Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])=[O:21])[CH:16]=[N:15]2)[N:12]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20](=[O:21])[NH:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:11]2[N:12]=[C:8]([CH2:6][OH:5])[S:9][CH:10]=2)[CH:18]=1
Reactant: CCOC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cnn(Cc2csc(CO)n2)c1)OCc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-[4-(2-chloro-benzyloxycarbonylamino)-pyrazol-1-ylmethyl]-thiazole-2-carboxylic acid ethyl ester (912 mg, 2.17 mmol) in THF (20.0 mL) at −78° C. was treated with DiBAL (8.70 mL of a 1M solution in toluene, 8.70 mmol). The reaction mixture was stirred at −78° C. for 1 h, then allowed to reach rt before being quenched with Rochelle's salt (100 mL). The resulting mixture was stirred for 2 h at rt, extracted with EA (2×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a yellow foam. TLC: rf (19:1 CH2Cl2-MeOH)=0.11. LC-MS-conditions 02: tR=0.83 min; [M+H]+=379.04.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=1.O[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:17][CH:16]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[S:8][CH:9]=3)=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: OCc1csc(-c2cccnc2)n1
Product: c1cncc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)c1
Yield: 35 %

Procedure:
In substantially the same manner as in Working Example 146, 2-(3-pyridyl)-4-thiazolylmethanol was mesylated, which was allowed to react with 1-[3-(4-hydroxyphenyl)propyl]imidazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-pyridyl)thiazole. The yield was 35%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 67-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]2[C:23](=[O:37])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:25]=[C:11]2[CH:10]=1.[F:38][C:39]([F:50])([F:49])[CH2:40]OS(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:40][C:39]([F:50])([F:49])[F:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]2[C:23](=[O:37])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)[N:25]=[C:11]2[CH:10]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CSc1ccc(-n2nc3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc-3cc2-c2ccc(O)cc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-n2nc3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc-3cc2-c2ccc(OCC(F)(F)F)cc2Cl)cc1
Yield: 28 %

Procedure:
A mixture of 0.45 g of the compound obtained in stage A of Example 18, 0.38 g of 2,2,2-trifluoroethyltrifluoromethanesulfonate and 0.28 g of NaHCO3 in 14 ml of EtOH is refluxed for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, elution being carried out with a mixture of DCM/EtOAc (100/30; V/V). 0.145 g of the expected compound is obtained after crystallization from iso ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].[C:36]([O-])(=[S:38])[CH3:37].[K+]>C(Cl)Cl.CN(C=O)C.[I-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:36](=[S:38])[CH3:37])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCOC(C)=S)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.5 %

Procedure:
A solution of 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol (2.16 g, 8.6 mmol), prepared as in Example 10, in 20 mL of methylene chloride was cooled to 0° C. under nitrogen and triethylamine (1.45 mL, 10.5 mmol) and methanesulfonyl chloride (0.74 mL, 9.5 mmol) in 20 mL of methylene chloride were added. The mixture was allowed to warm to room temperature and stirred for 45 minutes. The mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried (K2CO3) and concentrated by rotary evaporation. The residue was dissolved in 10 mL of DMF and the solution was added to a mixture of potassium thioacetate (1.18 g, 10.3 mmol) and sodium iodide (65 mg, 0.4 mmol) in 20 mL of DMF. The mixture was purged with nitrogen under a vacuum and then heated at 50° C. for 20 hours. The mixture was allowed to cool to room temperature and partitioned between water and hexanes/ethyl acetate (1:1). The organic layer was separated, washed with water and then brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (2:1) to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylthioacetate (1.43 g, 4.6 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7].[OH-].[Na+:17]>CO>[O:1]1[CH2:5][CH2:4][O:3][C:2]1([C:6]([O-:8])=[O:7])[C:11]([O-:13])=[O:12].[Na+:17].[Na+:17]
Reactant: CCOC(=O)C1(C(=O)OCC)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C1(C(=O)[O-])OCCO1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A solution of 11.0 g (0.05 mol) of diethyl 1,3-dioxolane-2,2-dicarboxylate of Example 1 in 50 ml methanol was slowly added to a solution of 8.8 g of 50% aqueous sodium hydroxide (0.11 mol) in 100 ml. methanol. After stirring overnight the mixture was filtered and the salt washed twice with methanol, twice with ether and vacuum dried at 80° yielding 9.9 g (95%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>ClCCl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (55.5 mg, 0.128 mmol) in dichloromethane (5 mL) at room temperature, triethylamine (0.045 mL, 0.320 mmol) and methanesulfonyl chloride (0.011 mL, 0.147 mmol) were added. The mixture was stirred for 1 h at room temperature. The residue was purified by prep TLC on silica gel, eluting with EtOAc/MeOH/NH4OH (90/9/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with TFA/CH2Cl2=1:1 for 1 h to give the title compound. (LC-MS: 411.92 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH2:27][OH:28]>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH:27]=[O:28]
Reactant: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(CC=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A mixture of chromium trioxide (1.2 g) and pyridine (1.9 g) in dichloromethane was stirred at ambient temperature for 15 minutes, and then 2-[3-methyl-1-(phenylsulfonyl)indol-2-yl]ethanol (630 mg) in dichloromethane (2 ml) was added. The resultant mixture was stirred at room temperature for 15 minutes. The separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% ethyl acetate in toluene) to give 3-methyl-1-(phenylsulfonyl)-2-indole acetaldehyde (423 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[S:12]([CH3:14])=[O:13])[CH:7]=[O:8])[CH3:2].[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[S:12]([CH3:14])(=[O:18])=[O:13])[CH:7]=[O:8])[CH3:2]
Reactant: OO
Reactant: CCOc1cc(C=O)cc(OCC)c1S(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(C=O)cc(OCC)c1S(C)(=O)=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of (±)-3,5-diethoxy-4-methanesulfinyl-benzaldehyde (0.60 g, 2.34 mmol, 1.0 equiv) in conc. acetic acid (10 mL) was added a solution of 35% hydrogen peroxide in water (0.41 mL, 0.46 g, 4.68 mmol, 2.0 equiv) and the solution stirred for 2 h at 40° C. Periodically, every 2 hours another 2.0 equivalents of hydrogen peroxide were added to the reaction mixture to drive the reaction to completion. After 6 h the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 0.27 g (42%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.0 Hz, 6H), 3.34 (s, 3H), 4.24 (q, J=7.0 Hz, 4H), 7.10 (s, 2H), 9.95 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 814.39, 46.59, 66.02, 106.62, 123.29, 140.08, 158.91, 190.95. MS (ISP): 273.0 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[O:7]=[C:8]1[CH2:12][CH:11]([C:13]2[CH2:14][S:15][C@@H:16]3[C@H:27]([NH:28]C(=O)COC4C=CC=CC=4)[C:26](=[O:39])[N:17]3[C:18]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][O:9]1.CN1CCOCC1.CO>ClCCl.O>[NH2:28][C@@H:27]1[C:26](=[O:39])[N:17]2[C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:13]([CH:11]3[CH2:10][O:9][C:8](=[O:7])[CH2:12]3)[CH2:14][S:15][C@H:16]12
Reactant: CC(C)(C)OC(=O)C1=C(C2COC(=O)C2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1=C(C2COC(=O)C2)CS[C@@H]2[C@H](N)C(=O)N12
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A solution of phosphorous pentachloride (0.380 g, 1.8 mmol) in dichloromethane (9.5 ml) was added to t-butyl (6R,7R)-3-[(4RS)-2-oxotetrahydrofuran-4-yl]-7-phenoxyacetamidoceph-3-em-4-carboxylate (0.554 g, 1.2 mmol) and N-methylmorpholine (265 μh, 2.4 mmol) in dichloromethane (15 ml) at <-20° C. under argon. Stirred 0.5 h at -15°±5° C. then methanol (3.5 ml) added, stirred 0.75 h then water (10 ml) added and stirred vigorously 1 h. The dichloromethane was removed in vacuo. ethyl acetate added and the aqueous layer adjusted to pH7 with dilute ammonium hydroxide and extracted twice with ethyl acetate. The extracts were washed with brine, dried, concentrated and flash chromatographed on silica gel eluting with 40,50,60,70,75% ethyl acetate in hexane to provide the title compound as a foam (0.120 g, 29%): (Found: M+, 340.1113. C15H20N2O5S requires M, 340.1093); νmax (CH2Cl2) 1775, 1715, 1367, 1155 cm-1 ; δH (250 MHz, CDCl3) 1.54 (9H, s , 1.97 (2H, bs), 2.35-2.95 (2H, m), 3.26 and 3.49 3.28 and 3.49 (2H, 2ABq, J 17.7 Hz), 4.0-4.45 (3H, m), 4.77, 4.79 (1H, 2d, J 4.7 Hz), 4.93, 4.95 (1H, 2d, J 4.7 Hz).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1>COCCOC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:37])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-{4'-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl} 2,4-pentanedione.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Yield: 103.9 %

Procedure:
L-Serine methyl ester hydrochloride (5 g, 32.13 mmol) dissolved in methylene chloride (200 ml) was added with TEA (2 equiv., 8.95 ml) and in one portion 5-chlorothiophene-2-sulfonyl chloride (1.0 equiv., 6.97 g). The reaction was refluxed for 4 hours. The solvent was evaporated and the crude was dissolved in AcOEt (100 ml) and washed with water (1×80 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from diethyl ether and petroleum ether afforded 10 g of the white product. Yield=93% 1HNMR (DMSO, 200 MHz) δ 2.81 (2H, q, J=7.2 Hz), 3.52 (3H, s), 3.92 (1H, t), 5.06 (1H, bs), 7.24 (1H, dd, J=4.2 Hz), 7.45 (1H, dd, J=4 Hz), 8.92 (1H, bs)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)(C)c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(CN)cc1
Yield: 68.8 %

Procedure:
A solution of methyl 2-(4-azidomethylphenyl)-2-methylpropionate (48.1 g)and triphenylphosphine (59.5 g) in a mixed solvent of tetrahydrofuran (480 ml) and water (24 ml) was refluxed for 30 min. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=10:1, chloroform:methanol:aqueous ammonia=10:1:0.3) to give the title compound (29.4 g) as a pale-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][C:3]1([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14].[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][C:3]1([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2ccccc2CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2ccccc2CCC1O
Yield: 74.7 %

Procedure:
To a solution of 0.2 g of methyl 3-oxo-2-[3-(4-phenyl-1-piperazinyl)propyl]-2,3,4,5-tetrahydro-1-benzothiepin-2-carboxylate obtained in Example 2 in 20 ml of methanol, 50 mg of sodium borohydride is added in small portions with stirring. After stirring for one hour, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane, to give 0.15 g of methyl 3-hydroxy-2-[3-(4-phenyl-1-piperazinyl)propyl]-2,3,4,5-tetrahydro-1-benzothiepin-2-carboxylate as crystals, obtained in Example 7: m.p. 152°-154° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:4]1[N:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc(Br)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Br)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
4-Bromo-2H-phthalazin-1-one (10.38 g, 46 mmol) was dissolved in dimethylformamide (DMF) (60 ml). To this was added NaH (60%, 1.55 g, 46.2 mmol) as a DMF suspension (20 ml). The mixture was stirred at RT for 30 mins then benzyl bromide (13.82 g, 50.8 mmol) was added in one portion as a solution in DMF (20 ml). The reaction mixture was stirred for 2 hours then the DMF was removed under reduced pressure and the resulting crude material purified by column chromatography (gradient elution: 100% heptane to 20% EtOAc: heptane) to give the title compound (8.16 g, 56% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 8.30 (1H, dd), 8.03 (1H, ddd), 7.97-7.91 (2 H, m), 7.34-7.27 (5H, m), 5.31 (2H, s); MS (ESI+)=(M+H)+ 315 & 317
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[C:3]([CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(C(C)=O)C(=O)OC
Yield: 62.3 %

Procedure:
465 g of methyl acetoacetate were added dropwise under nitrogen and stirring to 720 g of 30% sodium methylate solution in 1200 ml of methanol. Then, 727 g of 1-bromohexane were added and the reaction mixture was boiled at reflux for 20 hours. The majority of the methanol was distilled off and the residue was poured on to ice-water. The mixture was extracted with n-hexane and then with water. The organic phases were combined and dried over sodium sulphate. The solvent was evaporated and the crude ester was distilled. There were obtained 499.4 g of methyl 2-acetyloctanoate, b.p. 124°-128°/15 Torr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[C:3]([C:31]2[CH:30]=[CH:29][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH:2]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
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: COc1cc(C=C2C(=O)Nc3ccccc32)c(-c2ccc3ccccc3c2)cc1OC
Reaction time: 12 h
Yield: 30.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.20 g) in toluene (1 ml) and ethanol (1 ml) followed by addition of 2M aqueous sodium carbonate (1.1 ml). To this mixture was added naphthalene-2-boronic acid (0.11 g), and the mixture was held at 100° C. in a sealed tube for 12 hours. The precipitate which formed was filtered, washed with ethanol and then dissolved in 20% methanol/toluene, filtered and concentrated. The resulting solid was triturated with hexanes and dried to afford 0.07 g (29%) of 3-(4,5-dimethoxy-2-naphthalen-2-ylbenzylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC(OC)(C)C.[CH3:13][O:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[CH:18]=[C:17]([CH3:24])[N:16]=1>CC(OC)(C)C.C1COCC1>[CH3:13][O:14][C:15]1[C:20]([CH2:21][NH2:22])=[C:19]([CH3:23])[CH:18]=[C:17]([CH3:24])[N:16]=1
Reactant: COc1nc(C)cc(C)c1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1nc(C)cc(C)c1CN
Temperature: 25 °C

Procedure:
LiAlH4 (48.0 g, 1.27 mol) was added into MTBE (600 mL) portion-wise at room temperature. To the suspension was added 2-methoxy-4,6-dimethylpyridine-3-carbonitrile (Cpd S, 103 g, 0.636 mol) in MTBE/THF (1:1, 600 mL) portion-wise. The reaction mixture was stirred at room temperature for an hour then quenched with water (75 mL). The precipitate was collected by filtration and the solids washed with THF (3×100 mL). The filtrate was concentrated under vacuum to give the 1-(2-methoxy-4,6-dimethylpyridin-3-yl)methanamine (Cpd T), which was used in the next step directly.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[CH2:17]([OH:19])[CH3:18].[BH4-].[Na+]>C1COCC1>[C:17]([NH:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:19])[CH3:18]
Reactant: Cc1c(F)cc([N+](=O)[O-])c2c1C(=O)CCC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (4) above (1.35 gm) was dissolved into 5 ml of ethanol and 15 ml of THF. To the solution Was added 114 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, the reaction mixture was concentrated. To the concentrate were added 25 ml of toluene and 840 mg of p-TsOH, followed by heating under reflux for 30 minutes. Upon the addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into 20 ml of ethyl acetate and catalytically hydrogenated with the addition of 400 mg of platinum oxide for 4 hours. The catalyst was removed, the filtrate was concentrated, and 10 ml of dichloromethane was added to the concentrate. After the further addition of 1.2 ml of triethylamine and 0.81 ml of acetic anhydride, the mixture was stirred for 40 minutes. The reaction product was diluted with 50 ml of chloroform, washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1.23 gm of the title compound.