Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:12]([O:19][C:20]([NH:22]/[C:23](=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CO>[CH2:12]([O:19][C:20]([NH:22][CH:23]([CH:28]([S:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Using a method similar to that described in Example 1, part b (Method B) a solution of tert-butyl N-(2-mercaptoethyl)carbamate (2.4 mL), methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-phenylprop-2-enoate (0.87 g), triethylamine (0.39 mL) and methanol (15 mL) was stirred at RT for 3 days. Removal of the solvent and chromatograpy of the resultant crude oil on silica gel (10% to 25% ethyl acetate/hexanes) returned the title compound as a viscous oil (1.22 g, 90%). The proton NMR displayed a mixture of diastereomers of approximate ratio 7:3; the major diastereomer is reported. 1HNMR (300 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (t, 2H), 3.19 (br, 2H), 3.65 (s, 3H), 4.12 (q, 1H), 4.35 (t, 1H), 4.73 (t, 2H), 5.09 (d, 2H), 7.27-7.34 (m, 10H). MS APCI, m/z=389(M−t-BuOCO)+. HPLC Method A: 3.47 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#N)=[N:9]2)=[CH:4][CH:3]=1.C(O)=[O:23]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Reactant: O=CO
Product: O=Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To the cyanide (Step 1, 10 g) in formic acid (200 mL) at 100° was added portionwise Ni-Al alloy (3 g). The reaction mixture was heated at 110° for 6 hrs, filtered and evaporated. The residue was partitioned between NaHCO3 (aq) and ethyl acetate, and the organic layer was dried and evaporated. Flash chromatography using 30% ether in hexane afforded the title compound.
Reaction SMILES: IC.[C:3]1([C@:9]2([CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:22]([CH2:21][C@@:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][C@H:10]1[CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Iodomethane (2.12 g, 14.9 mmol, 4 eq) was added portionwise to N-[((1S,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]benzenesulfonamide (1.71 g, 3.74 mmol, 1 eq), accessed via the method of preparation 5A, in 7 mL DMF with potassium carbonate (1.03 g, 7.48 mmol, 2 eq) over 6 h at 80° C. Following addition, the reaction mixture was stirred 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3, water (4×) and brine, dried over MgSO4, filtered and concentrated to give a brown oil. The crude material was purified by flash chromatography (SiO2, eluted successively with hexanes and EtOAc/hexanes (1:4)) to give the title product (1.57 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58-7.19 (m, 15H), 4.57 (ABq, J=24.3, 11.9 Hz, 2H), 3.84-3.80 (m, 1H), 3.58-3.48 (m, 1H), 3.29 (d, J=14.1 Hz, 1H), 2.50 (s, 3H), 1.47 (m, 1H), 1.33 (m, 1H), 0.91 (m, 1H). ES-LCMS m/z 444.2 (M+Na).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:37])[C:4]1[CH:5]=[CH:6][C:7]2[C:16]([CH:17]=1)=[O+:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([N:18]([CH3:20])[CH3:19])[CH:13]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[C:22]=1[C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30].[I-:38].[CH3:39]N(C)C1C=CC2C(C=1)=[O+]C1C(=CC=C(N(C)C)C=1)C=2C1C=C(C(OC)=O)C(NC)=C(N)C=1OC(=O)C>>[I-:38].[CH3:20][N:18]([CH3:19])[C:12]1[CH:11]=[CH:10][C:9]2[C:14]([CH:13]=1)=[O+:15][C:16]1[C:7](=[CH:6][CH:5]=[C:4]([N:3]([CH3:2])[CH3:37])[CH:17]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH3:39])=[C:23]([NH2:28])[C:22]=1[C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30]
Reactant: CNc1c(C(=O)OC)cc(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)c(OC(C)=O)c1N
Reactant: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc(N)c1N
Agent: [Br-]
Agent: [I-]
Product: CNc1ccc(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)c(C(=O)OCOC(C)=O)c1N

Procedure:
From the above 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3,4-diaminophenyl)xanthylium bromide (133 mg), 3,6-bis(dimethylamino)-9-[2-acetoxy-methoxycarbonyl-3-amino-4-(N-methylamino)phenyl]xanthylium iodide was obtained (40.5 mg, 27.5%) in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.ClC1C=CC(O[CH2:18][C:19]#[N:20])=CC=1.CC([O-])(C)C.[K+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:18][C:19]#[N:20])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CC#N)n1
Temperature: -12.5 °C
Reaction time: 3 h

Procedure:
Under argon and in an anhydrous medium, 15 g (97.3 mmol) of 2-methoxy-5-nitropyridine and 17.9 g (107 mmol) of 4-chlorophenoxyacetonitrile are dissolved in 300 ml of anhydrous tetrahydrofuran; the solution is added by transfer to a solution of 24 g (214 mmol) of potassium tert-butylate in 220 ml of anhydrous tetrahydrofuran maintained at a temperature below −10° C. The reaction mixture is stirred for three hours at a temperature of from −10 to −15° C. An aqueous 5% hydrochloric acid solution (170 ml) is added dropwise to the reaction mixture, maintaining the temperature at —10° C. The mixture is extracted with ethyl acetate. After driving over magnesium sulphate and evaporation, the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 2:1). After washing with a petroleum ether/diethyl ether mixture (2:1), the title compound is obtained in the form of a brown product.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.S([O-])(O)=O.[Na+]>[O-2].[O-2].[O-2].[Cr+6].[Cr+6].O.CC(C)=O>[CH3:1][C@@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)=CCC[C@H](C)CC(C)O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C[C@@H](C)CCC=C(C)C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Acetone (2,000 ml) and (4S)-4,8-dimethyl-7-nonen-2-ol (240 g) synthesized in Synthetic Example 1—1 were placed in a 5-liter, 4-necked flask equipped with a dropping funnel, thermometer, condenser, and stirrer. Jones reagent {prepared from water (520 ml), concentrated sulfuric acid (165 g), and chromium trioxide (112 g)} placed in the dropping funnel was added dropwise over a period of 4 hours under cooling with ice. After the dropwise addition, the mixture was stirred for 2 hours. Then, sodium hydrogen sulfite was added gradually until the orange color of chromium (VI) disappeared. The liquid was then separated and the bottom layer was extracted with petroleum ether (1,000 ml). Since the liquid again separated into two layers when the extract was combined with the previous upper layer, the lower layer was added to the previous lower layer and further extracted three times with 500 ml of petroleum ether. After combining the petroleum ether layers and washing with a saturated brine, a saturated aqueous sodium hydrogen carbonate solution and again with a saturated brine, the solvent was evaporated. The resulting concentrated oil was distilled with a Widmer distiller to obtain 194 g of (4S)-4,8-dimethyl-7-nonen-2-one (b.p.: 63° C./133 Pa).
Reaction SMILES: [C:1]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])(=[O:4])[CH2:2][CH3:3].[CH2:20]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([N:27]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:19])[C:6]1[C:7]([CH3:13])=[CH:8][CH:9]=[CH:10][C:11]=1[CH3:12])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N(CCCC(=O)O)c1c(C)cccc1C
Reactant: CCOC(=O)CCCNCc1ccccc1
Product: CCOC(=O)CCCN(Cc1ccccc1)C(=O)CCCN(C(=O)CC)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-propionyl-4-(2,6-dimethylanilino)butyric acid and ethyl 4-(benzylamino)butyrate and suitable processing produces ethyl N-[N-propionyl-4-(2,6-dimethylanilino)butyryl]-4-(benzylamino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-propionyl-4-(2,6-dimethylanilino)butyryl]-4-(benzylamino)butyric acid (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[N:27][C:28]([O:32][CH2:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35]3)=[CH:29][C:30]=2[CH3:31])[CH:5]=[N:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[N:27][C:28]([O:32][CH2:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:35][CH2:36][CH2:37]3)=[CH:29][C:30]=2[CH3:31])[CH:5]=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1cnc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1cnc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Reaction time: 60 h
Yield: 61.9 %

Procedure:
In trifluoroacetic acid (3.1 mL) and water (0.3 mL) was dissolved 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl]oxy)methyl}cyclobutanecarboxylic acid (312 mg), and the mixture was allowed to stand at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid, isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-[({5′-chloro-4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (151 mg).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C1COCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:24]
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a stirred solution of 2-methylbut-3-yn-2-ol (2.15 g, 25.6 mmol) in dry THF (80 mL) was added n-BuLi (24.0 mL, 38.7 mmol, 1.6 M in hexane) drop wise at −20° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −20° C., a solution of N,4-dimethoxy-N-methylbenzamide (2.5 g, 12.8 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −20° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (100 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (2.25 g, 81%) as a colorless liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:43]([NH2:45])[CH3:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN1C(=O)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([NH:9][C:7](=[O:8])[C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:45][CH:43]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:44])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Reactant: CC(N)c1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The resin-bound 4-chloromethyl-N-dodecyl-benzamide (described in step b, 0.0426 mmol) was swelled in NMP (0.25 mL) for 15 min at rt. DIEA (33 mg, 0.256 mmol), tetrabutyl-ammonium iodide (94.4 mg, 0.256 mmol) and 1-naphthalen-1-yl-ethylamine (44 mg, 0.256 mmol) dissolved in NMP (0.75 mL) were added and the reaction mixture was shaken 14 h at 80° C. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}-methyl)benzamide which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=[O:23])C.[OH-].[Na+]>C(OO)(=O)C.O>[O:23]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]1[CH3:1]
Reactant: CC(=O)O
Reactant: CC=CCCCCCCCCCCCCCCCCC
Agent: CC(=O)OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC1OC1C

Procedure:
7 g of 2-eicosene are dissolved in 20 g of peracetic acid. The ethylenic function is oxidised into epoxide in the absence of heat. The acetic acid formed is neutralised in 10 ml of water by the addition of 1N NaOH. The aqueous solution thus obtained is extracted with ether. Removal of the ether leaves 6 g of 2,3-epoxy eicosane which is purified in the same way as described above. Mp: 40° C., bp 15 mm Hg : 200°-210° C.
Reaction SMILES: C1(O)C=CC=CC=1.C(O)/C=C/CCCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41]/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCCCCCC/C=C/COc1ccc(C(=O)OC)cc1
Yield: 65 %

Procedure:
Phenol 34 (486 mg, 3.2 mmol), 2-decenol 26g (500 mg, 3.2 mmol), TPP (965 mg, 3.68 mmol), and DEAD (641 mg, 3.68 mmol) in 32 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 603 mg (65%) of colorless needles.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)n(C)n1
Yield: 35 %

Procedure:
As described for example 42e, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (150 mg, 0.46 mmol) was converted, using isopropylamine instead of ethanolamine, to the title compound (57 mg, 35%) which was obtained as a colorless oil. MS: m/e=355.3 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[ClH:29].O1CCOCC1>>[ClH:29].[O:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:28])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3ccccc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCOC(c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[2-(4-Phenoxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (49 mg) was treated with HCl in 1,4-dioxane (0.5 mL; 4.0 mol/L, 2 mmol) and shaken overnight at room temperature. Removal of the solvent in vacuo yielded 3-[2-(4-phenoxy-phenyl)-morpholin-4-yl]-propionic acid hydrochloride as an amorphous broken white powder (48 mg). Rt=1.60 min.
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[O:16]1[CH2:15][CH2:14][CH2:13][O:12][CH:11]1[C:7]1[O:6][C:10]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1coc(C2OCCCO2)c1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point0.8 1 80° C.). 93 g were obtained.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[N:32]([CH:37]([CH3:39])[CH3:38])[C:33]([CH:35]=O)=[N:34][C:30]=2[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[N:32]([CH:37]([CH3:39])[CH3:38])[C:33]([CH2:35][C:9]3[C:10](=[O:12])[O:11][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=4)[CH2:7][C:8]=3[OH:13])=[N:34][C:30]=2[CH:29]=1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: CC(C)n1c(C=O)nc2cc(Cl)ccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4cc(Cl)ccc4n3C(C)C)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 below to 5-Chloro-1-isopropyl-1H-benzoimidazole-2-carbaldehyde using the AlCl3/reduction procedure described in Example B(13). ESIMS (MH+): 570.3
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2/[CH:15]=[C:27](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[C:28]([NH:30][NH2:31])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=Cc1ccccc1OCc1cccc2ccccc12
Solvent: CCO
Product: NNC(=O)/C(=C/c1ccccc1OCc1cccc2ccccc12)c1ccccc1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
To a solution of 2-(1-naphthylmethoxy)benzaldehyde (300 mg, 1.14 mmol) in EtOH (10 mL) is added phenyl acetic hydrazide (172 mg, 1.14 mmol) and the reaction is heated to 80° C. for 1 h. While cooling a white precipitate forms, and this solid is isolated by filtration and washed with portions of EtOH and Et2O. This solid is dried under vacuum to provide N′-{(1E)-[2-(1-naphthylmethoxy)phenyl]methylene-2-phenylacetohydrazide (254 mg, 57%). 1H-NMR (400 MHz, DMSO-d6) 11.60–11.55 (m, 1H), 8.43–8.38 (m, 1H), 8.11–7.74 (m, 4H), 7.60–7.56 (m, 2H), 7.44–7.42 (m, 2H), 7.31–7.21 (m, 4H), 7.05–7.04 (m, 1H), 5.65–5.63 (m, 2H), 3.96 (s, 1H), 3.54 (s, 1H), 3.34 (s, 3H). ESI+ for C26H22N2O2 m/z 395 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.Cl[CH2:16][C:17]([CH3:19])=[CH2:18]>>[CH3:18][C:17](=[CH2:16])[CH2:19][O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: C=C(C)CCl
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Product: C=C(C)COc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 90.1 %

Procedure:
Reaction, post-treatment, and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Reference Example 31 using 5-hydroxy-3,8-dimethylcarbostyril (3 g, 15.87 mmol) and 3-chloro-2-methyl-1-propene (1.58 g, 17.46 mmol). As a result, 3.48 g of the title compound was obtained as pale brown crystals (90.2%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([O:25][CH3:26])[N:19]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:24][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[N:19]=[C:18]([O:17][CH3:16])[N:23]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1cc(N)nc(OC)n1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc(OC)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2,6-dimethoxypyrimidin-4-amine (31 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 343.3. Found 344.1 (M+1)+. Retention time 2.87 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C(O[CH:18](N(C1C(C(C)C)CCC(C)C1)C1C(C(C)C)CCC(C)C1)[N:19]([CH:30]1C(C(C)C)CCC(C)C1)[CH:20]1C(C(C)C)CCC(C)C1)(C)(C)C>>[CH3:18][N:19]([CH3:30])[CH:20]=[CH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Reactant: CC1CCC(C(C)C)C(N(C2CC(C)CCC2C(C)C)C(OC(C)(C)C)N(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)C1
Product: COc1cc(C=CN(C)C)ccc1[N+](=O)[O-]

Procedure:
83.5 of 5-methyl-2-nitroanisole and 162.0 g of tert-butoxybis(dimenthylamino)methane is heated for 8 hours to 100° C. After cooling, 111.0 g of N,N-dimenthyl-N-[2-(3-methoxy-4-nitrophenyl)ethenyl]amine is crystallized, mp 57°-58.5° C.