Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C.[CH3:28][C:29]([CH3:31])=[O:30].C1COCC1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16](/[CH:17]=[CH:28]/[C:29](=[O:30])[CH3:31])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)/C=C/c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 3 h
Yield: 76.47 %

Procedure:
To a solution of aldehyde 29 (15 g, 0.0519 mol) in a mixture of 200 ml of Acetone:THF (1:1) was added 10% aq. NaOH solution and stirred for 3 hours. Dilute acetic acid was added till pH of mixture was acidic. The reaction mixture was evaporated to half volume and poured into water (200 ml). The solid separated out was filtered to yield (E)-4-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-but-3-en-2-one (13 g, 76.47%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:11]3[S:15][C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[N:13][C:12]=3[CH:22]=2)[CH:3]=1.CCN(CC)CC.Cl.[CH3:37][C:38]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CN(C=O)C>[CH2:20]([NH:19][C:17](=[O:18])[NH:16][C:14]1[S:15][C:11]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([N:41]4[CH2:42][CH2:43][C:38]([CH3:37])([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39][CH2:40]4)[N:7]=[N:6][CH:5]=3)=[CH:22][C:12]=2[N:13]=1)[CH3:21]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnnc(Br)c3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cnnc(N4CCC(C)(C(=O)OCC)CC4)c3)cc(-c3ccccn3)c2s1
Temperature: 90 °C
Yield: 48.2 %

Procedure:
To a solution of 1-(5-(6-bromopyridazin-4-yl)-7-(pyridin-2-yl)benzothiazol-2-yl)-3-ethylurea (Intermediate 10) (0.090 g, 0.19 mmol) in DMF (2 mL) was added Et3N (0.08 mL, 0.57 mmol) followed by the addition of ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.06 g, 0.29 mmol) and the mixture heated to 90° C. for 20 h then cooled to rt, water added and extracted with EtOAc (3×75 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 3% MeOH: DCM to obtain the desired product as yellow solid (0.05 g, 47%). MS: 546.40 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7](/[CH:20]=[CH:21]/[C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7](/[CH:20]=[CH:21]/[C:22]2[N:27]=[CH:26][C:25]([NH:28][S:34]([CH2:33][C:32]([F:39])([F:38])[F:31])(=[O:36])=[O:35])=[CH:24][CH:23]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(F)cc1-c1cc(/C=C/c2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: COc1ncc(F)cc1-c1cc(/C=C/c2ccc(NS(=O)(=O)CC(F)(F)F)cn2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
step 2—To a solution of 370 (90.0 mg, 0.221 mmol) in pyridine (3 mL) cooled to 0° C. was added 2,2,2 trifluoroethane sulfonyl chloride (40 μL, 0.364 mmol). After 20 min the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched with 30 mL of 1N HCl and thrice extracted with EtOAc (20 mL). The combined extracts were washed with sat'd. aq. CuSO4 (3×30 mL) and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (25 to 35% EtOAc) to afford 88.1 mg (72%) of 2,2,2-trifluoro-ethanesulfonic acid (6-{(E)-2-[3-tert-butyl-5-(5-fluoro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-pyridin-3-yl)-amide (372).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1>CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:15]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccnc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.6 %

Procedure:
A mixture of 4-nitro-phthalonitrile (3.46 g, 20 mmol), pyridin-3-ol (1.90 g, 20 mmol) K2CO3 (8.29 g, 60 mmol), and DMF (50 ml) was stirred at ambient temperature overnight. The reaction mixture was then combined with another batch of the same reaction performed on the same scale. Subsequently, the solid components were removed by filtration and the filtrate was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The organic phase was then washed with brine, dried, and evaporated in vacuo. The residue was recrystallized from EtOAc/MeOH to give 8.3 g of the title compound; 1H NMR (CDCl3): δ=8.56 to 8.59 (m, 1H), 8.45 to 8.47 (m, 1H), 7.76 (d, 1H), 7.42 to 7.44 (m, 2H), 7.22 to 7.32 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[C:11](Cl)(=O)[CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(N(CC)CC)C>[CH3:11][C:12]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(O)cc2o1

Procedure:
4-Aminoresorcinol hydrochloride (2.0 g, 12.4 mM), acetyl chloride (1.0 g, 12.6 mM), triethylamine (1.38 g, 13.6 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 18 hours. Additional PPTS (300 mg) was added and the mixture was then refluxed about 48 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layers were dried over MgSO4. Filtration and concentration provided 1.36 g. Filtration through a silica gel column eluted with 10% methanol/methylene chloride provided an orange solid, 0.3 g; m.p., 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15][N:14]=3)[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)(O)[O-].[Na+]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15][N:14]=3)[CH2:11][C:10](=[CH2:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)(c2nnc3n2CCCCCC3)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CC(c2ccc(Cl)cc2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-Chlorophenyl)-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)cyclobutanone (4-5) (52 mg) was dissolved in freshly distilled tetrahydrofuran (2 mL). Methyltriphenylphosphonium bromide (281 mg) was added followed by potassium bis(trimethylsilyl)amide (KHMDS, 0.5M in toluene, 1.25 mL). After stirring for 24 hours at room temperature, the crude product was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated. The product was purified by silica gel column chromatography to give 3-[1-(4-chlorophenyl)-3-methylenecyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-6).
Reaction SMILES: [N+:1]([C:4]1[C:21]2[C:22]3[C:7]([C:8]4[C:23]5[C:12]6=[C:13]([C:24]([N:26]([CH:29]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:27](=[O:28])[C:11]6=[CH:10][CH:9]=4)=[O:25])[CH:14]=[CH:15][C:16]=5[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1)([O-])=O.O.[OH-].[K+].[C:45](O)(=[O:47])[CH3:46]>[Fe]>[C:45]([NH:1][C:4]1[C:21]2[C:22]3[C:7]([C:8]4[C:23]5[C:12]6=[C:13]([C:24]([N:26]([CH:29]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:27](=[O:28])[C:11]6=[CH:10][CH:9]=4)=[O:25])[CH:14]=[CH:15][C:16]=5[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)O
Reactant: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5c([N+](=O)[O-])ccc(c6ccc(c2c36)C1=O)c54
Agent: [Fe]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5c(NC(C)=O)ccc(c6ccc(c2c36)C1=O)c54

Procedure:
100 mg (0.18 mmol) of 9-nitro-N-(1-hexylheptyl)perylene-3,4-dicarboximide (10) are suspended in 15 ml of glacial acetic acid, 80 mg (0.72 mmol) of iron dust are then added, and the red suspension is refluxed for 4.5 h, during which a slow colour change from red to red-brown and purple and then to dark-purple can be observed. First water is added to the cooled, violet solution, and the reaction mixture is then neutralized with 10 per cent KOH. The suspension which is now reddish purple is extracted three times with chloroform, the combined organic phases are dried with anhydrous sodium sulfate then evaporated on a rotary evaporator. According to the thin-layer chromatogram (chloroform/silica gel), the purple-coloured product obtained consists of 2 main products having Rf values of 0.02 and 0.43. This product is filtered by chromatography on silica gel using chloroform until the solution leaving the silica gel is no longer violet. The red-coloured silica gel is extracted with chloroform to give, after evaporation on a rotary evaporator, 50 mg of a red powder which is then recrystallized by extraction with methanol. Yield: 30 mg (30%) of 9-acetamido-N-(1-hexylheptyl)perylene-3,4-dicarboximide, m.p. >230° C.; from 172°-175° C. onwards product turns brown. Rf (CHCl3 /glacial acetic acid 20:1; silica gel)=0.90. UV (CHCl3): λmax (ε)=506 nm (31589, broad), 356 (2995). Fluorescence (CHCl3): λmax =574 nm (broad).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.O([CH2:83][CH2:84][O:85][CH2:86][CH3:87])S(C(F)(F)F)(=O)=O.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:83][CH2:84][O:85][CH2:86][CH2:87][O:55][C@H:50]1[C@H:51]([O:53][CH3:54])[CH2:52][CH:47]([CH2:46][C@H:44]([CH:27]2[O:28][C:29](=[O:30])[C@H:31]3[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37](=[O:38])[C:39](=[O:40])[C@:41]3([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]3[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26]2)[CH3:45])[CH2:48][CH2:49]1
Reactant: CCOCCOS(=O)(=O)C(F)(F)F
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)/C=C/C=C/C=C(\C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)C=CC=CC=C(C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a reaction flask, sirolimus (1 g, 1.1 mmol), ethyl di-isopropyl amine (7.8 g, 60.3 mmol), methylene chloride (3.5 ml) and 2-ethoxyethyl triflate (2.0 g, 8.8 mmol) as previously made in Example 3A were added into the flask, which is filled with nitrogen gas. The reaction mixture is heated to 60° C. and is agitated for one hour and twenty minutes. Then, it is cooled, added with ethyl acetate (100 ml) and aqueous solution of hydrochloric acid (1N, 100 ml) and is further agitated. After agitation, it is settled for separating the layers. The organic layer is collected and respectively washed with pure water (100 ml), saturated saline (80 ml). The washed organic layer is dried and concentrated. The residue is then separated and purified by silica gel column chromatography to obtain white product of Biolimus A9 (0.48 g, 0.49 mmol), with a yield of 44.5%.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:14][N:15]([CH2:16][CH:17]=[O:18])[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][N:8]=1)=[O:13]
Reactant: O=C=Nc1nnc(C2CCCC2)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCC2)s1

Procedure:
A mixture of 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-ureido] acetaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[K+:31]>O1CCCC1>[CH3:1][C:2]([CH3:29])([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[N:24]=3)=[CH:16][N:15]=2)=[CH:12][CH:13]=1)[C:3]([O-:5])=[O:4].[K+:31]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)c[nH]3)cn2)cc1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)c[nH]3)cn2)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 mL) was suspended 2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (1001 mg), and the mixture was stirred at room temperature for 30 minutes. 10M aqueous potassium hydroxide solution (0.25 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure to obtain potassium 2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (995 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH3:6].[Br:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.Cl>ClCCl>[Br:16][C:17]1[S:18][C:19]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: Brc1cccs1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (8.9 g) and 4-ethylbenzoylchloride (5.96 g) were added to a solution of 2-bromothiophene (3.2 ml) in dichloromethane (50 ml) at 0° C., and the mixture was stirred for four hours at room temperature. 10% hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (5-bromo-2-thienyl)(4-ethylphenyl) methanone (8.97 g). Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a solution of (5-bromo-2-thienyl)(4-ethylphenyl) methanone in acetonitrile (20 ml) at −40° C., and the mixture was stirred for two hours. Aqueous solution of saturated potassium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-(4-ethylbenzyl)thiophene (6.78 g).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([OH:17])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:26][CH2:27][OH:28]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:26][CH2:27][OH:28])=[O:17])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: NC(CCO)c1ccccc1Cl
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(NC(CCO)c1ccccc1Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(2-chlorophenyl)-1-propanol (Intermediate 2), the title compound was obtained in 94% purity by HPLC.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH2:12][CH3:13].C([O-])(=O)C.[Na+].[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][NH2:28])[CH3:24]>C(#N)C>[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][N:28]1[CH:10]([CH:11]([N+:14]([O-:16])=[O:15])[CH2:12][CH3:13])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:17])[CH3:24]
Reactant: CCC(=Cc1ccccc1C(=O)OC)[N+](=O)[O-]
Reactant: CCOC(CN)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(CN1C(=O)c2ccccc2C1C(CC)[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 2-(2-nitro-1-butenyl)-benzoic acid methyl ester (49 g, described in Example 29) sodium acetate (27.5 g) and 2,2-diethoxyethanamine (44 g) in acetonitrile (1000 ml) is stirred at 25° C. for 24 hr and filtered. The filtrate is evaporated and the residue is dissolved in chloroform. The organic solution is washed with water, 10% hydrochloric acid and brine, dried and evaporated to obtain the title compound as a mixture of isomers (67 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28]O)=[CH:26][CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1I]) to give 2-methyl-2-{4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-2-yloxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14](OC)([O:16]C)[CH3:15].CO>C1COCC1>[OH:8][CH2:9][CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15]
Reactant: COC(=O)C(C)CCCC(C)(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)CCCC(C)CO
Reaction time: 3 h
Yield: 80.6 %

Procedure:
0.74 g (content 80%, 15.6 mmol) of lithium aluminum hydride was suspended in 7.0 g of THF, and the resultant suspension was cooled to 0° C. Next, 2.37 g(content 84.4%, 9.2 mmol) of 6,6-dimethoxy-2-methylheptanoic acid methyl ester was dissolved in 3.0 g of THF to give a solution which was then dropped into the above-described suspension at 0° C. over a period of 1.5 hours. Next, the reaction mixture as stirred at the same temperature for 3 hours, then, 1.47 g (45.9 mmol) of methanol was dropped to quench unreacted lithium aluminum hydride. Then, 2.74 g of a 2% sodium hydroxide aqueous solution was dropped at room temperature into the reaction mixture, then, the generated aluminum hydroxide was removed by filtration using Radiolite (filtration aid, trade name: manufactured by Showa Chemical Industry Co., Ltd.), subsequently, an acid treatment was performed, to obtain a uniform solution containing 1.07 g (yield 80.9%) of 7-hydroxy-6-methylheptan-2-one.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[SH:20]>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:20][C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][N:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:7]
Reactant: Cn1ccnc1S
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCC(Sc1nccn1C)C(=O)OCC

Procedure:
2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clear oil; MS: 285 (M+H)+.