Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:ethyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [CH2:1](C(CC(OC)(C)CCCC)=C(O[SiH](C)C)[Sn](CCCC)(CCCC)CCCC)CCC.C([Li])CCC.C(P(CCCC)CCCC)CCC.C(C1CC(=O)C(CCCCCCC(OC)=O)=C1O[SiH](C)C)CCC.[CH2:75]([C:79]([O:105][SiH:106]([CH3:108])[CH3:107])([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C@@H:89]1[C@@H:93]([CH:94]=[CH:95][CH2:96][CH:97]([O:102][CH3:103])[CH2:98][CH2:99][CH2:100][CH3:101])[CH2:92][CH2:91][C:90]1=[O:104])[C:80]([O:82][CH3:83])=[O:81])[CH2:76][CH2:77][CH3:78]>C1COCC1.CCCCCC.[Cu]I.C(O)(=O)C>[CH2:75]([C:79]([O:105][SiH:106]([CH3:107])[CH3:108])([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C@@H:89]1[C@@H:93]([CH:94]=[CH:95][CH2:96][C:97]([CH3:1])([O:102][CH3:103])[CH2:98][CH2:99][CH2:100][CH3:101])[CH2:92][CH2:91][C:90]1=[O:104])[C:80]([O:82][CH3:83])=[O:81])[CH2:76][CH2:77][CH3:78]
Reactant: CCCCC(CC(C)(CCCC)OC)=C(O[SiH](C)C)[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCC(CC=C[C@H]1CCC(=O)[C@@H]1CCCCCC(CCCC)(O[SiH](C)C)C(=O)OC)OC
Agent: [Cu]I
Agent: CCCCC1CC(=O)C(CCCCCCC(=O)OC)=C1O[SiH](C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(C)(CC=C[C@H]1CCC(=O)[C@@H]1CCCCCC(CCCC)(O[SiH](C)C)C(=O)OC)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of (3R,4R)3-t.butyldimethylsilyloxy-4-methoxy-4-methyl-l-tributylstannyl-l-octene 2 (0.58 g, 1 mmol) in THF (1 ml) was treated at -78° C. under nitrogen with n-butyllithium (0.65 ml, 1.6 M in hexane), stirred for 10 min at -78° C. and a solution of copper (I) iodide (0.19 g, 1 mmol) and tri-n-butyl phosphine (0.65 ml, 2.6 mmol) in 1 ml of THF was added. The reaction mixture was warmed to -40° C. and stirred for 1 h when a solution of the (3R)3-t.butyldimethylsilyloxy-5-oxo-l-cyclopenteneheptanoic acid, methyl ester (0.35 g, 1 mmol) in THF (1 ml) was added. The mixture was stirred at -40° C. for 1 h before acetic acid (0.1 ml) was added. The mixture was allowed to warm to room temperature, diluted with 100 ml of hexane, washed with water, NaHCO3 saturated, and brine and then dried over MgSO4. Solvents were flash-evaporated (20 Torr, 30° C.) and the oily residue purified by chromatography on silica gel 25 g, 230-400 mesh, eluant: petroleum ether (100 ml), then petroleum ether/EtOAc: 95/5 (200 ml), then petroleum ether/EtOAc: 92/8. The product containing fractions were combined and solvents removed in vacuo to afford 0.13 g of pure (8R,11R,12R,15R,16R)-11,15-di-t.butyldimethylsilyloxy-16-methoxy-9-oxo-prost-13-en-1-oic acid, methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:3]=[C:4]([O:5][C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: FC(F)(F)c1cccnc1Oc1cc(Br)cc(Br)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ncccc3C(F)(F)F)c2)cc1C

Procedure:
2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine (2.05 g; 5.17 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.9 g; 4.0 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane→ethyl acetate:heptane 2:9). Yield 1.26 g (58%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH2:17](N(CC)CC)C.COC(ON=C(C#N)C(OCC)=O)=O>C(Cl)(Cl)Cl>[CH3:17][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)C(C#N)=NOC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-methoxycarbonyl-L-phenylalanine (1.65 g) and triethylamine (2.8 ml) in dry chloroform (15 ml), ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate (4.0 g) is added, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is treated as in Example B to give N-methoxycarbonyl-L-phenylalanine methyl ester (1.2 g) as an oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20](=[O:27])[NH:21]2>>[Cl:26][C:25]1[C:17]([CH3:16])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:27])[C:19]2=[CH:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-Chloro-3-(3-cyclopentyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.O1CCOCC1.[C:22](OC([O-])=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl>C(=O)([O-])O.[Na+].C(#N)C>[C:25]([O:24][C:22]([N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(O)CNc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
226 mg (1.03 mmol) of DL-[3-(trifluoromethyl)phenyl]-glycine are dissolved in 10 ml of an aqueous 5% sodium hydrogen carbonate solution and treated with 4 ml dioxan. 261 μl (1.13 mmol) of tert.-butyl dicarbonate are added and the mixture stirred overnight at RT. For the workup, the solution is carefully acidified to pH 2 with 1 N hydrochloric acid. The precipitated product is redissolved by addition of acetonitrile, and purified by preparative HPLC (Method 20). 135 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][CH:10]1[CH2:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:26])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C1CCN(CCc2ccc(F)cc2)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reaction time: 1.75 h
Yield: 108.8 %

Procedure:
A solution of -{4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-yl}-methanol (105 mg, 294 μmol) and triethylamine (62 μL, 442 μmol) in dichloromethane (1 mL) was stirred on an ice bath and treated with a solution of methanesulfonyl chloride (25 μL, 320 μmol) in dichloromethane (0.5 mL). After 1.75 hours, the mixture was concentrated and the residue was dissolved in ethyl acetate. The suspension was filtered, the solid was rinsed with ethyl acetate, and the filtrate was concentrated under vacuum to provide a yellowish gum (139 mg) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.32 (m, 5H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.57 (dd, J=10, 3 Hz, 1H), 4.29 (m, 1H), 3.72 (d, J=13 Hz, 1H), 3.50 (d, J=13 Hz, 1H), 3.4-3.1 (m, 2H), 3.00 (s, 3H), 2.83 (m, 2H), 2.70 (m, 2H), 2.48 (m, 1H), 2.35 (m, 1H), 2.22 (s, 3H), 2.07 (m, 2H), 2.0-1.7 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[N:26][NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1ccc(F)cc1)C(C=O)c1ccc(SC)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 5.3 %

Procedure:
The aldehyde-ester, hydrate, and hydroxy lactone from Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred at reflux in a Soxhelet apparatus containing molcular sieves. After 18 hours, the reaction mixture was cooled and the volatile materials removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (4:1 hexanes/ethyl acetate) to obtain the title compound (yield: 50 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.75 (d, J=12 Hz, 1H), 3.87 (d, J=12 Hz, 1H), 6.93–7.08 (m, 6H), 7.16 (d, J=9 Hz, 2H), 8.71 (s(br), 1H). MS (DCI/NH3) m/z 315 (M+H)+ and m/z 332 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25](O)=[O:26])=[CH:9]2.[CH2:28]([S:35][CH:36]([CH:39]([O:42][CH3:43])[O:40][CH3:41])[CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:28]([S:35][CH:36]([CH:39]([O:40][CH3:41])[O:42][CH3:43])[CH2:37][NH:38][C:25]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (4.24 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.88 g), 1H-1,2,3-benzotriazol-1-ol (1.80 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.70 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:3-1:4, volume ratio) to give the title compound (6.03 g, yield 91%) as a colorless amorphous solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[CH:6][N:5]=1.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[CH:13]=[C:12]([C:15]([F:18])([F:16])[F:17])[N:11]=2)=[CH:6][N:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)nc2)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (2.62 g) was added to a solution of 2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (13.65 g) dissolved in N,N-dimethylformamide (150 mL) under nitrogen atmosphere and under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (12.4 mL) under ice-cooling, and the mixture was stirred overnight while the temperature of the mixture was gradually raised to room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the aqueous layer at this time was extracted with ethyl acetate. The organic layers were combined and dried, and the residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyridine (9.42 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of benzyl bromide (1.4 g; 8.2 mmol), 3-hydroxybenzaldehyde (1.0 g; 8.2 mmol) and Cs2CO3 (2.67 g; 8.2 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature under N2. After evaporation of solvent in vacuo, the residue was diluted to 20 ml with CH2Cl2, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (1.33 g; 76%) as creamy foam. 1H-NMR (CDCl3) 5.11 (s, 2H); 7.2-7.48 (m, 9H); 9.96 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[O:16]([CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:25][CH2:26]1
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Reactant: c1ccc(OCC2CCNCC2)cc1
Solvent: CCO
Product: Nc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)cccc1[N+](=O)[O-]

Procedure:
A mixture of 40.0 g. 1-(2-amino-3-nitrophenoxy)-2,3-epoxypropane, 36.2 g. 4-phenoxymethylpiperidine and 450 ml. ethanol is stirred for 18 hours at ambient temperature and the solution thereby obtained of 2-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-3-nitrobenzene (m.p. 117°-118° C.) is subsequently hydrogenated at ambient temperature in the presence of 1.0 g. platinum oxide. After filtration, the filtrate obtained is acidified with dilute hydrochloric acid, evaporated and the evaporation residue redissolved in ethanol/ethyl acetate. There are obtained 72.3 g. 2,3-diamino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzene trihydrochloride (81% of theory) in the form of an amorphous substance.
Reaction SMILES: O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N([CH2:18][CH3:19])CC)C.[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][CH:31]([C:35]([OH:37])=O)[C:32]([OH:34])=[O:33])[CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C:31]2[C:32](=[O:33])[O:34][C:25]([C:24]3[CH:23]=[C:20]([CH3:22])[CH:21]=[C:18]([CH3:19])[CH:29]=3)=[CH:26][C:35]=2[OH:37])[CH2:21][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3CC3CC3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3,3'-dimethyl acetophenone (2 g, 13.51 mmol), trimethylsilyl triflate (3 g, 13.1 mmol), triethylamine (2.73 g, 27.02 mmol), methylene chloride (20 mL), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio]propandioic acid (2.18 g, 6.76 mmol). m.p. 168° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 2H), 0.39 (dd, 2H), 1.13 (m, 1H), 2.26 (s, 6H), 2.67 (d, 2H), 6.85 (s, 1H), 6.92 (m, 1H), 7.11 (m, 2H), 7.22 (s, 1H), 7.33 (m, 1H), 7.47 (s, 2H).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:17]3[C@H:13]([CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[C:12](=[O:25])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO.[OH-].[Na+]>[C:3]1([C:9]2([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:17]3[C@H:13]([CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[C@@H:12]([OH:25])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution of 1 g of sodium borohydride in 200 cm3 of methanol is added dropwise over 40 minutes to a solution, cooled to +4° C. of 17.8 g of (3aR,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolone in one liter of methanol, followed by 10 drops of caustic soda. The reaction mixture is stirred for 3 hours at +4° C. and then 2 cm3 of a 0.1N aqueous solution of hydrochloric acid are added and the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 350 cm3 of dichloromethane, washed with 100 cm3 of water and then with 50 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 40 cm3 of ethyl ether. The crystals obtained are drained and dried. 8.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol are obtained in the form of white crystals; melting point 190° C. The crystallization mother liquors are concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 33 cm), eluting under a nitrogen pressure of 0.4 bar with a dichloromethane and methanol mixture (96/4 by volume) and collecting fractions of 20 cm3. Fractions 18 to 21 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 1.88 g of (3aR,4R,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol are obtained in the form of a white meringue. Fractions 26 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 5 cm3 of ethyl ether. 2.88 g of (3aR,4S,7aR)-7,7-diphenyl-tert-butyloxycarbonyl-4-perhydroisoindolol are additionally obtained in the form of white crystals; melting point 190° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:20]2)=[CH:16][CH:15]=1.[CH3:38][C:39]1[O:40][C:41]([CH3:46])=[C:42]([CH2:44]O)[N:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:38][C:39]1[O:40][C:41]([CH3:46])=[C:42]([CH2:44][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[N:20]3)=[CH:36][CH:37]=2)[N:43]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1nc(CO)c(C)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(C)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 1.00 g) was added dropwise slowly to a mixture of methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), (2,5-dimethyl-4-oxazolyl]methanol (275 mg), triphenylphosphine (585 mg) and tetrahydrofuran (10 ml) at room temperature. After the mixture was stirred at room temperature for 8 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionate (288 mg, yield: 44%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (6:5, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([O:14][CH3:15])[C:3]=1[N+:16]([O-])=O>Cl>[Cl:1][C:2]1[C:3]([NH2:16])=[C:4]([O:14][CH3:15])[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:7]=1
Reactant: COc1cc(N2CCOCC2)nc(Cl)c1[N+](=O)[O-]
Agent: Cl
Product: COc1cc(N2CCOCC2)nc(Cl)c1N
Temperature: 75 °C
Yield: 82.8 %

Procedure:
To a solution of 4-(6-chloro-4-methoxy-5-nitropyridin-2-yl)-morpholine (0.38 g) in concentrated hydrochloric acid (20 mL) was added a solution of stannous dichloride (1.57 g) in concentrated hydrochloric acid (60 mL). The reaction mixture was heated to 75° C. for 5 minutes and then poured on to chrushed ice (100 g) and extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo, to furnish 0.28 g (83% yield) of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): 3.35 (m, 4H), 3.65 (br s, 2H), 3.80 (m, 4H), 3.90 (s, 3H), 6.10 (s, 1H).