Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26])[CH2:9]2.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-]>C(O)=O>[N:8]12[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]1)[C@@H:10]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH:1]=[O:3])[CH2:9]2
Reactant: Nc1ccccc1/C=C/C(=O)N[C@H]1CN2CCC1CC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=CNc1ccccc1/C=C/C(=O)N[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Formic acid (98%, 2.9 mL) and acetic anhydride (1.0 mL) were combined under an inert atmosphere while cooling with a cold water bath. (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-(2-aminophenyl)propenamide) (0.16 g, 0.00059 moles) was added and the reaction was stirred for three days at room temperature. The solution was poured into saturated sodium carbonate and more solid carbonate was added until the solution was basic. The aqueous layer was extracted four times with chloroform. The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. The product was transferred using chloroform and this was stripped and chased with two portions of ether. The white solid was dried at room temperature with high vacuum, giving 64 mg; MS (ES+) 300 (MH+).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=1.O>CN1C(=O)CCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([N:20]2[C:5](=[O:7])[CH2:4][C@@H:2]([C:1]([OH:9])=[O:8])[CH2:3]2)[CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred solution of itaconic acid (35 g, 269 mmol) in NMP at 70° C. was added (R)-1-(4-methoxyphenyl)ethanamine (37 g, 245 mmol) via syringe. The mixture was heated at 80° C. for 1 hour and warmed to 120° C. for an additional 4 hours. The reaction was cooled to rt and poured into 550 mL of water with vigorous stirring. The mixture was aged for 1 hour over which time a slurry was formed. The solids were collected via filtration and washed with water. The solids were dried and transferred to a flask and recrystallized from iPrOH. Upon cooling and stirring, a thick slurry was obtained which was filtered to afford solids enriched in the major diastereomer. This material was again recrystallized from iPrOH to obtain (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH2:23][OH:24])[C:11]1=[O:25])=[O:4].O[Li].O.Cl>C1COCC1.O.CO>[CH:16]1([CH:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:25])[C@H:12]([CH2:22][CH2:23][OH:24])[CH2:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@H](CCO)CCC1C1CCCCC1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@H](CCO)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
To a solution of 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (123 mg, 0.28 mmol, 1 equiv.) in THF/H2O/MeOH (1.0 mL/1.0 mL/0.5 mL) was added LiOH.H2O (60 mg, 1.38 mmol, 5 equiv) and the resulting solution was stirred at 50° C. for 20 minutes. The solution was then acidified to pH=5 by addition of 3.0 N HCl aq. solution. The solution was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give product 28 mg (yield 23%). MS: 432 [M+H+]. 1H-NMR (400 MHZ, CD3OD): 6.85 (s, 1H), 3.92 (br, 1H), 3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.78 (m, 7H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40]C(=O)C(F)(F)F)[O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[NH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C@H:14]1[O:13][C@@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:15]1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CO[C@@H]1O[C@H](COCCCCCNC(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CO[C@@H]1O[C@H](COCCCCCN)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
To a stirred solution of methyl 2,3,4-tri-O-benzyl-6-O-(N-trifluoroacetyl-5-aminopentyl)-β-D-glucopyranoside (799 mg, theoretically 1.71 mmol, structure (13) from Example 4) in 10 mL of ethanol at room temperature was added a solution of 5M (3 mL, 15 mmol). The solution was heated to reflux for 2 hours. The solvents were removed under reduced pressure. The reaction mixture was diluted with dichloromethane (70 mL) and washed with aqueous HCl (25 mL, 15 mmol). The water layer was re-extracted with dichloromethane (3×50 mL), and the combined organic layers were washed with saturated aqueous NaCl (1×75 mL) and dried over magnesium sulfate. Concentration and crystallization from ethyl acetate/petroleum ether provided pure analog having structure (8), methyl 6-O-(5-aminopentyl)-2,3,4-tri-O-benzyl-β-D-glucopyranoside, (675 mg, 72% from methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-β-D-glucopyranoside) as a white solid: m.p. 95°-95.5° C.; RF 0.19 (6% methanol in dichloromethane); 1H NMR (500 MHz, CDCl3) δ7.35-7.24 (m, 15H), 4.92 (d, J=7.5 Hz 1H), 4.90 (d, J=7.6 Hz, 1H), 4.85 (d, J=11.0 Hz, 1H), 4.78 (d, J=11.0 Hz, 1H), 4.70 (d, J=11.0 Hz, 1H), 4.60 (d, J=11.0 Hz, 1H), 4.32 (7.8, 1H), 3.66-3.59 (m, 3H), 3.56 (s, 3H), 3.48-3.36 (m, 3H), 2.94 (dd, J=12.5, 2.1 Hz, 1H), 2.68 (dd, J=12.0, 6.8 Hz, 1H), 2.64-2.53 (m, 2H), 1.71 (s, 2H), 1.59-1.53 (m. 2H), 1.51-1.45 (m, 2H), 1.42-1.36 (m, 2H), 13C NMR (500 MHz, CDCl3) δ138.55, 138.47, 138.17, 128.39, 128.33, 128.03, 127.95, 127.85, 127.77, 127.60, 127.57, 104.72, 84.56, 82.45, 79.74, 75.66, 75.02, 74.74, 74.16, 62.62, 57.20, 50.69, 49.72, 32.49, 29.65, 23.37; IR (thin film) 3280(m), 3095(w), 3065(w), 3035(w), 2935(s), 2915(s), 2860(s), 1496(w), 1454(m), 1404(w), 1393(w), 1358(m), 1214(m), 1115(s), 1072(s), 1037(m), 1027(m), 1009(m), 911(w), 826(s), 747(s), 696(s) cm-1 ; HRMS m/e calc'd for C33H43O6N (M+H): 550.3168, found 550.3179; [α]D20 +9.3° (c=0.15, acetonitrile).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH:12](I)([CH3:14])[CH3:13]>>[CH:12]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1)([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: O=c1ccc2c([nH]1)CCCC2
Product: CC(C)Oc1ccc2c(n1)CCCC2

Procedure:
Following the procedure described in Example 1A, step 2, 5,6,7,8-tetrahydroquinolin-2 (1H)-one and i-PrI gave the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl-].[OH:14][NH3+:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:15][OH:14]
Reactant: [NH3+]O
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccccc1)C(F)(F)F
Yield: 89.6 %

Procedure:
25 g (0.144 mol) of 2,2,2-Trifluoro-1-phenyl-ethanone are dissolved in 40 ml of ethanol at 80° C. To the solution are added dropwise 10.5 g (0.151 mol) of hydroxylammonium chloride and 20.1 g (0.245 mol) of sodium acetate dissolved in 20 ml of water. The reaction mixture is refluxed overnight, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, the white precipitate is rinsed with water and dried under vacuum, yielding 24.4 g of 2,2,2-trifluoro-1-phenyl-ethanone oxime. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:36]=[CH:35][C:22]([CH2:23][N:24]([CH2:32][CH2:33][OH:34])C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:34][CH2:33][CH2:32][NH:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=3[CH2:3][C:2]([NH2:1])=[O:41])[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNCCO)cc2)ncc1C(F)(F)F
Yield: 23.3 %

Procedure:
A solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate (A75) (0.301 g, 0.525 mmol) and trifluoroacetic acid (1.0 mL) in DCM (10 mL) was stirred at room temperature for 22 hours. The volatiles were removed in vacuo and 2 M aqueous sodium hydroxide solution (20 mL) added to the residue. The resulting suspension was sonicated for several minutes then filtered, washing the filter cake with water. Semi preparative HPLC of the filter cake gave the title compound 19 as a white solid (58 mg, 23%); 1H NMR (300 MHz, d4-MeOH) δ 8.61 (s, 1H), 8.53 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.29-7.19 (m, 4H), 4.19 (s, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.68 (s, 2H), 3.22-3.10 (m, 6H). LCMS-B: rt 5.313 min; m/z 474 [M+H]+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH2:9].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Fe+2].[Fe+2].C(#N)C>[OH:2][C:1]1[C:3]([OH:4])=[CH:5][C:6]2[C:3]3[C:1](=[CH:8][C:7]([OH:9])=[C:6]([OH:9])[CH:5]=3)[C:7]3[C:6](=[CH:5][C:3]([OH:4])=[C:1]([OH:2])[CH:8]=3)[C:7]=2[CH:8]=1
Reactant: O
Reactant: Oc1ccccc1O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC#N
Product: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Temperature: 30 °C
Yield: 45.5 %

Procedure:
Catechol (22.0 g, 0.2 moles) and diiron trioxide (ferric oxide) (31.9 g, 0.2 moles) were added into water (110 mL), and 98% sulfuric acid (440 g, 4.4 moles) was added dropwise to the solution while temperature of the solution was maintained at 30° C. or lower, to adjust the concentration in percent by weight of sulfuric acid in the reaction system at 80%. The solution was reacted at 30° C. for 6 hours with stirring. After completion of the reaction, water (500 mL) was added dropwise to the reaction solution, and the reaction solution was stirred for another 30 minutes. The resultant precipitate was collected by filtration, and the obtained crude crystal was washed with water and dried to give crude crystal (19.2 g). After a part of the crude crystal (5.0 g among 19.2 g) was dispersed in a mixed solvent of water (50 mL) and acetonitrile (200 mL), the dispersion liquid was heated up and stirred for 1 hour. After that, this dispersion liquid was filtered in hot state to filter off insoluble matter, the filtrate was then concentrated under reduced pressure, and the precipitated crystal was collected by filtration, and then dried, to give 2,3,6,7,10,11-hexahydroxytriphenylene (2.56 g, theoretical yield from catechol: 45.5%) in black powder form. 1H-NMR data of the obtained 2,3,6,7,10,11-hexahydroxytriphenylene measured were in accordance with those of 2,3,6,7,10,11-hexahydroxytriphenylene described in the reference. Also, the measurement results of 1H-NMR are shown below. In addition, content of iron ion in the obtained crystal was measured by inductively-coupled plasma optical emission spectroscopy (ICP-OES), and was found that content of iron ion (reduced quantity from metal iron) in the obtained 2,3,6,7,10,11-hexahydroxytriphenylene (2.56 g) was 0.087 mg (0.034 mg/g). Also, the measurement of iron ion content by inductively-coupled plasma optical emission spectroscopy was carried out using inductively-coupled plasma optical emission spectrometer SPS 3100 (manufactured by SII Nanotechnology Inc.) as follows. Several samples containing appropriate amount of metal iron dissolved in n-methyl-2-pyrrolidone were measured and a calibration curve was obtained based on the measurement results, in advance. Content of iron ion in 2,3,6,7,10,11-hexahydroxytriphenylene was obtained from the calibration curve.
Reaction SMILES: [CH2:1]([N:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:19][NH2:20])=[C:13]([CH2:17][NH2:18])[CH:14]=2)[CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[N:22]>N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([N:4]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][NH:18][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][CH:27]=3)(=[O:31])=[O:30])=[C:12]([CH2:19][NH:20][S:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH:11]=2)[CH2:16]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN(CCC)C1Cc2cc(CN)c(CN)cc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCN(CCC)C1Cc2cc(CNS(=O)(=O)c3ccc(C#N)cc3)c(CNS(=O)(=O)c3ccc(C#N)cc3)cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(N,N-dipropylamino)-5,6-bis(aminomethyl)indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled in ice, and 4-cyanobenzenesulfonyl chloride (0.61 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10% sodium carbonate solution and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a dark oil. Purification by flash chromatography (230-400 mesh silica gel, 60-80% ethyl acetate/hexane) gave the title compound (54) as an oil. The compound was dissolved in ethyl acetate and excess ethereal hydrochloric acid was added. The mixture was diluted with diethylether and filtered. The precipitate was washed with diethylether and dried under vacuum giving the hydrochloride salt of 54 as a tan solid (0.143 g).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:4]1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[C:29](I)[S:30][C:23]=12)[NH2:17]>>[NH2:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[C:29]([C:11]#[C:10][CH2:9][N:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:12])[CH3:1])[CH2:8][CH2:7]4)[S:30][C:23]=23)=[C:14]([F:13])[CH:15]=1
Reactant: C#CCN1CCC(N(C)C)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CN(C)C1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C

Procedure:
Prepared from N,N-dimethyl-1-(prop-2-ynyl)piperidin-4-amine (32 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was partially purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (34 mg, 31%; 50% purity by 1H NMR), and carried forward without further purification. LRMS (APCI pos) m/e 425 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[Cl:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccccc1Cl
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3Cl)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chlorobenzyl chloride (0.38 mL) as starting materials, 5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>O>[CH3:1][O:2][C@@H:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=C(OC)c1ccccc1
Solvent: O
Product: CCOC(=O)C[C@@H](OC)c1ccccc1
Yield: 54 %

Procedure:
Ethyl 3-methoxy-3-phenylpropenoate (206 mg, 1 mmol) was reacted with yeast (10 g) and water (10 ml) according to method I. The product was obtained in 54% yield. Reaction according to method II gave the product in 60% yield.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH2:36])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>COCCOC>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH:36][C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NC(=O)C(=O)O
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: COc1ccc(CCNC(=O)C(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a suspension of oxamic acid (1.76 g, 20 mmol) in 1,2-dimethoxyethane (75 mL) under an argon atmosphere was added dropwise N-methylmorpholine (2.55 mL, 23 mmol) followed by ethyl chloroformate (2.20 mL, 23 mmol). After stirring for 1 h at room temperature, a solution of 2-(3-cyclopentyloxy-4-methoxy-phenyl)ethylamine (4.65 g, 20 mmol) in 1,2-dimethoxyethane (30 mL) was added over 5 min, and the resulting mixture was stirred for 2 h. Saturated aqueous ammonium chloride was added and the solvent was removed under reduced pressure. The solid residue was dissolved in methanol/methylene chloride, washed successively with water, 10% hydrochloric acid, aqueous sodium bicarbonate and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 1% i-propanol/methylene chloride to provide the oxamide (1.82 g, 30%): m.p. 175°-175.5° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)(O)[O-:13].[Na+]>C(#N)C.O>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=1)=[O:13]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of [4-(methylthio)phenyl]boronic acid (1.008 g) in acetonitrile (60 ml) and water (6 ml) was cooled with a dry ice-acetone bath until it just began to freeze. A solution of ceric ammonium nitrate (6.72 g) in water (10 ml) was added with swirling. The resulting solution was left to warm to room temperature. The mixture was then basified to pH5 by addition of 8% aqueous sodium bicarbonate (16 ml) and evaporated to dryness by re-evaporation with absolute ethanol. The dried residue was purified by SPC (Merck 7729) using ethyl acetate-ethanol (9:1 followed by 4:1 and 7:3) as eluent, to give a colourless solid. The solid was further purified by FCC eluting with dichloromethane:ethanol (9:1) to give the title compound (1.00 g) as a colourless gum.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[C@@H:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:4]1[O:6][C@@H:5]12.[CH:18]([Mg]Br)=[CH2:19].[NH4+].[Cl-]>C1COCC1>[CH2:11]([O:10][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C@H:5]([CH:18]=[CH2:19])[C@H:4]1[OH:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C[Mg]Br
Reactant: c1ccc(CO[C@H]2[C@@H]3O[C@@H]3[C@@H]3OC[C@H]2O3)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: 60 °C

Procedure:
To a stirred solution of 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose (7, 5.0 g, 21.3 mmol) in dry THF (25 ml), was added a solution of 1.77M vinylmagnesiumbromide 16 in THF (120.5 ml, 213 mmol). The mixture was gently refluxed for 3 h at 60° C. After cooling to room temperature a 2M NH4Cl aq. solution (650 ml, pH 8) was slowly added. The aqueous layer was extracted with ethyl acetate (2×250 ml). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product (4.87 g, 87%) was purified by flash chromatography using ethyl acetate/pentane 1:2 as eluent, to give 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-β-D-glucopyranose (8) as a white crystalline compound in 75.5% (4.23 g) yield. After recrystallization in ethanol: mp. 88°-91° C.; [α]D20 =-2.3° (c 4.1, CHCl3) (lit17 mp. 91°-93° C. [α]D20 =+1.2° (c 1.3, CHCl3)). 13C-NMR (50 MHz, CDCl3):δ135.5 (CH=), 137.7, 128.3), 127.6, 127.5 (Ph), 117.2 (CH2 =), 103.5 (C-1), 78.8 (C-4), 74.6 (C-3), 71.3, 70.4 (C-5, OCH2Ph), 65.4 (C-6), 51.8 ppm (C-2). 1H NMR (200 MHz, CDCl3): δ7.35 (d, 5H, Ph), 5.99 (m, 1H, CH=CH2), 5.25 and 5.17 (s, 1H og d, 1H, CH2 =), 4.63) (dd, 3H, OCH2Ph and H-5), 4.09 and 3.75 (d, 1H and m, 2H, H-3, H-6 and H-6'), 3.43 (s, 1H, H-4), 2.80 (broad s, 1H, OH), 2.45 (d, 1H, H-2). Anal. Calc. for C15H18O4 : C, 68.69; H, 6.92. Found: C, 68.58; H, 6.94.
Reaction SMILES: Cl.Cl.C(OC1C=CC([CH:17]([N:26]2[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]2)[CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=CC=1[Cl:34])C1C=CC=CC=1.Cl.Cl.N[C@@H]1CCN(CC(C2(O)CCCCC2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:47]([Cl:59])[CH:46]=2)C1>>[ClH:34].[ClH:59].[CH2:52]([O:51][C:48]1[CH:49]=[CH:50][C:45]([CH:18]([C:19]2([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:17][N:26]2[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]2)=[CH:46][C:47]=1[Cl:59])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CN(C)[C@@H]1CCN(C(CC2(O)CCCCC2)c2ccc(OCc3ccccc3)c(Cl)c2)C1
Reactant: N[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN(C)[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 36, 1-{-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol (See Example 383). MS (ES) m/z 457.1; HRMS: calcd for C27H37ClN2O2+H+, 457.26163. found (ESI, [M+H]+), 457.2608.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][C:7]3[CH:20]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][C:6]=3[S:12][C:11]=2[CH:13]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(CO)cc1CC2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)CCc1ccc(CO)cc1S2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.