Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCCCCC>[Cl:22][CH2:23][C:24]([O:21][C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109 %

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, thermometer and condenser is placed 65 g (0.23 mol) of trans-2-(2'-benzyloxyphenyl)cyclohexanol. This is dissolved in 200 ml of methylenechloride, and then 28.5 g (0.25 mol) of chloroacetyl chloride is added followed by 0.14 g (0.001 mol) of 4-dimethylaminopyridine. The mixture is heated to reflux and monitored by TLC (silica gel: 20% ethyl acetate, hexane). After 4 hours TLC shows the reaction to be complete, it is cooled to room temperature and 200 ml of saturated sodium bicarbonate is added. The reaction mixture is stirred rapidly for another 3 hours. The organic phase is then separated, dried with anhydrous potassium carbonate, filtered and evaporated under reduced pressure to yield 90 g of an amber oil. This oil is dissolved in 100 ml of hexane from which it crystallizes to afford 74 g of off-white solid trans-2-(2'-benzyloxyphenyl)cyclohexyl chloroacetate, which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:5].C1COCC1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 0 °C

Procedure:
Trans-2-Chloro-N-(4-hydroxymethyl-cyclohexyl)-5-trifluoromethyl-benzamide (Intermediate D, step 2) (1 g, 2.98 mmol) was suspended in DCM. THF (6 ml) was added to solubilise the alcohol. The mixture was cooled to 0° C. and treated with triethylamine (0.623 ml, 4.47 mmol) followed by dropwise addition of methanesulfonyl chloride (0.255 ml, 3.28 mmol). The reaction mixture was allowed to warm to RT stirring O/N and then diluted with DCM (50 ml). The mixture was washed with water, 1M HCl and brine. The organic portion was dried (MgSO4) and reduced under vacuum to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 7.53 (1H, d), 7.45 (1H, d), 5.91 (1H, d), 4.00 (2H, d), 3.90 (1H, m), 2.94 (3H, s), 2.14 (2H, m), 1.86 (2H, m), 1.71 (1H, m), 1.19 (4H, m).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH:17](O)[CH3:18])[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: CC(O)c1cc(Cl)ncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)c1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
(Diethylamino)sulphur trifluoride (0.337 mL, 2.55 mmol) was added to DCM (13 mL), cooled to −78° C. and treated dropwise with a solution of 1-(6-chloro-4-pyrimidinyl)ethanol (Intermediate 20, 328 mg, 2.068 mmol) in DCM (4 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding water (5 mL) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-25% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (125 mg);
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[C:10]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[S:9][C:8]=2[CH:37]=1.B(Cl)(Cl)[Cl:39].C(O)C.CO>ClCCCl>[Cl:1][CH2:8][CH2:37][Cl:39].[ClH:39].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12](=[O:28])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)=[C:10]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[S:9][C:8]=2[CH:37]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: ClB(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Solvent: CCO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 35 °C
Reaction time: 18 h

Procedure:
A solution of 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride (2.0 g) in 1,2-dichloroethane (20 mL) was treated with boron trichloride (2.0 mL). The resulting mixture was stirred at 35° C. for about 18 hours. A mixture of ethanol and methanol (10 mL, 95:5, 3A) was treated with the reaction mixture from above, causing the alcoholic mixture to reflux. Upon complete addition, the resulting crystalline slurry was stirred at 25° C. After one hour, the crystalline product was filtered, washed with cold ethanol (10 mL), and dried at 40° C. in vacuo to give 1.78 g of the title compound. The X-ray powder diffraction pattern is identical to that reported in Table 1.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cccc(CO)c1

Procedure:
To a solution of isophtalaldehyde (8 g) in ethanol (80 mL) at room temperature was added NaBH4 portion wise, until about 50% reaction by TLC. The reaction mixture was quenched with 25% ammonium acetate, extracted with ethyl acetate, which was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by flash chromatography using 50% ether in hexane afforded the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)(=[O:15])=[O:14])=[C:10]2[C:5]([C:6]([O:25][CH3:26])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[O:25][CH3:26])(=[O:14])=[O:15]
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c(Cl)ccc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3N)c(Cl)ccc12
Yield: 92.3 %

Procedure:
In a similar fashion using route 19 general procedure 29, N-(7-chloro-4-methoxy-quinolin-8-yl)-2-nitro-benzenesulfonamide 569 (580 mg, 1.4 mmol), SnCl2 (1.66 g, 7.3 mmol) in EtOH (20 ml) gave the title compound (470 mg, 92%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14](OC)[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[CH:14]=1)[CH2:23][CH:24]([CH3:25])[CH3:26])(=[O:30])[CH3:29]
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CC(C)C)c1ccc2c(c1)C(=O)OCc1cccc(C)c1O2

Procedure:
100 mg (0.27 mmol) of penicillide (Ib) are stirred in 2 ml of pyridine and 1 ml of acetic anhydride for 14 h at 25° C. with the exclusion of moisture. The reaction mixture is evaporated in vacuo, the residue is taken up in methylene chloride and the solution is washed with water. The evaporation residue of the dried organic phase is chromatographed on silica gel using hexane/diethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH3:18]>>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:18])=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: N
Reactant: C[C@H]1CCCN1[C@H]1C[C@H](c2ccc(Br)cc2)C1
Product: C[C@H]1CCCN1[C@H]1C[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 1C except substituting the product from Example 13A for the product from Example 1B. 1H NMR (300 MHz, CD3OD) δ 1.36 (d, J=6 Hz, 3 H), 1.72 (m, 1 H), 2.01 (m, 2 H), 2.24 (m, 1 H), 2.55 (m, 1 H), 2.63 (m, 1 H), 2.78 (m, 2 H), 3.02 (m, 1 H), 3.25 (m, 1 H), 3.42 (m, 1 H), 3.69 (m, 1 H), 3.90 (m, 1 H), 7.47 (d, J=9 Hz, 2 H), 7.68 (d, J=9 Hz, 2 H), 7.80 (AB q, 4 H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NCCc1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.2 g, 0.85 mmol) in tetrahydrofuran (6 mL) was cooled to 0° C. and was treated with triethylamine (0.13 mL, 0.92 mmol) and methoxyacetyl chloride (0.078 mL, 0.85 mmol). The reaction was stirred under an argon atmosphere for 0.25 h, then was partitioned between methylene chloride and water. The extract was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 5% methanol/chloroform, provided an oil; additional 0.1 g of impure product also obtained).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
Combine 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (0.304 g, 1.07 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.339 g, 2.14 mmol), and diisopropylethyl amine (0.19 mL, 1.07 mmol) in a mixture of toluene (3 mL) and dimethylsulfoxide (1 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (s)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.110 g, 0.283 mmol, 26%) as a yellow oil. Mass spectrum (APCI): m/z=389.1 (M+1).
Reaction SMILES: Cl.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[Na+].[Cl-].[OH:16][P:17]([O-:20])([O-:19])=[O:18].[K+].[K+].[Cl-].[Cl-].[Ca+2:25].C(O)C(N)(CO)CO.C([O-])(O)=O.[Na+]>O>[P:17]([O-:20])([O-:19])([O-:18])=[O:16].[Ca+2:25].[P:17]([O-:20])([O-:19])([O-:18])=[O:16].[Ca+2:25].[Ca+2:25]
Reactant: O=P([O-])([O-])O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])O
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 16 h

Procedure:
Three of the samples were first exposed to a formulation containing 6.4N HCl and 0.15M ammonium persulfate for about one hour, resulting in microtexturing. Three other samples were first exposed to a formulation containing 8N HCl for about 24 hours, resulting in nanotexturing. The final three samples were not exposed to an etching formulation. All nine samples were vertically oriented on a Teflon fixture, and immersed in 1 L of a coating solution for about 16 hours at about 37° C. The coating solution included NaCl (150.2 mM), K2HPO4 (2.4 mM), MgCl2.6H2O (2.5 mM), CaCl2. 2H2O (6 mM), Tris(hydroxymethyl)aminomethane (17.5 mM), NaHCO3 (8 mM), 18 mL of 1N HCl, and water to create a total 1 L solution. The final coating solution had an initial pH of about 6.9 before samples were added. After 16 hours of the coating process, the samples were removed from the coating solution, rinsed three times in ethanol, and dried at ambient room conditions.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>CO>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(C)cc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CO
Product: Cc1cc2nc3ccc(C(=O)O)cn3c(=O)c2s1

Procedure:
A mixture of 1.7 g (0.01 mol) of 3-amino-5-methyl-2-thiophenecarboxylic acid, methyl ester (German Pat. No. 1055007, Apr. 16, 1959) and 1.6 g (0.01 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) is heated in an oil bath at 180° C. for two hours. The mixture is cooled, dissolved in hot methanol, cooled and 0.23 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid is collected; mp 338°-340° C. after recrystallization from methanol.
Reaction SMILES: [I-].[CH:2]1([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reactant: c1ccc([PH](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphine iodide (725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixture was stirred at 0° C. for 45 minutes and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction mixture was warmed to 25° C. where it was stirred for 20 h. The reaction mixture was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)N(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(C)CCOc1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
18.6 g of p-phenoxyphenol are dissolved in 100 ml of dimethylformamide. 18.2 g of ethyl (2-chloroethyl)-methylcarbamate and 27.6 g of potassium carbonate are added thereto and the reaction mixture is heated at 80° C. while stirring for 15 hours. The reaction mixture is poured into 300 ml of water and extracted with diethyl ether. The ether extract is washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography on silica gel using n-hexane/ethyl acetate (9:1) as the eluent yields ethyl [2-(p-phenoxyphenoxy)ethyl]methylcarbamate; nD20 =1.5503.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1>CN(C)C=O.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(/C=C/COCCCN2CCCC2)cc1
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: Fc1ccc(CCCOCCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A suspension of platinum dioxide (300 mg) in a solution of trans-1-{3-[3-(4-fluorophenyl)allyloxy]propyl}pyrrolidine (330 mg) in N,N-dimethylformamide (3 mL) is stirred overnight at room temperature under an atmosphere of dihydrogene. An additional amount of platinum dioxide is added and the suspension is stirred for 24 hours at room temperature under an atmosphere of dihydrogene. The suspension is filtered over a celite pad and rinsed with ethyl acetate. Ethyl acetate is evaporated from the filtrate, platinum hydroxide (190 mg) is added and the suspension is stirred for 48 hours at room temperature under an atmosphere of dihydrogene. The suspension is filtered over a celite pad, rinsed with ethyl acetate, concentrated under reduced pressure and dissolved in a mixture of ethanol (2 mL) and diethyl oxide (200 μL). A solution of oxalic acid (58 mg) in ethanol (2 mL) is added. The mixture is concentrated under reduced pressure and suspended in diethyl oxide. The precipitate is filtered, rinsed with diethyl ether, dissolved in water (5 mL). The aqueous layer is made alkaline with ammonia and extracted twice with diethyl oxide (10 mL). The organic extracts are pooled, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol/ammonia from 99/10/0.1 to 92/2/0.2. Fractions containing the expected product are pooled, concentrated under reduced pressure, dissolved in diethyl oxide (2 mL). A solution of oxalic acid (21 mg) in acetone is added and the precipitate that appears is filtered and dried under reduced pressure at 40° C. under a film of diethyl oxide to give 96 mg of 1-{3-[3-(4-fluorophenyl)propoxy]propyl}pyrrolidine, oxalate as a white solid melting at 106° C.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([NH:13][CH:14]([CH3:18])[CH2:15][C:16]#[N:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]([CH:14]([CH3:18])[CH2:15][C:16]#[N:17])[CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CC#N)NCc1ccccc1
Reactant: OCC1CO1
Solvent: CCO
Product: CC(CC#N)N(Cc1ccccc1)CC(O)CO
Yield: 26.6 %

Procedure:
A solution of glycidol (70 ml, 1.05 mol) and 3-(benzylamino)butyronitrile (111 g, 0.64 mol) in ethanol (800 ml) was heated to reflux for 18 hours. Additional glycidol (50 ml, 0.75 mol) was added, and the mixture was heated at reflux for an additional 24 hours. Removal of solvent in vacuo left a residue which was partitioned between water and ethyl acetate. The organic layer was washed with water, washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration in vacuo provided an oil, which was purified by column chromatography (eluant: 5% methanol in chloroform) to give the title product as an oil (42 g, 0.17 mol, 27% yield). 1H NMR (CDCl3): 7.31 (m, 5H), 3.77 (d, J=13.4 Hz, 1H), 3.67 (m, 3H), 3.49 (d, J=13.5 Hz, 1H), 3.43 (m, 1H), 3.18 (m, 1H), 2.55 (m, 4H), 2.30 (m, 1H), 1.16 and 1.08 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
To a solution of racemic a-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 8 mL (66.0 mmol) of 1-(hydroxyethyl)piperazine. The reaction mixture was refluxed for three hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a yellow oil. MS (ion spray) 279.1 (M+).
Reaction SMILES: C([C:3]1([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=2[OH:18])[NH:7][CH:6]([C:8]([O-:10])=[O:9])[CH2:5][S:4]1)C.Cl.N[C@H:21](C(O)=O)CS>>[OH:18][C:12]1[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=1[CH:3]1[NH:7][CH:6]([C:8]([O:10][CH3:21])=[O:9])[CH2:5][S:4]1
Reactant: CCC1(c2cc(O)ccc2O)NC(C(=O)[O-])CS1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: COC(=O)C1CSC(c2cc(O)ccc2O)N1

Procedure:
The procedure described below for preparation of ethyl-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylate (7) was employed to make 6, except the methyl ester of L-cysteine hydrochloride was employed as starting material.
Reaction SMILES: [Na].C(O)C.[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[CH2:6][CH3:7].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C(O)C.O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:5](=[O:8])[CH:6]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:7])[CH3:14]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)Cc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
Sodium (1.25 g) was added to 60 mL of absolute ethanol under nitrogen atmosphere at room temperature. When all of the metal had reacted the mixture was cooled in ice and ethyl propionylacetate was added in one portion. The reaction mixture was brought to reflux temperature for 0.25 hours, an ethanol-tetrahydrofuran solution (10:1, 120 mL) of 2-bromomethylnaphthalene (10 g) added, and the resulting mixture heated at reflux temperature 15 hours. The reaction mixture was cooled to room temperature and the volatile materials removed in vacuo on the rotary evaporator. The residue was partitioned between saturated, aqueous NaCl solution and ethyl acetate. The organic phase was dried over MgSO4 and concentrated to an oily mixture which was purified by HPLC (hexane, ethyl acetate gradient elution) to give 5.2 g of ethyl-α-(2-naphthalenylmethyl)propionylacetate as a yellow oil.