Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cr](Cl)([O-])(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dilinoleyl methanol (2.0 g, 3.8 mmol) and anhydrous sodium carbonate (0.2 g) in 100 mL of CH2Cl2 was added pydimium chlorochromate (PCC, 2.0 g, 9.5 mmol). The resulting suspension was stirred at room temperature for 60 min. Ether (300 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of silica gel (300 mL). The silica gel pad was further washed with ether (3×200 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 3.0 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 250 mL) eluted with 0-3% ether in hexanes. This gave 1.8 g (90%) of dilinoleyl ketone (V). 1H NMR (400 MHz, CDCl3) δ: 5.25-5.45 (8H, m, 4×CH═CH), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.39 (4H, t, 2×COCH2), 2.05 (8H, q, 4× allylic CH2), 1.45-1.7 (4H, m), 1.2-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.CN(C)CCN(C)C.[F:22][C:23]([F:43])([F:42])[C:24]1[CH:41]=[CH:40][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>O.O1CCCC1>[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:28]([C:27]1[CH:40]=[CH:41][C:24]([C:23]([F:22])([F:42])[F:43])=[CH:25][CH:26]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=1)[OH:29]
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
9.1 Ml. (0.015 mol) of n-butyl lithium solution (15% in n-hexane) were added dropwise with stirring at -60° C. and under a nitrogen atmosphere to a solution of 1.7 g (0.015 mol) of 1-(methoxymethyl)imidazole and 1.8 g (0.015 mol) of N,N,N',N'-tetramethylethylenediamine in 75 ml. of anhydrous tetrahydrofuran. Stirring was continued for 1.5 hours and then 2.9 g (0.0091 mol) of 4,4'-bis(trifluoromethyl)benzophenone in 50 ml. of anhydrous tetrahydrofuran were added dropwise under the same conditions, which made the colour change from light red into very dark brown. The reaction mixture was kept standing overnight at room temperature and it was then decomposed by addition of 40 ml. of water. The mixture was extracted with diethyl ether and the extract was concentrated. The residue was extracted with a mixture of 2 N hydrochloric acid and diethyl ether. The ethereal phase was dried over sodium sulphate and the ether was distilled off. The residue was boiled a few times with petroleum ether (boiling range 40°-60° C.) to remove ketone starting material and it was then once crystallised from a mixture of toluene and petroleum ether (boiling range 28°-40° C.) twice from petroleum ether (boiling range 100°-140° C.). 1-(Methoxymethyl)-α,α-bis(p-trifluoromethylphenyl)imidazole-2-methanol was obtained. Melting point 160°-161° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[CH:46](N1CCOCC1)=[O:47].O>C1COCC1.CCCCCC>[OH:47][CH2:46][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: O=CN1CCOCC1
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(CO)ccc2c1)c1c[nH]cn1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 106.7 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (5.0 g) was dissolved in THF (100 ml), and was cooled to −70° C. To the solution was slowly added a solution of n-butyllithium in hexane (1.6 M; 11.7 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added dropwise a solution of 4-formylmorpholine (1.96 g) in THF (10 ml), and the mixture was stirred for 30 min. To the mixture was added water, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent, hexane:THF=4:1→2:1), followed by recrystallization from hexane-THF (6:1) to give the titled compound (2.69 g) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[ClH:14].[CH3:15]O>>[ClH:14].[ClH:14].[NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([O:5][CH3:15])=[O:4]
Reactant: NC(CF)(Cc1cnc[nH]1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)(CF)Cc1cnc[nH]1

Procedure:
A suspension of 4.4 g (0.024 mole) of 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid in 30 ml of methanol at 0° C. is saturated with dry hydrogen chloride after which the solution is heated under reflux for 12 hours. The solution is then concentrated and allowed to crystallize to afford methyl 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionate, dihydrochloride (4.0 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCCCCCC=C(C)c1ccc(I)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(C)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 91 %

Procedure:
A mixture of 12.50 g (38.08 mmol) of 2-(4-iodophenyl)-2-nonene and 6.42 g (55.2 mmol) of triethylsilane was cooled to 0° C. Trifluoroacetic acid (13.03 g, 114.2 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 22 hrs before it was heated to reflux for 30 min. The mixture was cooled and partitioned between 200 ml hexanes and 100 ml of 10% K2CO3 in water. The hexane layer was washed with brine (50 ml) and dried over Na2SO4. The colorless solution was concentrated in vacuo to 12.31 g of a colorless oil The oil was purified by flash chromatography on 370 g of silica gel with hexane as the eluent. Concentration in vacuo afforded 11.45 g (91%) of product as a mobile colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]#[N:15])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCCCCBr
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3,5-bis(trifluoromethyl)phenyl)cyclopentanecarbonitrile (455) was synthesized from 2-(3,5-bis(trifluoromethyl)phenyl)acetonitrile (454) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:24][C:25](C)(C)[C:26]1([OH:37])[CH:33]2[CH:29]([O:30][C:31]([CH3:35])([CH3:34])[O:32]2)[C:28]([Cl:36])=[CH:27]1)(C)(C)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[Cl:36][C:28]1[CH:29]2[O:30][C:31]([CH3:35])([CH3:34])[O:32][CH:33]2[C:26]([CH2:25][OH:24])([OH:37])[CH:27]=1
Reactant: CC1(C)OC2C(Cl)=CC(O)(C(C)(C)O[SiH2]C(C)(C)C)C2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)OC2C(Cl)=CC(O)(CO)C2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran (27 mL, 1.3 equiv) was added to a stirred solution of silyl ether 52 (6.7 g, 20 mmol, 1.0 equiv) in tetrahydrofuran (80 mL) at 25° C. The resulting brown solution was stirred at 25° C. for 3 h. The reaction mixture was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (25% hexane in ethyl acetate) to afford S5 (4.4 g, 99% yield) as a brown oil. Rf=0.44 (25% hexane in ethyl acetate); 1H NMR (500 MHz, C6D6) δ 5.37 (t, 1H, J=1 Hz, CHCCl), 4.79 (dd, 1H, J=0.5, 5.5 Hz, CH(OR)), 4.23 (dd, 1H, J=1, 5.5 Hz, CH(OR)), 3.64 (d, 1H, J=11 Hz, CH2(OH)), 3.37 (d, 1H, J=11 Hz, CH2(OH)), 1.23 (s, 3H, CH3), 1.07 (d, 3H, J=0.6 Hz, CH3); 13C NMR (125 MHz, C6D6) δ 139.51, 130.65, 113.46, 85.82, 85.33, 83.12, 65.29, 27.29, 26.08; IR (neat film) 3401 (m), 2989 (w), 2937 (w), 1624 (w) cm−1; HRMS (ESI) m/z: Calcd for C9H13ClNaO4 (MNa+) 243.0400, observed 243.0412.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:27]2[CH2:28][CH2:29][N:24]([C:19]3[N:18]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:25][CH2:26]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=137-138° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:44][CH3:45])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:44][CH3:45])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (3.57 g, 21.00 mmol) and N,N-dimethylaminopyridine (13.50 g, 111.00 mmol) is added anhydrous chloroform (120 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (37 ml), followed by 5-bromo-2-ethylphenyllead triacetate (10.69 g, 24.00 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours, then allowed to stand overnight at room temperature. The mixture is diluted with dichloromethane (185 ml) and dilute aqueous hydrochloric acid (185 ml), followed by swirling for 5 minutes and filtration to remove inorganic residues (additional washing with dichloromethane). All organic fractions are combined, washed with brine, dried over anhydrous magnesium sulfate, then concentrated in vacuo to afford a crude oil which is further purified by flash column chromatography (hexane/ethyl acetate 5:1 ratio) to give the product as a yellow solid (4.47 g). Lead residues are removed by dissolving this solid in chloroform (50 ml) and stirring with 3-mercaptopropyl-functionalized silica gel (5.50 g, 1.20 mmol/g loading) overnight. After filtration and concentration 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (4.36 g) is afforded as a cream powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[N:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])(=[O:35])=[O:34])=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Product: O=S(=O)(Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1)c1ccccc1F

Procedure:
N-{4-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was prepared according to the procedure outlined in Example 44 starting with 4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (100 mg) and 2-fluorobenzenesulfonyl chloride (55 mg). The resultant white solid was purified using an ISCO autocolumn eluting with 100% ethyl acetate to afford N-{4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide. MS (APCI): 511 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:41][C:40](=[O:42])[NH:39][C:38]=2[CH:43]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:41][C:40](=[O:42])[NH:39][C:38]=4[CH:43]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc2oc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc4oc(=O)[nH]c4c3)n2)c1

Procedure:
Intermediate 4 was coupled to 5-(2-Amino-ethyl)-3H-benzooxazol-2-one following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 11.6 (s, 1H) 8.5 (d, 1H) 8.1 (m, 2H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 1H) 7.0 (m, 3H) 4.4 (s, 2H) 3.7 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)C(=O)OC(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N(CCCCl)CCc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCNCCCCl)cc1

Procedure:
A solution of 626 mg (1.94 mmol) of tert.-butyl (3-chloropropyl)-[2-(4-cyanophenyl)ethyl]carbamate and 5.0 ml of trifluoroacetic acid in 20 ml of dichloromethane was stirred at room temperature for 1.5 hours and then evaporated to dryness. The residue was triturated with diethyl ether. The precipitate formed was then filtered off and dried under reduced pressure over calcium chloride. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: [CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Li+].[Cl-].[CH3:26][S+:27]([CH3:37])[CH2:28]C(C1C=CC=CC=1)=O>O>[CH3:26][S+:27]([CH3:37])[CH2:28][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S+](C)CC(=O)c1ccccc1
Agent: CCCC[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: C[S+](C)Cc1ccccc1

Procedure:
An aqueous solution of 10.11 g of lithium butyltriphenylborate in 100 ml of water was added to an aqueous solution of 6.24 g of dimethylphenacylsulfonium chloride in 150 ml of water, and the resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the resultant crystal was washed with water and dried to give 13.58 g of dimethylbenzylsulfonium-butyltriphenylborate as a white crystal.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(2-bromoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.906 g; 2.49 mmol) and sodium azide (0.486 g; 7.48 mmol) in DMF (7 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to yield 0.900 g (quantitative) of the title compound as a brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 62 %

Procedure:
To a stirred solution of (±)-trans-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.62 g, 1.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.38 g, 1.94 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.61 g, 2.91 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.60 g, 62%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H), 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([C:18]([OH:20])=O)[O:3]1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[O:20]=[C:18]1[C:4]2[N:24]([C:2](=[O:3])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22][NH:23]1
Reactant: O=C(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: NCCN
Product: O=C1NCCn2c1c(-c1ccccc1)c1ccccc1c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (500 mg) and ethylenediamine (15 ml) was stirred at room temperature overnight. After evaporation of the solvent, concentrated hydrochloric acid (10 ml) and acetic acid (10 ml) were added to the residue. The mixture was heated under reflux for 48 hours. To the mixture was added water, and extracted with ethyl acetate. The extract was washed successively with water, aqueous sodium hydrogen carbonate and water, dried, and evaporated to yield the title compound as colorless crystals (115 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CS([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)(=O)=O.ClCC1C=CC(C(=O)C)=CC=1>CC#N>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)c1ccc(CS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)c1ccc(CCl)cc1
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc piperazine (485 mg, 2.61 mmol) was added to a stirred solution of a mixture of 1-(4-methanesulfonylmethyl-phenyl)-ethanone, 1-(4-chloromethyl-phenyl)-ethanone (obtained in STEP A, 580 mg) and TEA (0.522 ml, 3.75 mmol) in CH3CN (5 ml). The resulting mixture was stirred at room temperature overnight and then further TEA (0.250 ml, 1.80 mmol) and N-Boc piperazine (100 mg, 0.53 mmol) were added. After 4 h the solution was partitioned between water and AcOEt, the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 7:3 to 6:4) to give 700 mg of 4-(4-acetyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][NH:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][N:19]1C(OC(C)(C)C)=O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][NH:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][NH:19]1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)NOCCNC(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: O=C(NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1)OCc1ccccc1
Reaction time: 2 h
Yield: 95.7 %

Procedure:
(2S,5R)—N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxamide (2.91 g, 5.362 mmol) was dissolved in 1,4-dioxane (5 mL), to which was added under ice cooling 4M hydrochloric acid-dioxane solution (10 mL). After stirring for 2 h., the mixture was concentrated under reduced pressure, dissolved in water (30 mL), and washed with ether. The aqueous layer was ice-cooled, and pH was set to ca. pH 7 with 5M sodium hydroxide and acetic acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform chloroform/methanol=3:1) to afford 2.27 g of the title compound (yield 95%).