Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:22][C:23]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26]>C(Cl)Cl>[CH2:1]([N:54]1[CH2:53][CH2:52][CH:51]([C:48]2[CH:49]=[CH:50][C:23]([OH:22])=[C:24]([CH:47]=2)[C:25]([NH:27][C:28]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][C:29]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[CH2:56][CH2:55]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetaldehyde (0.016 mL), acetic acid (0.024 mL), and sodium triacetoxyborohydride (0.11 g) were sequentially added to a methylene chloride (1.0 mL) suspension of tert-butyl 2-(2-hydroxy-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 1 hour. Acetaldehyde (0.016 mL) and sodium triacetoxyborohydride (0.11 g) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. After removal of the insoluble substance by filtration, a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.045 g of tert-butyl 2-(5-(1-ethylpiperidin-4-yl)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[F:41].[BrH:42]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:42][C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[F:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium nitrite (0.034 g, 0.49 mmol) was added to a 0° C. solution of 6-(N-(4-amino-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.235 g, 0.444 mmol) in Acetonitrile (3 ml) and aq HBr (48%) (3 mL). The reaction mixture was stirred for 30 min at 0° C. and copper (I) bromide (0.076 g, 0.53 mmol) was added. The reaction mixture was stirred at 90° C. for 2 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.094 g, 36%) as a white foam. LCMS (m/z, ES+)=593.2, 595.2 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=4[F:31])(=[O:23])=[O:22])[CH:15]=3)[C:11]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])C.[NH3:38]>CO>[F:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[S:21]([NH:20][C:16]1[CH:15]=[C:14]([C:12]2[C:11]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:8]3[S:9][CH:10]=[C:6]([C:4]([NH2:38])=[O:5])[N:7]3[N:13]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:23])=[O:22]
Reactant: N
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)nn12
Solvent: CO
Product: NC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)nn12
Reaction time: 18 h
Yield: 93 %

Procedure:
6-[3-(2,5-Difluoro-benzenesulfonylamino)-phenyl]-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester (30 mg, 0.055 mmol) was suspended a 7 N ammonia solution in methanol (1 mL) at 0° C. and stirred at this temperature for 18 hours. The mixture was evaporated to dryness and taken up with DCM and evaporated to dryness three times. The beige solid was dried under vacuum at room temperature to give 26 mg (93%) of 6-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid amide.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([CH3:24])([OH:23])[C:21]#[CH:22])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([O:23][C:32]([C:33]1[C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:42])([C:21]#[CH:22])[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C#CC(C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of 21.25 g (0.064 mol) of (rac.-5-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-3-methyl-1-pentyn-3-ol), 12.12 g (0.12 mol) of triethylamine, 2.44 g (0.02 mol) of 4-dimethylaminopyridine, and 11.84 g (0.08 mol) of phthalic anhydride in 100 mL of dichloromethane was stirred at 25° C. for 3.0 h, then heated under reflux for 10 h. The reaction mixture was cooled to 25° C. and diluted with 200 mL of diethylether. The solution was washed with 3×150 mL of 1.0N HCl. The aqueous phase was further extracted with 2×200 mL of diethylether. The organic phases were combined and extracted with 3×100 mL of 1.0N ammonium hydroxide. The basic aqueous extracts were combined, cooled in an ice-bath, and acidified carefully to pH 5.0 with approximately 60 mL of cold 6.0N HCl. It was then extracted with 4×200 mL of dichloromethane. The combined extracts were dried over MgSO4. Filtration and solvent removal on a rotary evaporator (35° C., 40 mm) gave a light yellow oily residue. This material was transferred to a flask with about 100 mL of diethylether, and the solvent was evaporated as described above to give a foam, which was further dried at 25° C./0.5 mm for 18 h to yield 31 g of rac.-benzenedicarboxylic acid [3-[2,5-bis (acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl] ester as a pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:34][CH2:33][Br:32])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (352 mg, 2.50 mmol) and 1,2-dibromoethane (0.129 μL, 1.25 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (278 mg, 2.50 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 μL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (80 mg, 100% yield).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:22]1[CH:23]=[CH:24]C2N(O)N=[N:28][C:26]=2[CH:27]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.N1CCCCC1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]([N:28]4[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]4)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(C(=O)N4CCCCC4)cc3s2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxylic acid (800 mg, 2.1 mmol) in THF (14 mL) was added HOBt (342 mg, 2.5 mmol), EDAC (807 mg, 4.2 mmol), triethylamine (1.7 g, 17 mmol) and piperidine (718 mg, 8.5 mmol) at room temperature. The reaction mixture was stirred at 40-50° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of CH2Cl2/MeOH (100:1→50:1) to give the crude product, which was further purified by preparative HPLC to give 167 mg (21%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-6-yl]piperidin-1-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:14][CH2:13]1
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 3-bromo-1-propanol (0.185 ml, 2.0 mmol). Yield: 0.16 g (29%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 259-261° C. MS m/z (relative intensity, 70 eV) 305 (M+, 4), 261 (16), 260 (bp), 217 (5), 177 (9).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[O:10][C:9](=O)[CH:8]=[C:7]([OH:12])[C:6]=1[CH2:13][CH3:14])[CH3:2].CO.[NH3:20]>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[NH:20][C:9](=[O:10])[CH:8]=[C:7]([OH:12])[C:6]=1[CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(OCC)c1oc(=O)cc(O)c1CC
Reactant: N
Solvent: CO
Product: CCOC(OCC)c1[nH]c(=O)cc(O)c1CC
Temperature: 60 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
A mixture of intermediate 19 (20 g; 82 mmol) in CH3OH/NH3 (150 ml) was stirred at 60° C. for 4 hours, evaporated till dryness and taken up in diisopropyl ether. The precipitate was filtered to yield 1.5 g of intermediate 20 (7.5%). The product was used without further purification in the next reaction step.
Reaction SMILES: [CH2:1]([Si:4]([CH2:16][CH:17]=[CH2:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]=[CH2:3].[BH4-].[Na+].[OH-:21].[Na+].[OH:23]O>O1CCCC1>[OH:21][CH2:3][CH2:2][CH2:1][Si:4]([CH2:16][CH2:17][CH2:18][OH:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=CC[Si](CC=C)(CCCCC)c1ccccc1
Reactant: OO
Reactant: [OH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[Si](CCCO)(CCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 g of boron trifluoride ether complex was dripped into a mixed solution of 100 g of diallylphenyl-n-pentylsilane, 9.6 g of sodium borohydride and 500 g of tetrahydrofuran. After the reaction mixture was stirred for 4 hours at room temperature, a 300 ml aqueous solution of 20% sodium hydroxide and then a 100 ml aqueous solution of 30% hydrogen peroxide were dripped into the mixture. After an overnight stirring were dripped into the mixture. After an overnight stirring at room temperature, extraction was conducted using ethyl acetate. Following conventional washing and concentration procedures, 120 g of di(3-hydroxypropyl)phenyl-n-pentylsilane was obtained. IR (liquid film) νmax: 3030 (s, br), 2920 (s), 2870 (s), 1420 (m), 1105 (s), 1050 (s), 1005 (s) and 850 (m) cm-1
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=1.NC1C=NC=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:28][CH2:27][N:26]([C:36]([NH:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:25][CH2:24]2)=[N:13][CH:14]=1
Reactant: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyrimidine trifluoroacetate (0.315 mmol, from Step 5), in acetonitrile (1.5 mL) was treated with phenyl pyridin-3-ylcarbamate (75 mg, 0.35 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridine) and diisopropylethylamine (0.192 mL, 1.10 mmol) and stirred at room temperature. After 72 h, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (0-10% ethanol (containing 11% aq NH4OH):dichloromethane) to afford the title compound (0.114 g, 78% yield) as a white foam. MS (APCI) M+1=466; 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=5.36 Hz, 2H) 2.61 (t, J=5.36 Hz, 2H) 3.55-3.63 (m, 2H) 3.66-3.73 (m, 2H) 6.41 (s, 1H) 7.01-7.09 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.40 (t, J=7.80 Hz, 1H) 7.43-7.48 (m, 1H) 7.89 (br. s., 1H) 8.21 (d, J=4.29 Hz, 1H) 8.48 (d, J=8.97 Hz, 1H) 8.58 (s, 2H) 8.88 (br. s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[S:12][CH:13]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[S:12][C:13]=1[CH:31]=[O:32]
Reactant: FC(F)(F)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (100 mL) of the compound (8.0 g, 23 mmol) obtained in Example 89a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 18 mL, 28 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.3 mL, 30 mmol) was added to the reaction mixture, and the mixture was stirred at −78° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (5.5 g, 64%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31]([OH:34])(=[O:33])[CH3:32].[OH2:35]>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]([O:33][C:31](=[O:34])[CH3:32])[CH2:27][OH:28])=[O:35])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Reactant: CC(=O)O
Reactant: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(CO)OC(C)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 8.35 g of 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate and 7.0 ml of acetic acid is heated at 100° C for four hours, allowed to cool, and diluted with water. Filtration affords 2-acetoxy-3-hydroxypropyl 4-(n-hexadecylamino)benzoate, mp 67° C unchanged by recrystallization.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH:17]1([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[CH:17]1([CH2:23][C:24]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)CC1CCCCC1
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 76.6 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and cyclohexylacetyl chloride (0.88 g, 5.5 mmol) in pyridine (10 mL) provided 2-cyclohexyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan-2-yl]acetamide (1.3 g). Mp 180-181° C.;MS (El) m/z 340 ([M+H]+); Anal. Calcd. for C22H29NO2: C, 77.84; H, 8.61; N, 4.13; Found: C, 77.96; H, 8.70; N, 4.16.
Reaction SMILES: C([O:4][C:5](=[O:29])[C@@H:6]([CH2:26][O:27][CH3:28])[CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])C=C.N1CCOCC1>C1COCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:12][CH2:11][O:10][CH2:9][C@@H:8]([NH:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)=[O:17])[CH2:7][C@H:6]([CH2:26][O:27][CH3:28])[C:5]([OH:29])=[O:4])[CH3:14]
Reactant: C=CCOC(=O)[C@@H](COC)C[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOCOC[C@H](C[C@H](COC)C(=O)O)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To the solution of the compound prepared in Example 5 (1.45 g) and morpholine (0.38 ml) in THF (3.6 ml), tetrakis(triphenylphosphine) palladium(0) (20 mg) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with 1N aqueous solution of hydrochloride and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.33 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:17]/[C:16](=[O:15])[CH3:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmole) of 1-triphenylphosphorylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluent to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); doublet 7.5 δ (2 H); doublet 7.4 δ (2 H); doublet 6.95 δ (1 H); doublet 6.6 δ (1 H); multiplet 4.5 δ (1 H); doublet of doublets 4.0 δ (1 H); multiplet 4.2 δ (3 H); singlet 2.45 δ (3 H); singlet 2.4 δ (3 H).
Reaction SMILES: C1C2(CCCC=C2C(=O)C)CC=C1.O[CH:15]([CH3:29])[CH2:16][C:17]([C:19]1[C:20]2([CH2:25][CH2:26][CH2:27][CH:28]=1)[CH2:24][CH:23]=[CH:22][CH2:21]2)=[O:18].CC(OC(C)=O)=O.C(O[Na])(C)=O>CCCCCC.CC(OC)(C)C>[CH2:24]1[C:20]2([CH2:25][CH2:26][CH2:27][CH:28]=[C:19]2[C:17](=[O:18])/[CH:16]=[CH:15]/[CH3:29])[CH2:21][CH:22]=[CH:23]1
Reactant: CC(O)CC(=O)C1=CCCCC12CC=CC2
Agent: CC(=O)C1=CCCCC12CC=CC2
Agent: CC(=O)O[Na]
Solvent: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: C/C=C/C(=O)C1=CCCCC12CC=CC2

Procedure:
Prepared as described in Example 10, from 1-(spiro[4.5]deca-2,6-dien-6-yl)ethanone via 3-hydroxy-1-(spiro[4.5]deca-2,6-dien-6-yl)butan-1-one (LDA, acetaldehyde, THF, 72% after FC (SiO2, hexane/MTBE 1:1); 17% starting material recovered) and subsequent Ac2O/AcONa treatment (35% after FC (SiO2, hexane/MTBE 30:1)). Boiling point: 110° C. (0.08 mbar).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCO
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCL3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.