Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C[C@@H](O)C[C@@]1(C)C(OC)=O)(OC(C)(C)C)=O.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.CC1(C)CC=CC(C)(C)N1.FC(F)(F)S([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])(=O)=O.[F-].[K+].CCN(C(C)C)C(C)C.ClC1C=C(S(Cl)(=O)=O)C=CC=1>CN(C=O)C.O.CN(C1C=CN=CC=1)C>[Si:19]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CC1(C)C=CCC(C)(C)N1
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@]1(C)C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-BOC-4(S)-hydroxy-2-methyl-(L)-proline, methyl ester (Step A, 2.2 g, 8.5 mmol), tert-butyldimethylsilyl chloride (1.8 g, 12 mmol), and imidazole (1.1 g, 17 mmol) in 40 mL of anhydrous DMF was stirred at rt overnight. The reaction mixture was partitioned between Et2O and water, and the product was extracted with Et2O (2×200 mL). The combined extracts were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (15 mL), and was added with 2,6-dimethyllutidine (3.0 mL, 26 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.9 mL, 17 mmol) at rt. After stirring for 2 h, the reaction mixture was cooled by an ice-water bath, and was added potassium fluoride (1.4 g, 24 mmol) in 20 mL of water. After stirring at 0° C. for 2 h, the reaction mixture was partitioned between ether and water. The product was extracted with Et2O (3×50 mL), and the organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was azeotroped with toluene and was dissolved in CH2Cl2 (10 mL) and THF (10 mL). The solution was cooled with an ice water bath, and was added DIPEA (4.4 mL, 25 mmol), 4-DMAP (0.10 g, 0.85 mmol) and 3-chlorobenzenesulfonyl chloride (2.7 g, 12 mmol). The reaction was allowed to warm to rt overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tert-butyldimethylsilyl ether of the title compound, which was used immediately. Thus, to a solution-of the silyl ether in acetonitrile (40 mL) at 0° C. was added aqueous HF (48%, 4 mL), and the reaction was allowed to warm up to rt overnight. The reaction mixture was partitioned between 5 N aqueous NaOH, brine and EtOAc, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound (3.0 g, 96% from the product of Step A).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)([CH3:32])([CH3:31])[CH3:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.8 %

Procedure:
N-Benzyloxycarbonyl-L-valine (121.3 g), 1-hydroxybenzotriazole (130.5 g) and dry dimethylformamide (DMF) (800 ml) were placed in a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a calcium sulfate drying tube, under nitrogen atmosphere. The mixture was cooled to 0° for 15 min and proline t-butyl ester (82.6 g) in dry DMF (800 ml) was added at a fast dropwise rate over 2 h while the temperature of the reaction mixture was maintained at 0°. Dicyclohexylcarbodiimide (109.4 g) in dry DMF (400 ml) then was added in one portion to the reaction mixture. The reaction was stirred at 0° for 3 h, allowed to warm to room temperature gradually over 1 h, and stirred for 48 h, whereupon the reaction was shown to be complete by TLC [Rf =0.55, chloroform:ethyl acetate (85:15)]. The reaction mixture was chilled in ice/water and filtered cold to remove the precipitated dicyclohexyl urea. The DMF was evaporated using a mechanical vacuum pump and at a maximum bath temperature of 40°. The remaining oil was diluted with ethyl acetate (2 liter), chilled, and refiltered to remove additional dicyclohexyl urea. The ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium chloride solution, saturated sodium bicarbonate solution (twice), and saturated sodium chloride solution), dried (MgSO4), and evaporated to afford crude benzyloxycarbonyl-L-valyl-L-proline t-butyl ester as an amber oil (208.3 g, 100%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][O:26]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: Cc1cn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
A solution of nucleoside 36 (97 mg, 0.215 mmol) in ethanol (1.5 cm3) was stirred at room temperature and 20% palladium hydroxide over carbon (50 mg) was added. The mixture was degassed several times with argon and placed in a hydrogen atmosphere with a balloon. After stirring for 4 h, the mixture was purified by silica gel column chromatography using dichloromethane-methanol (97:3, v/v) as eluent to give nucleoside 37 as a white solid material (57 mg, 98%). δH ((CD3)2SO) 11.33 (1H, br s, NH), 7.62 (1H, d, J 1.1 Hz, 6-H), 5.65 (1H, d, J 4.4 Hz, 3′-OH), 5.41 (1H, s, 1′-H), 5.19 (1H, t, J 5.6 Hz, 5′-OH), 4.11 (1H, s, 2′-H), 3.91 (1H, d, J 4.2 Hz, 3′-H), 3.82 (1H, d, J 7.7 Hz, 1″-Ha), 3.73 (1H, s, H′-5a), 3.76 (1H, s, 5′-Hb), 3.63 (1H, d, J 7.7 Hz, 1″-Hb), 1.78 (3H, d, J 0.7 Hz, CH3). δC (CDCl3) 166.7 (C-4), 152.1 (C-2), 137.0 (C-6), 110.9 (C-5), 90.5, 88.4 (C-1′, C-4′), 80.9, 72.5, 70.4 (C-2′, C-3′, C-5′), 57.7 (C-1″), 12.6 (CH3). EI-MS m/z 270 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.P.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]([CH3:19])[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: Fc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C(C)c2ccc(F)cc2)cc1
Yield: 97.9 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 4-fluorophenyl chloride (130.2 mg, 1.0 mmol), 1-(4-methoxyphenyl)-1-propanone (198.4 mg, 1.2 mmol), palladium acetate (11.1 mg, 0.050 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (30.8 mg, 0.075 mmol), t-BuONa (115.0 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 12 h. 2-(4′-Fluorophenyl)-1-(4′-methoxyphenyl)-1-propanone (252.8 mg, containing 19% of 1-(4-methoxyphenyl)-1-propanone as determined by 1H NMR analysis) was obtained with a yield of 85% as solid. m.p.: 83.3-84.0° C. (n-hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.98-7.89 (m, 2H, ArH), 7.29-7.20 (m, 2H, ArH), 7.00-6.81 (m, 4H, ArH), 4.64 (q, J=6.9 Hz, 1H, CH), 3.76 (s, 3H, OCH3), 1.49 (d, J=6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 198.5, 163.1, 159.9, 137.4 (d, J=2.9 Hz), 130.8, 129.0 (d, J=8.6 Hz), 128.9, 115.5 (d, J=21.0 Hz), 113.5, 55.2, 46.3, 19.4; 19F NMR (282 MHz, CDCl3) δ −115.9; IR (KBr) v (cm−1) 3072, 2975, 2934, 2840, 1674, 1600, 1574, 1510, 1456, 1419, 1373, 1338, 1311, 1258, 1225, 1171, 1114, 1030; MS (70 eV, EI) m/z (%): 258 (M+, 0.32), 135 (100); Anal. Calcd. for C16H15FO2: C, 74.40; H, 5.85. Found: C, 74.23; H, 5.82.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Si](C)(C)[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C1COCC1>[OH:17][CH:16]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:15]1[CH:18]=[CH:19][C:12]([OH:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Br)nc1
Reactant: C[Si](C)(C)Oc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc(O)cc2)nc1
Temperature: -40 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 2-bromo-5-methylpyridine (3.45 g, 20 mmol) in THF (10 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (12 mL, 19.2 mmol) over a 10-min period at −78° C. The mixture was stirred at −78° C. for 2 min before 4-trimethylsilyloxybenzaldehyde (4.2 g, 21.6 mmol) dissolved in THF (10 mL) was added. The mixture was allowed to warm to −40° C. and quenched with water. The pH of the aqueous phase was adjusted to 7 which causes precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol. This was isolated by filtration to give 1.13 g (27%) of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol as crystals. This intermediate was dissolved in CH2Cl2 (15 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at 50° C. Evaporation gave 99% of 4-(5-methyl-pyridin-2-ylmethyl)phenol as a hygroscopic solid. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent and N-phenyl-N-methyl carbamoyl chlorid) to give 99% of the title product as its crystalline hydrochloride after purification by flash chromatography (Quad flash 12, EtOAc-heptane) and treatment with HCl in Et2O.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[CH2:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[Mg]Cl)[CH3:15].C(C1CCCCN1)C.C([Mg]Cl)(C)C>O1CCCC1>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:14][CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CCC1CCCCN1[Mg]Cl
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: CC(C)[Mg]Cl
Agent: CCC1CCCCN1
Solvent: C1CCOC1
Product: CCC1CCCCN1[Si](CCC(F)(F)F)(OC)OC
Temperature: 70 °C
Yield: 87.8 %

Procedure:
Following the same general procedure described on Example 1, a flask was charged with one mol (218 gm) of 3,3,3-trifluoropropyltrimethoxysilane was added to one mol of 2-ethylpiperdinylmagnesium chloride, the salt having been prepared in situ by adding 2-ethylpiperidine (120 g, 1.05 mol) to isopropylmagnesium chloride (1 mol) in 500 ml of tetrahydrofuran. The reaction was mildly exothermic and the temperature rose to 45° C. at the end of the addition time of one hour. The reaction mixture was refluxed at the pot temperature of 70° C. for one hour and then cooled to room temperature. The 3,3,3-trifluoropropyl(2-ethylpiperidino)dimethoxysilane was filtered under nitrogen atmosphere from the magnesium methoxychloride. The filter cake was washed with ether (2×200 ml) to obtain the residual product. The solvent was removed by distillation to a pot temperature of 100° C. The residue was distilled under vacuum to yield 263 g of 3,3,3-trifluoropropyl(2-ethylpiperidino)dimethoxysilane as a colorless oil (purity>98%); bp 70° C./0.1 mm. The total yield was 88% of theoretical.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[OH:2][CH2:1][CH:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][CH:16]([OH:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](CC[C@]3(C)C(CO)CC[C@@H]23)[C@@]2(C)CCC(O)C=C12

Procedure:
A solution of 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (2.30 g, 5.33 mmol), example 1, part E, in methylene chloride (70 mL) at -78° C. is treated with diisobutylaluminum hydride (1.5M in toluene, 15 mL, 22.5 mmol). After 20 minutes the reaction is quenched with methanol (4 mL), methylene chloride added (150 mL), washed with 2N NaOH and water, dried over MgSO4 and concentrated to give crude 17hydroxymethyl-3-hydroxy-6-t-butoxycarbonyl-6-azaandrost-4-ene of sufficient purity to carry on to the following steps; yield: 2.16 g (99%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH:22]=[CH2:23])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]O>C1COCC1.CCOCC.[OH-].[Na+].CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][OH:24])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of 4-(3-phenoxyphenyl)-1-vinyl-2-oxabicyclo[2.2.2]octane (14 mg, 0.046 mmol) in THF (1 mL) at 0° C. was added BH3.SMe2 complex (0.046 mL of a 2.0 M solution in Et2O; 0.091 mmol). The reaction mixture was stirred at 0° C. for 10 min and then warmed to rt. After stirring for 1 h at rt, the reaction mixture was cooled to 0° C. and a few drops of 1 N aqueous NaOH and 30% aqueous H2O2 solution were added. The resulting mixture was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 70% gradient EtOAc:hexanes) to afford the title compound (9 mg, 57% yield) as a colorless oil. LCMS, [M+H]+=325.1. 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 3H), 7.14-7.08 (m, 2H), 7.04-6.95 (m, 4H), 6.84 (ddd, J=8.1, 2.3, 0.8 Hz, 1H), 4.01-3.94 (m, 2H), 3.85-3.78 (m, 2H), 2.17-1.89 (m, 6H), 1.74-1.69 (m, 2H), 1.68-1.62 (m, 2H).
Reaction SMILES: [Li]CCCC.[C:6]1([O:14][CH3:15])[C:7](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:8][CH3:9].COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>CCCCCC.O1CCCC1>[CH3:9][O:8][C:7]1[C:6]([O:14][CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of n-BuLi (2.5M, 452 mL) in hexane was added to a solution of veratrole (149 g, 1.08 mol) in anhydrous tetrahydrofuran (1.2 L) over 10 minutes at −78° C. under nitrogen. The resulting solution was stirred at 0° C. for 1 hour and room temperature for 4 hours. A solution of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (275 g, 1.01 mol) in tetrahydrofuran (800 mL) was added to the reaction slurry at −65° C. over 20 minutes. The mixture was warmed to room temperature, stirred for 18 hours and quenched with saturated ammonium chloride (1 L). After stirring for 1 hour, the phases were separated and the aqueous layer was extracted with ethyl ether (1 L). The combined organic solutions were washed with brine (2 L) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30° C./20 torr) to a residue (413 g). The solution may be used directly in Scheme L, step a, Example 108.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].N1C=CN=C1>>[Si:5]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1

Procedure:
In a manner analogous to example 1 g, by reaction of 42.7 g (0.275 mol) of tert-butyldimethylchlorosilane with 30.5 g (0.2 mol) of 3-hydroxybenzaldehyde and (20.4 g, 0.3 mol) of imidazole. After purification on a silica column (dichloromethane 20-heptane 80), a yellow oil is obtained (m=55.9 g; Y=95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][C:11]([CH:8]1[CH2:9][CH2:10][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)=[O:13]
Reactant: CCOC(=O)N1CCC(C(=O)O)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C(=O)Cl)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 44 parts of 1-(ethoxycarbonyl)-3-pyrrolidinecarboxylic acid in 520 parts of dichloromethane were added dropwise 35.7 parts of thionyl chloride at 20° C. Upon complete addition, stirring was continued overnight and the reaction mixture was evaporated, yielding 49 parts (100%) of ethyl 3-(chlorocarbonyl)-1-pyrrolidinecarboxylate as an oily residue (int. 25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][CH:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][CH:10]3[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.Cl>C(#N)C.CCOC(C)=O.C(Cl)Cl.CCO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][C:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:34][CH2:35][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc(N2C=CC3C=C(c4ccc(Cl)cc4)SC3C2=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
Suspend 2-(4-chloro-phenyl)-6-(4-hydroxy-3-methoxy-phenyl)-3 a,7a-dihydro-6H-thieno[2,3-c]pyridin-7-one (0.233 g, 0.61 mmol) in acetonitrile (12 mL). Add Cs2CO3 (0.40 g, 1.22 mol) and reflux for 1 h. Add a solution of 1-(2-chloro-ethyl)-pyrrolidine hydroloride salt (114 mg, 0.67 mmol) in acetonitrile (5 mL) dropwise over a period of 5 min. Reflux the reaction for 2.5 h. Allow to cool to RT and dilute with EtOAc (50 mL). Wash with water (2×30 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 2% NH3—H2O, 50% CH3OH/EtOAc to give 0.164 g. Dissolve the material in CH2Cl2 (5 mL) and treat with 1.0 M HCl in EtOH (340 μL). Stir at RT for 5 min and concentrate to give 0.172 g, (59%) of the title compound. LC-MS/ES m/z (37Cl) 482.0 [M+]. 1H NMR (DMSO-d6) δ 1.82-1.96 (m, 2H), 1.98-2.12 (m, 2H), 3.08-3.23 (m, 2H), 3.58-3.70 (m, 4H), 3.82 (s, 3H), 4.04 (t, J=4.8 Hz, 2H), 6.82 (d, J=7.1 Hz, 1H), 7.02 (dd, J=8.3, 2.4 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.84-7.89 (m, 3H), 10.69 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Reactant: BrCc1ccccc1
Product: COc1cc(C(=O)O)cc(CCCOCc2ccccc2)c1OC
Yield: 68 %

Procedure:
3-(3-Benzyloxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3,4-dimethoxy-5-hydroxypropylbenzoic acid (Example 10, Step 1) and benzyl bromide in 68% yield by following Method I and used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8]S[C:5]=2[CH2:4][CH2:3]1.[N:12]1C=CC=C2C(=O)CC[C:13]=12.ICC>>[CH2:7]([CH:6]1[C:10](=[O:11])[C:13]2=[N:12][CH:1]=[CH:2][CH:3]=[C:4]2[CH2:5]1)[CH3:8]
Reactant: CC1CCc2sccc2C1=O
Reactant: O=C1CCc2ncccc21
Solvent: CCI
Product: CCC1Cc2cccnc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and iodoethane, and making non-critical variations provided the title compound as a oil:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10][C:9]=2[CH:27]=1)(=O)C.Cl.[OH-:29].[Na+]>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:29])[C:9]=2[CH:27]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC1(CCN(Cc3ccc(N)cc3)CC1)O2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(CN2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)cc1
Yield: 88 %

Procedure:
A solution of 3,4-dihydro-6-acetamido-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine] (136 mg, 0.36 mmol) and hydrochloric acid (6N solution, 13.6 ml) in methanol (13.6 ml) was heated at reflux temperature for 1 hr. The reaction mixture was cooled to 0° C. and basified with 20% sodium hydroxide solution. Extraction with methylene chloride, drying and solvent evaporation gave 3,4-dihydro-6-amino-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (107 mg, 88%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:26][CH3:27])[C:10]=2[CH:9]=1.[BH4-].[Na+].C(O)(=O)C.C1(C)C=CC=CC=1.C(OC(C)C)(C)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][CH:23]([OH:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:26][CH3:27])[C:10]=2[CH:9]=1
Reactant: CCn1c2ccccc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CCn1c2ccccc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3O

Procedure:
0.3 g (2.13 mmole) 4-(2-chlorophenyl)-6-ethyl-1,2,3,6-tetrahydro-1,3-dioxopyrrolo[3,4-c]carbazole (Example 2a) are suspended in 20 ml 90% methanol, a solution of 0.16 g (4.23 mmole) sodium borohydride in 5 ml methanol added dropwise thereto with vigorous stirring and stirred for 5 days at room temperature. The excess sodium borohydride is decomposed with acetic acid, the solvent is distilled off, and the crystalline residue is chromatographed on silica gel with toluene/ethyl acetate 1:1. The fraction with the Rf of 0.3 is isolated, stirred up with toluene/diisopropyl ether, and the crystals formed are filtered off. One obtains 4-(2-chlorophenyl)-6-ethyl-1,2,3,6-tetrahydro-1-hydroxy-3-oxopyrrolo[3,4-c]carbazole (Example 4a) in the form of pale beige crystals of the mp 225°-228° C.