Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH:18]=[CH2:19])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@H:6]1[N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@:9]1([CH:18]=[CH2:19])[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@@H:6]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 42 h
Yield: 97.3 %

Procedure:
To a stirred solution of nucleoside 23 (3.90 g, 7.7 mmol) in anhydrous methanol (40 cm3) was added sodium methoxide (0.83 g, 15.4 mmol). The mixture was stirred at room temperature for 42 h and then neutralised with dilute aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×150 cm3), and the combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give nucleoside 24 as a white foam (3.48 g, 97%). δH (CDCl3) 8.89 (1H, br s, NH), 7.60 (1H, d, J 0.9, 6-H), 7.36-7.26 (10H, m, Bn), 6.23 (1H, d, J 7.8, 1′-H), 5.98 (1H, dd, J 11.2, 17.7, 1″-H), 5.66 (1H, d, J 17.7, 2″-Ha), 5.55 (1H, d, J 11.5, 2″-Hb), 4.75-4.37 (6H, m, 2′-H, 4′-H, Bn), 3.84 (1H, dd, J 2.7, 10.8, 5′-Ha), 3.58 (1H, d, J 11.2, 5′-Hb), 3.23 (1H, d, J 10.6, 2′-OH), 1.50 (3H, s, CH3). δC (CDCl3) 163.7 (C-4), 151 3 (C-2), 138.0, 136.9 (Bn), 136.0 (C-6), 131.2 (C-1″), 128.8, 128.6, 128.3, 127.8, 127.7, 127.3 (Bn), 120.7 (C-2″), 111.3 (C-5), 87.3 (C-1′), 84.6 (C-3′), 81.4 (C-4′), 78.0 (C-2′), 73.7 (C-5′), 70.0, 66.4 (Bn), 11.8 (CH3). Found: C, 66.8; H, 6.2; N, 5.9. C26H28N2O6 requires C, 67.2; H, 6.1: N, 6.0%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>C(Cl)(Cl)Cl>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-aminopropyl)-4-(4-chlorobenzhydryl)piperazine (1.7 g) and triethylamine (0.7 g) in chloroform (20 ml) was dropwise added benzoyl chloride (0.7 ml) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate and water, and then extracted with 10% hydrochloric acid. After neutralizing the aqueous extract with aqueous sodium carbonate, the desired product was extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated in vacuo to give an oil. According to a conventional manner, the oily product was converted to fumaric acid salt, which was recrystallized from a mixture of ethanol and diethyl ether to afford 1-(3-benzoylaminopropyl)-4-(4-chlorobenzhydryl)piperazine fumarate (0.82 g) as white crystals. mp: 173°-175° C. (dec.).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:25])([CH3:24])[NH:15]1)=[O:13])[CH3:10].C[Si](C=[N+]=[N-])(C)C.[CH3:33][OH:34]>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:34][CH3:33])[CH:21]=2)[C:16]([CH3:24])([CH3:25])[NH:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1Cc2ccccc2C(C)(C)N1
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)ccc2C(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the triflate salt of 1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (1.5 g, 3.76 mmol, 1.0 eq.) in MeOH (20 mL) and CH2Cl2 (2 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 3.7 mL, 2.0 eq.). The resulting mixture was warmed to r.t. and stirred overnight, and then the solution was concentrated. Purification by flash chromatography (125 g SiO2 linear gradient, 40 mL/min, 1:1 EtOAc/hexane for 33 minutes) afforded about 900 mg of the final compound (96%). LRMS (electrospray): 250.2 (M+1).
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:25]3[C@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@H:20](O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:18][CH2:19][C@@H:20]([F:8])[C@@H:21]3[C@H:25]2[CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FS(F)(F)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 4 h

Procedure:
A solution of 3.5 cm3 of morpholinosulphur trifluoride in 50 cm3 of dichloromethane is added to a solution, cooled to +5° C., of 9.4 g of (3aR, 4S, 7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol in 250 cm3 of dry dichloromethane. The reaction mixture is stirred for 4 hours at +5° C. and then diluted with 300 cm3 of dichloromethane, washed with 250 cm3 of an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and 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 3.5 cm, height 42 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 120 cm3. Fractions 13 to 17 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from cyclohexane. 2.55 g of (3aR, 7R,7aR)-4,4-Diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydroisoindole are obtained in the form of white crystals; melting point 202° C.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26][NH2:27]>>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)cc(OC)c1
Yield: 95 %

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.020 g, 0.075 mmol) was reacted with 3,5-dimethoxybenzylamine (0.25 g, 1.50 mmol) (Procedure E) to yield (2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol, (−)-29f, 0.03 g (Yield; 95%, [α]D=(−)58.60, c=1, CHCl3).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (2.00 g, 0.00522 mol) in 30 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filtered off the catalyst, the filtration was concentrated to dry and used directly in next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:19]
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A 3-L flask equipped with a nitrogen (N2) inlet, thermometer and addition funnel was charged with dichloromethane (CH2Cl2, 1400 mL) and 2-amino-6-methylpyridine (130 g, 1.2 mol, Aldrich). After cooling the reaction to 0° C. in a wet ice/water bath, triethylamine (Et3N, 151.5 g, 1.5 mol) was added. Trimethylacetyl chloride (159.15 g, 1.32 mol) was diluted with CH2Cl2 (100 mL) and added dropwise to the reaction over 1.5 h. The reaction was stirred for an additional 30 min at room temperature. The salts were filtered from the reaction and the filtrate was washed twice with H2O. Drying the filtrate with anhydrous magnesium sulfate (MgSO4) and stripping all solvent in vacuo left a yellowish colored solid. Recrystallization from diethyl ether (Et2O)/hexanes (Hex) provided 167.3 g (73%) of pure product. The identity of this material and that of subsequent examples were confirmed by NMR (300 MHZ), microanalysis, and infrared spectroscopy, unless otherwise noted.
Reaction SMILES: [C@@H:1]1([N:10]2[C:18]([NH2:19])=[C:17]3[C:13](=[N:14][CH:15]=[N:16]3)[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C@@H:1]1([N:10]2[C:18]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]3[C:13](=[N:14][CH:15]=[N:16]3)[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1c2ncnc-2ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1c2ncnc-2ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1

Procedure:
introducing an acyl group at the N6 position of 1-β-D-arabinofuranosyl adenine with an acylating agent, for example, using benzoyl chloride under conditions suitable for obtaining 1-β-D-arabinofuranosyl-N6-benzoyl adenine,
Reaction SMILES: F[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)C=1.[NH:15]1C=CN=N1>>[N:4]1[N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[N:15]=[CH:2][CH:3]=1
Reactant: CCOC(=N)C1(n2cc(F)cn2)CC1
Reactant: c1c[nH]nn1
Product: CCOC(=N)C1(n2nccn2)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 64, but using 1,2,3-triazole as the starting material.
Reaction SMILES: C(=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:24])=[O:23])=[C:18]([CH3:34])[CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:35][C:36]([CH3:43])([CH3:42])[C:37](=O)[CH2:38][C:39]#[N:40].Cl>C(O)C>[NH2:40][C:39]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])=[C:18]([CH3:34])[CH:17]=2)[N:14]=[C:37]([C:36]([CH3:43])([CH3:42])[CH3:35])[CH:38]=1
Reactant: Cc1cc(NN=C(c2ccccc2)c2ccccc2)ccc1S(=O)(=O)NCCN1CCOCC1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(-n2nc(C(C)(C)C)cc2N)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 4-(N′-benzhydrylidene-hydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzene sulfonamide (1.00 g, 2.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile (392 mg, 3.13 mmol, 1.5 eq) in anhydrous ethanol (10.5 mL, 0.2 M) was added p-toluenebenzene sulfonic acid (402 mg, 4.18 mmol, 2.0 eq), and the reaction mixture was stirred at reflux under nitrogen. After 18 h, concentrated HCl (2 mL) was added and the reaction mixture was stirred at reflux under nitrogen for an additional 4 h. The reaction mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between EtOAc (500 mL) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (70% to 90% EtOAc/hexane) to give 799 mg (91%) of the desired product. 1H-NMR (DMSO-d6) δ 7.85 (d, J=8.4 Hz, 1H), 7.61 to 7.55 (m, 3H), 5.40 (s, 1H), 5.38 (broad s, 2H), 3.46 (t, J=4.5 Hz, 4H), 2.88 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 2.27 to 2.18 (m, 6H), 1.20 (s, 9H); MS LC-MS [M+H]+=422, RT=1.95 min.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>C1COCC1>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:5]
Reactant: O=C(Cl)c1cccnc1F
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1cccnc1F
Reaction time: 15 h
Yield: 91 %

Procedure:
A homogeneous mixture of 2-fluoronicotinic acid (Aldrich, 0.45 g, 3.2 mmol), in anhydrous THF (12 mL), was treated with oxalyl chloride (0.56 mL, 6.4 mmol) followed by anhydrous DMF (2 drops). After heating at reflux for 1.5 hours, the reaction mixture was concentrated in vacuo to afford 2-fluoronicotinoyl chloride as a residue which was used without further purification. The residue was dissolved in anhydrous THF (8 mL), anhydrous DCM (2 mL), pyridine (1 mL) and DMF (to a total volume of 16 mL). This homogeneous 2-fluoronicotinoyl chloride mixture (2 mL) was then added to a rapidly stirred mixture of o-toluidine (Aldrich, 0.17 mL, 1.6 mmol) in anhydrous THF (2 mL). After 15 hours, the reaction was quenched with water, and then extracted with 10% isopropanol in chloroform. The organic layer was washed once with sat. aq. NaHCO3, once with sat. aq. NaCl, then dried over anhydrous Na2SO4 and concentrated in vacuo to afford the desired product (0.084 g, 91%) as a pale orange solid which was used without further purification. MS(ESI+) m/z 231 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH:13](O)[CH3:14])[CH:2]=1.C(O)(=O)CC.[C:21](OCC)([O:26]CC)([O:23][CH2:24][CH3:25])[CH3:22]>[Cl-].[Na+].O>[CH2:24]([O:23][C:21](=[O:26])[CH2:22][CH:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=[CH:13][CH3:14])[CH3:25]
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(O)C=Cc1cnc2ccccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CC=CC(CC(=O)OCC)c1cnc2ccccc2c1

Procedure:
A solution of the allylic alcohol 22-2 (1.2 g, 6.1 mmol) in triethyl orthoacetate (50 mL) was treated with propionic acid (0.022 mL, 0.31 mmol) and refluxed for 2 h. The cooled mixture was treated with a solution of 1:1 sat. brine/1N HCl (150 mL), then extracted with CH2Cl2 (3×125 mL). The pooled organic extracts were washed with sat. NaHCO3, dried, filtered and evaporated. Chromatography on silica gel (EtOAc) afforded 22-3 as a yellow glass.
Reaction SMILES: N#N.II.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH3:13].[O:14]1[CH2:16][CH2:15]1>C1COCC1>[CH2:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:16][CH2:15][OH:14])[CH3:13]
Reactant: C1CO1
Reactant: CCc1ccccc1Br
Agent: II
Agent: N#N
Solvent: C1CCOC1
Product: CCc1ccccc1CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Into a 250-mL round-bottom flask protected by N2 was placed tetrahydrofuran (100 mL), Mg (1.0 g, 41.67 mmol, 2.14 equiv) and I2 (0.010 g). Then a solution of 1-bromo-2-ethylbenzene (3.6 g, 19.45 mmol, 1.00 equiv) in THF (15 mL) was added dropwise. The resulting mixture was heated to reflux for 1 h. Then it was cooled to 0° C. and oxirane (50 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 1.83 g (63%) of 2-(2-ethylphenyl)ethan-1-ol as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(=O)CC>[CH2:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:23]=[CH2:22]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 6.5 h

Procedure:
4-hydroxybenzophenone (186.7 g, 940 mmol, Fluka Chemical) was dissolved in 2-butanone (700 mL, Fisher Scientific) in a 2L four-necked flask equipped with a mechanical stirrer, reflux condenser, addition funnel and internal temperature probe. K2CO3 (195 g, 1.41 mol, Aldrich Chemical) was added to the reactor, and the contents was placed under a slow N2 purge. Allyl bromide (123 mL, 1.41 mol, Aldrich Chemical) was charged to the addition funnel. The pot temperature was raised to 65° C., at which point the allyl bromide was added over the course of 30 minutes. The reaction was stirred for 6.5 h at 65° C. after the addition was completed. At this point no starting material was present as determined by GC analysis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.25 g of tert-butyl 3-{2-[2-(2-aminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at room temperature with a solution of 0.12 ml of triethylamine in 1 ml of dichloromethane. Subsequently, a solution of 0.034 ml of methanesulphonyl chloride in 1 ml of dichloromethane is added dropwise. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane, washed with 1M aqueous potassium bisulphate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.07 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[CH3:18][N:19]1[C:23]([CH2:24]O)=[CH:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:20]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:24][C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:30][CH:31]=4)[CH:22]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)n1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], [rac]-2-(6-hydroxy-indol-1-yl)-propionic acid ethyl ester (J. E. D. Barton, D. Cartwright, C. J. Mathews, Brit. UK Pat. Appl. (1992), GB 2253848 A1) was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 11 d]) in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give [rac]-2-{6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[CH:5]=1)[CH3:29]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CC(N)CO
Product: COc1ccc(C(=O)NC(C)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and (±)-2-amino-1-propanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[SH:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:44][C:45]5[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: Oc1ccc(S)cc1
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccc(O)cc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate (see ex. C1a) (300.0 mg, 0.45 mmol) was dissolved in 3 ml N,N-dimethylformamide, then 4-mercaptophenol (58.0 mg, 0.45 mmol), followed by triethylamine (62.7 ml, 0.45 mmol) was added. After 22 h the reaction mixture was poured on diethyl ether and the solid was collected by filtration. The brown solid material was suspended in water: acetonitrile (1:1) and chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (9:1, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.