidazole are placed in 400 ml chloroform and cooled to 0° C. 21.5 g (15.0 mmol) (S)-tetrahydrofuran-2-carbonyl chloride are added dropwise, then stirred for 1.5 hours at ambient temperature. After cooling again to 0° C. the reaction mixture is extracted with semisaturated sodium chloride solution. The organic phase is dried and evaporated to dryness. Yield: 23.5 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:22])C1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
To a solution of 100 g (0.33 mol) of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone in 1 L of DMSO, 75 g (0.42 mol) of NBS was added and the mixture was stirred over a weekend. The reaction was poured into 8 L of water and stirred for 30 min. The yellow solid formed was filtered and dried. This solid was purified by passing through a plug of 1 Kg of silica gel using hexane and 5% EtOAc-hexane to isolate the title compound. 1H NMR: (500 MHz, CDCl3): δ 7.4–8.0 (m, 7H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)cc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (2.8 ml) was added dropwise to 70% nitric acid (4.0 ml) in an ice-water bath. This mixture was added to a solution of 2,4,6-trichlorobenzoic acid (5.13 g) in concentrated sulfuric acid (23 ml) dropwise for 20 minutes in an ice-water bath. The mixture was stirred for 16 hours at ambient temperature and poured into ice-water (300 ml) slowly. This mixture was stirred for 1 hour at ambient temperature. The precipitate was collected by vacuum filtration and washed with water to give 2,4,6-trichloro-3-nitrobenzoic acid (5.26 g) as colorless fine crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48]Br>>[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1

Procedure:
Analogously to Method D, 1.30 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.0 g of 2-bromo-1-bromomethyl-3-nitrobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.29 (1:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>>[F:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([F:18])[CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cc(F)cc(F)c2)CC1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cc(F)cc(F)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3,5-difluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.148 g, 0.548 mmol) and hydrazine hydrate (0.106 ml, 2.19 mmol) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:11](=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]=[CH:20][C@@H:19]1[C:23]([O:25]CC)=[O:24])=[O:17])=[O:5])C.Cl>>[C:23]([C@H:19]1[CH:20]=[CH:21][CH2:22][N:18]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]([N:7]1[CH2:8][CH:9]=[CH:10][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:28])([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H]1C=CCN1C(=O)CCCCC(=O)N1CC=C[C@@H]1C(=O)OCC
Agent: Cl
Product: O=C(O)[C@H]1C=CCN1C(=O)CCCCC(=O)N1CC=C[C@@H]1C(=O)O
Yield: 118.9 %

Procedure:
0.09 g (0.0002 mol) (R)-1-[6-[(R)-2-ethyloxycarbonyl-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid ethyl ester were stirred with aqueous HCl at 50° C. for 3 hours. The solvent was evaporated and the residue dissolved in water and lyophilized to yield 0.08 g (97%) (R)-1-[6-[(R)-2-carboxy-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid as light yellow foam. ISP-
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26])(=[O:22])[CH3:21].CC[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][S:26][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])(=[O:22])[CH3:21]
Reactant: O=C(O)CCCBr
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CSC(=O)CCCBr)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 4-bromobutyric acid (5.1 g, 30.6 mmoles) and 1,1′-carbonyldiimidazol (5.61 g, 34.6 mmoles)) in chloroform (50 ml) is left at room temperature under stirring for 1 hour. To the reaction mixture N-acetyl cysteine (5 g, 30.6 mmoles) dissolved in N,N-dimethylformamide (5 ml) and sodium ethylate (50 mg) is added under stirring. After 24 hours the solution is washed with HCl 1% and brine, the organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel column, eluting with ethyl acetate/chloroform 7/3. N-acetyl-S-(4-bromobutyroyl)cysteineis obtained.