Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([O:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[CH:19][CH:20]=1)([O-:9])=[O:8]
Reactant: Oc1ccccc1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 19.3 g of p-nitrocinnamic acid suspended in 300 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, upon which p-nitrocinnamoyl chloride precipitated. The precipitates thus obtained were dissolved in 300 ml of ethyl acetate, and 9.4 g of phenol was added to the resulting solution, after which 12 g of triethylamine was slowly added thereto at room temperature with stirring. After reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to obtain phenyl p-nitrocinnamate. Yield: 25.5 g (95%); melting point: 151°-152° C.; IR (cm-1): 1720, 1529, 1345.
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][NH2:31])[N:25]=[CH:24]1>C(#N)C.C(O)C>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:31][CH2:30][CH2:29][CH2:28][C:26]1[N:25]=[CH:24][NH:23][CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C1NCC(COc2ccccc2)O1)c1ccccc1
Reactant: NCCCc1c[nH]cn1
Solvent: CC#N
Solvent: CCO
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1ccccc1)c1ccccc1
Yield: 38 %

Procedure:
1.48 g (5 mmol) of 2-benzoylimino-5-phenoxymethyloxazolidine and 0.69 g (5.5 mmol) of 3-(imidazole-4-yl)-propylamine are heated together under reflux in a mixture of 40 ml of acetonitrile and 10 ml of ethanol for 8 hours. The reaction mixture is concentrated by evaporation under vacuum and the product is isolated and purified by preparative layer chromatography (silica gel 60 PF254 containing gypsum: solvent; chloroform/methanol 98:2, ammoniacal atmosphere). Crystallisation from acetonitrile results in 0.8 g (38%) of colourless crystals, melting point 129° C.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(O)(=O)C.[CH3:10][C:11]1[O:15][C:14]([CH:16]=[CH:17][CH2:18][CH2:19]O)=[CH:13][CH:12]=1.[Cl-].[Na+]>O>[CH2:17]([C:16]1[C:14](=[O:15])[CH2:13][CH:12]([OH:3])[C:11]=1[CH3:10])[CH:18]=[CH2:19]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h
Yield: 219.8 %

Procedure:
A buffer solution was prepared by dissolving sodium acetate (1.03 g) and Paion D-408 (polyoxyethylene alkyl phenyl ether; manufactured by Takemoto Yushi Inc.) (0.44 g) in water (200 ml) and adjusting the pH value to 6.0 with acetic acid. In a reaction vessel, 5-methyl-2-furylallylcarbinol (5 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 3.5 hours. After ice-cooling, sodium chloride (50 g) was added, and the mixture was extracted with methyl isobutyl ketone (100 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (4.6 g) was obtained. The crude product was purified by column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (4.2 g). Yield, 84%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.Br[CH:15](Br)[CH3:16]>C1COCC1>[Cl:3][C:4]1[C:9]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15]2)=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: CC(Br)Br
Reactant: N#CCc1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)nc2Cl)CC1
Temperature: 0 °C
Yield: 60.7 %

Procedure:
5.92 g of sodium hydride (60% in oil) was suspended in 200 ml of dry THF and 10.13 g of (2,6-dichloro-pyridin-3-yl)-acetonitrile in 25 mL of dry THF was added dropwise at 0° C. The reaction mixture was stirred at 0° C. until the end of gas formation. Then 37.4 g of dibromoethane was added at 0° C. and the reaction mixture was stirred at ambient temperature for 14 h. Subsequently, the reaction mixture was quenched with 60 ml of aqueous saturated ammonium chloride. The reaction mixture was extracted with two 500 ml portions of ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. 19 g of crude material was obtained as a dark solid which was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (4:1) as a solvent. Thus, 7 g of 1-(2,6-dichloro-pyridin-3-yl)-cyclopropanecarbonitrile was obtained as an orange solid. 1H-NMR (CDCl3): 7.64 ppm (d, 1H), 7.30 ppm (d, 1H), 1.83 ppm (m, 2H), 1.36 ppm (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH2:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCCc1ccccc1N
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCc1ccccc1N
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with 2-(2-amino-phenyl)-ethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.BrCCCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:66]([C:68]1([C:105]2[CH:110]=[CH:109][C:108]([OH:111])=[CH:107][CH:106]=2)[CH:77]([CH2:78]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:76]2[C:71](=[CH:72][C:73]([OH:104])=[CH:74][CH:75]=2)[O:70][CH2:69]1)[CH3:67]>>[CH2:66]([C:68]1([C:105]2[CH:106]=[CH:107][C:108]([OH:111])=[CH:109][CH:110]=2)[CH:77]([CH2:78][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:29])([F:1])[C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:6]([OH:8])=[O:7])[C:76]2[C:71](=[CH:72][C:73]([OH:104])=[CH:74][CH:75]=2)[O:70][CH2:69]1)[CH3:67]
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Agent: C=CCCCCCCBr
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethyl malonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 5 and the allyl compound prepared in Example 21, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1([CH2:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>O.ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([NH:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To solution of 8.5 parts of intermediate 18, namely 5-benzoyl-2-nitrobenzoic acid, in 66.5 parts of dichloromethane were added 5.3 parts of 1,1'-carbonylbis[1H-imidazole]. After stirring for 1 hour at room temperature, there were added 9.8 parts of benzenemethanamine. Stirring at room temperature was continued for 8 hours. The reaction mixture was diluted with 100 parts of water and acidified with HCl. The organic layer was separated, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CHCl3 /CH3OH 98:2; CH3COOC2H5 /C6H5CH3 10:90). The eluent of the desired fractions was evaporated and the residue was crystallized from methylbenzene, yielding 8.1 parts (72.5%) of 5-benzoyl-2-nitro-N-(phenylmethyl)benzamide; mp. 167.4° C. (interm. 19).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:23]3[CH2:27][C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])=[CH:25][C:24]3=[O:36])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]2)[CH2:4][O:3]1.Cl.ClC1C=CC=CC=1OC1CN(C(CC2C=CC=CC=2)C(NC2C=CN(C[C@@H](O)CO)N=2)=O)C(=O)C=1>O1CCCC1.C(OCC)(=O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][C:26]1[CH2:27][N:23]([C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[N:9]=2)=[O:37])[C:24](=[O:36])[CH:25]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(Cc3ccccc3)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Agent: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(Cc1ccccc1)N1CC(Oc2ccccc2Cl)=CC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccccc1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-phenyl-propionic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.010 g, 0.017 mmol) in tetrahydrofuran (1 mL) was treated with 2N aqueous hydrochloric acid solution (1 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated to afford, 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-phenyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (0.007 g, 82%) as an off-white powder: HR-ES-MS m/z calculated for C23H27ClN4O6 [M+H]+ 497.1587, observed 497.1586; 1H NMR (300 MHz, CDCl3) δ ppm 1.75 (br. s., 2H), 3.17 (dd, J=14.0, 8.8 Hz, 1H), 3.39 (dd, J=14.0, 6.9 Hz, 1H), 3.44-3.55 (m, 2H), 3.56-3.65 (m, 1H), 3.95-4.10 (m, 2H), 4.16 (d, J=18.1 Hz, 1H), 4.30 (d, J=18.1 Hz, 1H), 4.77 (s, 1H), 5.02 (t, J=7.8 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 7.17 (dd, J=8.2, 1.8 Hz, 1H), 7.19-7.26 (m, 6H), 7.28-7.35 (m, 2H), 7.46 (dd, J=7.8, 1.5 Hz, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:7](=[O:8])[O:5][CH2:1][C:2]([CH3:3])=[CH2:4])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: C=C(C)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methallyl alcohol [CAS No. 513-42-8] (5 g) and 4-nitrophenyl chloroformate [CAS No. 7693-46-1] (12.6 g) were dissolved in THF (70 mL), and pyridine (6.69 mL) was added to the resulting mixture under ice-cooling, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture, ice and saturated aqueous ammonium chloride solution were added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (10.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:28]2[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: CCN1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In an ice bath under N2-atmosphere, 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster; 11.8 g, 50 mmol), CH2Cl2 (150 ml), a few drops of DMF and oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 3 h at rt. The resulting solution is concentrated in vacuo. The residue is dissolved in CH2Cl2 (170 ml) and added dropwise to an ice cooled solution of N-ethyl-piperazine (12.7 ml, 0.10 mol) in CH2Cl2 (100 ml). After stirring for 1 h at rt, the mixture is washed with a diluted solution of Na2CO3, 2 portions of water and finally brine. The aqueous layers are re-extracted twice with AcOEt, the combined organic phases dried (Na2SO4) and concentrated giving the title compound as an oil: MS: [M+1]+=332; 1H-NMR (CDCl3): 8.53 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 3.84 (m, 2H), 3.43 (m, 2H), 2.57 (m, 2H), 2.48 (q, 2H), 2.44 (m, 2H), 1.12 (t, 3H).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: OC1CCOc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a stirred solution of 4-hydroxychroman (10.14 g, 67.5 mmol) in acetic acid (150 mL) under Ar was added acetic anhydride (12.7 mL, 135 mmol) and the mixture was heated at reflux for 3 h, then allowed to cool to ambient temperature. Palladium on carbon (10 wt %; 1.8 g, 2.5 mol %) was added and the mixture was shaken in a Parr hydrogenerator under a 42 psi atmosphere of hydrogen overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was taken-up in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the product (7.73 g, 85%) as a pale yellow liquid: IR νmax (film)/cm−2937, 2863, 1737, 1609, 1582, 1490, 1456, 1304, 1267, 1228, 1189, 1116, 1065, 1008 and 754; NMR (400 MHz, CDCl3) δH 2.00 (2H, m), 2.78 (2H, t, J 6.5 Hz), 4.17 (2H, t, J 7 Hz), 6.81 (2H, m) and 7.05 (2H, m).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:25]12[CH:31]([CH2:32][CH2:33][NH2:34])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:34][CH2:33][CH2:32][CH:31]2[CH:25]3[CH2:30][CH2:29][CH:28]2[CH2:27][CH2:26]3)=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: NCCC1C2CCC1CC2
Reactant: CCSc1ncc(C(=O)O)s1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 moles of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 moles of 2-(bicyclo[2.2.1]hept-7-yl)ethylamine in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured in 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]-thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Cc1cccc(C(=O)CCC(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 24.5 g. 3-(m-toluoyl)propionic acid (0.10 mole) and 10.1 g. triethylamine (0.10 mole) in 250 ml. of chloroform cooled to 0°C., there is added dropwise 10.8 g. (0.10 mole) of ethyl chloroformate at such a rate that the critical temperature does not exceed 10°C. The reaction is stirred for 2 1/2 hours to obtain the mixed anhydride of 3-benzoylpropionic acid which is then treated with 3.1 g. of methylamine (0.10 mole) in 100 ml. of chloroform. The cooling apparatus is removed and the reaction is stirred for about 20 hours. The chloroform layer is then washed with 50 ml. of water, 100 ml. 1N hydrochloric acid, 100 ml. saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-tolyl) pyrrolidone; m.p. 128°-130°C.
Reaction SMILES: COC1C=CC2N=C(N[C:11](=O)[NH:12][CH2:13][C:14]3C=CC(C(O)=O)=CC=3)SC=2C=1.[C:26](=[O:29])([O-])N.NC1S[C:33]2C=C(OC)C=C[C:34]=2[N:35]=1.NCC1C=CC(C(O)=O)=CC=1>>[NH2:35][CH2:34][CH2:33][N:12]1[CH2:11][CH2:26][O:29][CH2:14][CH2:13]1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: COc1ccc2nc(NC(=O)NCc3ccc(C(=O)O)cc3)sc2c1
Reactant: NC(=O)[O-]
Agent: NCc1ccc(C(=O)O)cc1
Product: NCCN1CCOCC1
Yield: 28 %

Procedure:
The title compound 165 was obtained following the same procedure as for the carbamate formation described in scheme 32, step 1 (example 75) substituting compound 129 for 2-amino-6-methoxybenzothiazole and using 4-aminomethylbenzoic acid instead of 4-(2-aminoethyl)-morpholine (28% yield). 1H NMR: (DMSO-d6) δ(ppm): 7.92 (t, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.95 (d, J=7.0 Hz, 1H), 4.45 (s, 2H), 3.77 (s, 3H). m/z: 358.3 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccnc1
Yield: 22.4 %

Procedure:
To a solution of toluene (50 mL) cooled to −78° C. was added 2.5 M butyllithium in hexanes (6.31 mL, 15.1 mmol) and the reaction mixture was stirred until the temperature returned to −78° C. 3-Bromopyridine (1.88 g, 11.9 mmol) in toluene (5 mL) was added to the reaction mixture a rate such that the temperature never went above −65° C., and then the reaction was stirred at −78° C. for 1 hour. (S,E)-N-(2-(tert-Butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 10.8 mmol) in toluene (1 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −70° C., and then the reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine and the mixture partitioned between ETOAc/water. The organic layer was washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (15-80% EtOAc in DCM) to provide (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.862 g, 22% yield) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][C:15](=[O:29])[C:16]4[CH:17]=[C:18](CC([O-])=O)[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2.C1C[O:33]CC1>>[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH:15]([OH:29])[C:16]4[CH:17]=[C:18]([OH:33])[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CC(=O)c3cc(CC(=O)[O-])ccc3[C@H]1CC2
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2
Yield: 10 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 ml of anhydrous THF was added estra-1,3,5(10),16-tetraen-6-one-3-yl-acetate (6) (422.9 mg, 1.360 mmol) in 5 ml of anhydrous THF dropwise, with stirring. The reaction was stirred 50 min., after which further LAH (46.5 mg, 1.16 mmol) was added and the reaction stirred 22 h. After refluxing 4 h TLC still showed starting material. The reaction was quenched with 0.5 ml of water +0.5 ml of 20% (w/w) sulfuric acid and concentrated under reduced pressure. The residue was extracted four times with 10 ml portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give solid product (0.05 g, 0.2 mmol, 10%), m.p. 150-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:11]([O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:10])=[C:4]([CH3:9])[CH:5]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)cc(C)c1O
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)c2ccccc2)cc(C)c1O

Procedure:
Using 4.70 g of 2,6-dimethyl-1,4-dihydroxybenzene, 4.0 ml of benzoyl chloride and 100 ml of pyridine, reaction and workup carried out as in Reference Example gave 6.35 g of 4-benzoyloxy-2,6-dimethylphenol as white crystals, m.p. 139.5-141.0° C. Using 6.35 g of the white crystals, 1.26 g of sodium hydride, 4.2 ml of benzyl bromide and 50 ml of DMF, reaction and workup carried out as in Example 12 gave 4.22 g of yellow oil.