Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[F:7][C:8]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([C:45]2[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1.FC1C=CC(S)=CC=1>O1CCCC1.C(OCC)(=O)C.O>[F:7][C:8]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:9]=1/[CH:10]=[CH:49]/[C:48]1[CH:47]=[CH:46][C:45]([S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:52][CH:51]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Agent: Fc1ccc(S)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Butyllithium (1.6M in hexanes, 0.35 mL, 0.57 mmol) was added dropwise to a cooled (0° C.) suspension of (2,4-difluorobenzyl)triphenylphosphonium bromide (266 mg, 0.57 mmol) in tetrahydrofuran (2.5 mL). The orange suspension was allowed to warm to room temperature for 1 hour. A solution of 4-[(4-fluorophenyl)sulfonyl]benzaldehyde (prepared according to the method of Example 46 Steps 1–4 using 4-fluorobenzenethiol in Step 1, 150 mg, 0.57 mmol) in tetrahydrofuran (0.5 mL) was added and the reaction was stirred overnight at room temperature. Water and ethyl acetate were added and the organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate/isohexane, followed by preparative HPLC to give the title compound (46 mg, 22%). 1H NMR δ (ppm)(DMSO): 8.01–7.99 (2H, m), 7.83 (2H, d, J=8.5 Hz), 7.47–7.42 (2H, m), 7.37 (2H, d, J=8.4 Hz), 7.27–7.17 (2H, m), 6.99 (1H, td, J=2.2, 8.6 Hz), 6.82 (1H, d, J=12.3 Hz), 6.70 (1H, d, J=12.0 Hz).
Reaction SMILES: [OH-].[Na+].CO.[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C(\c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to 35 ml of a methanol solution containing 3.41 g of ethyl (E)-3-phenyl-3-(4-pyridyl)acrylate (prepared as described in Preparation 2), and the mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction solution was poured into 50 ml of water and washed with methylene chloride. Sufficient hydrochloric acid was added to the aqueous phase to adjust the pH to a value of 2.8. The resulting precipitate was collected, giving 2.131 g of the title compound, as a white powder, melting at 239°-241° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([S:15][CH:12]([CH3:14])[CH3:13])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CC(C)S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(SC(C)C)CC1=O
Reaction time: 5 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), isopropylmercaptan (20 g), triethylamine (1 g) and toluene (45 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was washed with an acid, an alkali and water in order. The organic layer was separated and concentrated to give 2-allyl-3-methyl-4-isopropylthio-2-cyclopentenone (20.2 g). Yield, 96.3%. The product was purified by silica gel chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.5196.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=C[C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C[NH2+]C1CC[O:26][CH2:25]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][N:12]([CH:13]1[CH2:14][CH2:15][O:26][CH2:25]1)[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: C[NH2+]C1CCOC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (2.19 g, 7.27 mmol), N-methyltetrahydrofuran-3-aminium chloride (1.00 g, 7.27 mmol) and triethyl amine (1.01 mL, 7.27 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (10-100% EtOAc/hexanes) to afford tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate.
Reaction SMILES: [CH2:1](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([NH:22][C@H:23]([C:33]([OH:35])=[O:34])[CH2:24]OCC1C=CC=CC=1)(OC(C)(C)C)=O.CN(C=O)C.C([N:43]([CH2:46][CH3:47])CC)C>ClCCl>[NH2:22][C@H:23]([C:33]([OH:35])=[O:34])[CH2:24][CH2:1][CH2:47][CH2:46][NH2:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: ClCCCl
Reactant: CCN(CC)CC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
A mixture of EDC (8.0 g, 41,73 mmol), HOBt (5.63 g, 41.73 mmol), N-BOC-(O-benzyl)-L-serine (12.45 g, 41.73 mmol) was stirred in-DMF (300 mL) at room temperature for 2 hours. To this reaction mixture was added N-ε-(carbo-benzoxy)-L-lysine-, methyl ester hydrochloride (13.80 g, 41.73 mmol), followed by triethylamine (5.81 mL), and the stirring was continued for 18 hours. The mixture was dissolved in dichloromethane (1 L), and the organic phase was washed with dilute hydrochloric acid (1N, 500 mL), saturated sodium bicarbonate (500 mL), and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford 23 g of L-lysine, [N-ε-(carbobenzoxy)]-N-α-[L-[N-BOC-(O-benzyl) seryl]]-, methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][O:8]C(C)(C)[O:6]1)=[O:4].Cl.O1CCOCC1.N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C@H:5]([OH:6])[CH2:9][O:8][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (R)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid methyl ester (2.5 g, 15.6 mmol) in methanol (15 mL) was added HCl in dioxane (4N, 5 mL, 20 mmol) and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in THF (20 mL) and imidazole (1.28 g, 18.7 mmol) and tert-butylchlorodimethylsilane (2.47 g, 16.4 mmol) added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-50% EtOAc in cyclohexane) to yield (R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acid methyl ester as a colorless oil (2.29 g, 63%). 1H NMR (400 MHz, CDCl3) 4.26-4.20 (1H, m), 3.93 (1H, dd, J=10.1, 3.4 Hz), 3.86 (1H, dd, J=10.1, 2.8 Hz), 3.79 (3H, s), 3.01 (1H, d, J=7.8 Hz), 0.88 (9H, s), 0.06 (3H, s), 0.04 (3H, s)
Reaction SMILES: COC[CH:4]1[O:8][CH:7]([C:9]2[CH2:10][S:11][C@@H:12]3[C@H:28]([NH:29]C(=O)COC4C=CC=CC=4)[C:27](=[O:40])[N:13]3[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:6][CH2:5]1.CN1CC[O:45][CH2:44]C1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:54]O>ClCCl.O>[NH2:29][C@@H:28]1[C:27](=[O:40])[N:13]2[C:14]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:16])=[C:9]([C@:7]3([CH3:54])[CH2:6][CH2:5][C@H:4]([O:45][CH3:44])[O:8]3)[CH2:10][S:11][C@H:12]12
Reactant: CN1CCOCC1
Reactant: CO
Reactant: COCC1CCC(C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](NC(=O)COc4ccccc4)[C@H]3SC2)O1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)C2=C([C@]3(C)CC[C@H](OC)O3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-methoxybenzyl (6R,7R)-3-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-yl]-7-phenoxyacetamidoceph-3-em-4-carboxylate (1.93 g) in dichloromethane (25 ml) was cooled to -15 to -20° C., N-methylmorpholine (0.75 ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (26.5 ml of a solution containing 40 mg.ml-1). The mixture was stirred at the same temperature for 0.5 h and then methanol (6.8 ml) was added and the mixture stirred at room temperature for 0.5 h. Water (10 ml) was then added and the mixture vigorously stirred for 0.5 h. The dichloromethane was then removed on a rotary evaporator and the residue was partitioned between ether and water. The aqueous phase was stirred with ethyl acetate and the pH was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The products were separated by column chromatography of the residue using gradient elution (silica gel, 1:1 hexane : ethyl acetate going to neat ethyl acetate). The following were obtained in order of elution 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxy-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (388 mg); νmax (CHCl3) 3410, 1776 and 1725 cm-1 ; δH (CDCl3) 1.59-1.78 (2 H,m), 1.93-2.08 (1 H,m), 2.18-2.32 (1 H,m), 2.54 (2 H, br s), 3.33-3.54 (3 H,m), 3.38 (3 H,s), 3.80 (3 H,s), 4.00-4.11 (1 H,m), 4.76 (1 H,d, J 4.99 Hz), 4.90 (1 H,d, J 4.97 Hz) 4.96 (1 H,t, J 8.23 Hz) 5.17 (2 H,s), 6.88 (2 H,d, J 8.60 Hz) and 7.33 (2 H,d, J 8.61 Hz). [Mass spectrum: M+ (434)]; 4-methoxybenzyl (6R,7R)-7-amino-3-((2R,5S)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (305 mg); νmax (CHCl3) 3409, 1776 and 1725 cm-1 ; δH (CDCl3) 1.60-1.81 (2 H, m), 1.85-2.01 (2 H, m), 3.30-3.50 (2 H, m), 3.38 (3 H, s), 3.44 (1 H,d, J 17.78 Hz), 3.69 (1 H, d, J 17.75 Hz), 3.80 (3 H, s), 4.00-4.17 (1 H,m), 4.70 (1 H, d, J 4.92 Hz), 4.93 (1 H, d, J 4.95 Hz), 5.10-5.20 (1 H, m), 5.18 (1 H, d, J 11.88 Hz), 5.24 (1 H, d, J 11.89 Hz), 6.88 (1 H,d, J 8.65 Hz) and 7.35 (1 H, d, J 8.64 Hz). [Mass spectrum: M+(434)].
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]=[CH:20][CH:19]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:30]1
Reactant: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
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: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2ccc3ccc4c(-c5cccc6ccccc56)ccc5ccc2c3c54)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 7 g (17.2 mmol) of 1-bromo-6-(naphthalen-1-yl)pyrene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)Palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.4 g (yield 47%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 670.1; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.11 (s, 1H), 8.89 (d, J=8.00 Hz, 1H), 8.82 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J=8.00 Hz, 2H), 8.38 (d, J=9.20 Hz, 1H), 8.30˜8.26 (m, 3H), 8.19˜8.05 (m, 7H), 8.02˜7.98 (m, 2H), 7.83˜7.82 (m, 2H), 7.78˜7.68 (m, 5H), 7.61˜7.59 (m, 2H), 1.79 (s, 6H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](N)=O)=[C:5]([SH:13])[CH:4]=1.[C:14](O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:10]([CH3:14])[S:13][C:5]=2[CH:4]=1
Reactant: NC(=O)Nc1ccc(Cl)cc1S
Reactant: CC(=O)O
Agent: [Na]
Solvent: O
Product: Cc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
112.25 parts of the sodium salt of 4-chloro-2-mercaptophenylurea, which salt is obtainable according to Example 6 of European Pat. No. 0,039,483, are suspended in 450 parts of glacial acetic acid in an autoclave. The pressure vessel is closed and heated slowly to 150° C.-160° C. in the course of 2 hours, a pressure of about 5 bar being established. The water formed is discharged continuously via a pressure release valve. The reaction is complete after 5 hours. The autoclave is cooled to room temperature and opened, the reaction mixture is allowed to run into 1000 parts of water, and the precipitated 6-chloro-2-methylbenzothiazole is isolated by filtration, washed neutral and dried in vacuo at 40° C. 85.6 parts of a product of the formula ##STR21## of melting point 85° C.-86° C. are obtained; this corresponds to a yield of 93.3% of theory, based on sodium salt employed.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH2:1]([C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Yield: 99 %

Procedure:
2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (70 mg, 0.193 mmol) of Preparation 38, Step B, was dissolved in dioxane (5 ml) and Caesium carbonate (251 mg, 0.77 mmol), trimethylboroxine (0.054 ml, 0.385 mmol) and Catalyst 1 (10 mg) were added. The reaction was refluxed under nitrogen for 3 h. The reaction was filtered over arbocel and diluted with ethyl acetate, washed with water, dried over MgSO4 filtered and concentrated in vacuo to afford the title compound as a colourless oil in 99% yield, 66 mg.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:11][CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCO
Reactant: C=C(C)C(=O)Oc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1ccc(C2OCCO2)cc1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask fitted with reflux condenser, Dean Stark trap and nitrogen line was charged with 30.0 g of 4-formylphenyl methacrylate, 19.0 g of ethylene glycol, 250 mL of toluene and a catalytic amount of p-toluenesulfonic acid monohydrate. The solution was heated at reflux for 1 day, during which time the water formed in the reaction was removed periodically from the Dean Stark trap. Toluene was added to make up for losses from the Dean Stark trap, and the solution was heated at reflux for an additional 15 hours. Thereafter the solution was cooled to room temperature, was washed with three 75 mL portions of saturated sodium bicarbonate solution, and the toluene extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude acetal was chromatographed on silica gel (20:1 silica gel to compound weight ratio) with hexane/ethylacetate (4:1 volume ratio) to give purified acetal (18.8 g). 1H NMR (CDCL3) 7,5 (d, 2H), 7,1 (d, 2H), 6.3 (s, 1H), 5.78 (s, 1H), 5.7 (s, 1H), 4.15-3.85 (m, 4H), 2.02 (s, 3H); 13C NMR (CDCl3) 165, 151, 135, 128, 127, 121, 103, 65, 18; IR (neat) 1,735 cm-1 ester carbonyl. The spectral data are consistent with the postulated structure. The chromatographed acetal was used directly in the free radical polymerizations.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])OC.[BH4-].[Na+]>CO>[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH:27][CH2:1][C:3]2[S:7][C:6]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Reactant: NCCc1cccc(F)c1
Agent: COC([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccc(F)c3)s2)cc1
Reaction time: 3 h

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (90 mg, 0.36 mmol) from Example 1, part B, method B, with 2-(3-fluoro-phenyl)-ethylamine (61 mg, 0.44 mmol), methyl orthoformate (0.48 mL) and methanol (0.7 mL). Stir the resulting mixture for 3 hours and then add sodium borohydride in portions. Stir the reactiom misture until the reaction is complete by TLC or HPLC analyses. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (4 mL) and CH2Cl2 (6 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound. 1H NMR (CDCl3): 7.72 (d, J=8.7 Hz, 2H), 7.21-7.13 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.92-6.80 (m, 3H), 6.56 (d, J=3.6 Hz, 1H), 6.36 (d, J=3.7 Hz, 1H), 5.82 (bs, 2H), 3.83 (s, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:35][CH2:34][CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.395 g; 1.206 mmol), LHMDS 1N in THF (1.327 mL; 1.327 mmol), 1-iodopropane (0.177 mL; 1.810 mmol) in DMF (4.8 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.335 g (75%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([CH3:12])([NH2:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+].[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([NH:11][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:10])[CH3:12]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CCCN(C)CCC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Crude N1-(3-(Dimethylamino)propyl)-N1,3-dimethylbutane-1,3-diamine (18.0 g, 31.9 mmol) was dissolved into THF (200 mL). Sodium hydrogen carbonate (14.0 g, 0.167 mol) dissolved in water (200 mL) was added to reaction to give a solution. CbzOSu (7.95 g, 1 equiv, 31.9 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed via rotovap and the aqueous concentrated to ˜100 mL. The aqueous was extracted with DCM (2×200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. The desired fractions were collected and lyophilized to give a colorless oil (5.57 g, yield: 52.1%). LRMS (ESI+) for C19H33N3O2 (335.3); Found: 336 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](Cl)=[O:29])=[CH:22][CH:21]=1>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:3]2[C@H:2]([CH3:1])[C@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[O:29])=[CH:24][CH:25]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Temperature: -78 °C
Yield: 92 %

Procedure:
To a cooled (−78° C.) solution of 4-(R)-methyl-5-(S)-phenyl-oxazolidin-2-one, 31, (600 mg, 3.39 mmol) in anhydrous tetrahydrofuran (20 mL) is added n-butyl lithium (2.5 mL, 1.6M solution in hexanes, 4.07 mmol). The resulting solution is stirred at −78° C. for ninety minutes and then 3-(4-chloro-phenyl)-propionyl chloride (894 mg, 4.41 mmol) is slowly added. The solution is warmed to room temperature for thirty minutes and then the solvents removed under reduced pressure. The crude product is purified over silica (20:80 ethyl acetate:hexanes, Rf˜0.3) to afford 1.07 g (92% yield) of the desired compound as a colorless solid. 1H NMR (CDCl3 300 MHz) δ 0.91 (d, J=6.6 Hz, 3H), 3.01 (t, J=7.8 Hz, 2H), 3.18–3.40 (m, 2H), 4.77 (m, 1H), 5.67 (d, J=7.2 Hz, 1H), 7.18–7.48 (m, 9H). MS (ESI) m/z 344 (M+H+)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]12([OH:17])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:17][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A total of 13 mmole of acryloyl chloride was added dropwise to a mixture of 10 mmole of 1,3-adamantanediol, 15 mmole of triethylamine and 100 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at 50° C. for 1.5 hours. After the addition of water, the reaction mixture was extracted with ethyl acetate, the organic layer was concentrated, and the resulting concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 63%.