Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:14][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[O:15]1
Reactant: Cc1cc(C)c(CCCC(C)(C)O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c2c(c1)OC(C)(C)CCC2
Yield: 97.9 %

Procedure:
A solution of the diol (D) (100 mg, 0.45 mM) and p-toluenesulphonic acid (10 mg) in benzene (20 ml) was heated for 1 hour under reflux in an apparatus for the azeotropic removal of water. The reaction solution was cooled, and washed with aqueous sodium hydroxide (2M), followed by brine. The dried (Na2SO4) solution was concentrated in vacuo. The residual oil was purified by flash chromatography, eluting with toluene/hexane (1:1 v/v), to give 2,3,4,5-tetrahydro-2,2,6,8-tetramethyl-1-benzoxepin (E) as a colourless oil (90 mg, 98% yield); NMR: 1.25(6H,s), 1.63(4H,m), 2.23(3H,s), 2.25(3H,s), 2.73(2H,m), 6.57(1H,s), 6.69(1H,s).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([OH:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([O:25][C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[Cl:17])[CH:24]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 18 step (iv).
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC([NH:8][CH2:9][CH2:10][O:11][CH3:12])=NC=1.[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])[CH2:63][N:64]2[C:72]3[C:71]([F:74])([F:73])[CH2:70][CH2:69][C:68]([F:76])([F:75])[C:67]=3[C:66]([CH:77]([F:79])[F:78])=[N:65]2)[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1>>[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])[CH2:63][N:64]2[C:72]3[C:71]([F:74])([F:73])[CH2:70][CH2:69][C:68]([F:76])([F:75])[C:67]=3[C:66]([CH:77]([F:79])[F:78])=[N:65]2)[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44]([NH:8][CH2:9][CH2:10][O:11][CH3:12])=[N:45][CH:46]=1
Reactant: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: COCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (12D) was prepared according to the method presented for the synthesis of compound 11I of Example 11 utilizing 12C. MS (m/z) 671.34 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[K].[CH3:14]I>CN(C)C=O>[CH3:14][N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11]
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CN1Cc2cccc(Cl)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.6 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 85 mls of dry dimethylformamide was cooled and treated with 10 g of potassium t-butoxideat such a rate that the temperature remained below 6° C. The resulting suspension was stirred at 5° to 10° C. for 30 minutes, treated with 6.1 mls of methyl iodide at 10° to 15°C. and stirred at room temperature for 16 hours. The mixture was poured into ice water and the resulting solid was filtered, washed with water anddried in vacuo at 50° C. for 1.5 hours to give 15.4 g of the title compound as a pinkish solid, m.p. 95°-97° C.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCC(C)CC2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 4-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 206 mg of 4-(2-butynyloxy)-6-(4-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (18)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.[OH-].[CH2:15]([N+](CC)(CC)C1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC>[CH2:15]([O:12][C:11](=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CC[N+](CC)(Cc1ccccc1)c1ccccc1
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Yield: 80.4 %

Procedure:
Indole 3-acetic acid 1 (9.45 g, 0.054 mol) was dissolved in methanolic benzyl diethyl anilinium hydroxide (0.54 mol) and the solvent removed in vacuo. The oily residue of the benzyl dimethyl anilinium salt was agitated with benzene, the benzene evaporated and the salt refluxed in toluene (170 ml, 1 h). Traces of unreacted acid and dimethyl aniline by-product were removed by extracting the toluene solution with water, dilute hydrochloric acid (1N) and water. The organic layer was dried over sodium sulphate and concentrated in vacuo to obtain the crude product. Final purification was obtained by crystallization in EtOAc:Hexane to give 11.52 g (80%) indole-3-acetic acid benzyl ester 13 as white crystals (melting point 71°-72° C.); IR (Nujol, cm-1); 3 400, 1, 720; 1H-NMR (CDCl3, δ): 3.8 (s, 2H), 5.1 (s, 2H) 6.8-8.0 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of [1-hydroxy-4-methoxymethyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.20 g, 0.56 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (0.110 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give [1-hydroxy-4-methoxymethyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.150 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 5.60 (s, 1H), 4.50 (m, 2H), 3.30 (s, 3H), 3.10 (m, 1H), 2.17 (m, 1H). MS (ESI) m/z: 329 [M−1]−. HPLC purity: 97.28% (220 nm), 96.84% (Maxplot).
Reaction SMILES: C[O-:2].[Mg+2].C[O-].C[C:7]1[O:14][C:12](=O)[CH:11]([C:15]([CH3:17])=[O:16])[C:9](=[O:10])[CH:8]=1>CO>[O:10]=[C:9]([CH2:11][C:15](=[O:16])[CH3:17])[CH2:8][C:7]([O:14][CH3:12])=[O:2]
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)CC(=O)CC(C)=O
Reaction time: 5 h

Procedure:
Magnesium methoxide (6% in MeOH, 530 mL) was added to a suspension of dehydroacetic acid (31 g) in methanol (600 mL) at room temperature. The reaction mixture was refluxed and stirred for 5 h. The solvent was removed and the residue dissolved in HCl 1M (1.5 L). The aqueous phase was extracted with EtOAc (2×750 mL) and then the solvent was evaporated under reduced pressure to give a yellow oil, which was filtered on a silica cartridge using dichloromethane as eluent. After the solvent removal, methyl 3,5-dioxohexanoate was obtained as a light yellow oil (19.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:7]1([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCSc1ccccc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(4-chlorobutyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 396.8 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
TFA (10 mL) was added in one portion at ambient temperature to a stirred solution of methyl 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-indole-5-carboxylate (4.58 g, 12.78 mmol) in DCM (30 mL). The resulting solution was stirred for 30 minutes then applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Pure fractions were combined and concentrated by evaporation then triturated with ether to give a solid which was collected by filtration and air dried to give methyl 3-(piperidin-4-yl)-1H-indole-5-carboxylate (2.69 g, 81%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].S(=O)(=O)(O)O>[Ni].CO>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccc(O)cc1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=O)N1CCN(Cc2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 22.4 g=0.2 mole of p-hydroxybenzaldehyde, 25.6 g=0.2 mole of acetylpiperazine, 200 ml of methanol, 10 g of Raney nickel and 0.1 ml of concentrated sulfuric acid is stirred for 4 hours in an autoclave at 80° C. and under a hydrogen pressure of 100 atmospheres. After cooling, and releasing the pressure, the catalyst is filtered off, the solvent is removed in vacuo on a rotary evaporator, the residue is taken up in methylene chloride, the mixture is washed with 2 N sodium carbonate solution, the organic phase is dried with sodium sulfate, the solvent is removed as above and the residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether. This gives 33.4 g (71% of theory), melting point: 130°-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([OH:26])=[O:25])[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2].I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([O:26][CH:30]([CH3:32])[CH3:31])=[O:25])[C:9]1=[O:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)O)C(=O)N2CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.0 g of 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.42 ml of 2-iodopropane and 0.67 g of anhydrous potassium carbonate at ambient temperature, the resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=17:3] gave 1.0 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate as a light yellow oily product.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[C:9]([O:13][C:14](=[O:17])[CH2:15]Br)([CH3:12])([CH3:11])[CH3:10]>C1COCC1.ClCCl>[C:9]([O:13][C:14](=[O:17])[CH2:15][O:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:1]([OH:8])[CH2:2]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O[C@H]1CCC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 5.0 g (43 mmol) of cis/trans-1,3-cyclohexanediol (approx. 1.2:1 cis/trans mixture) in 20 ml of absolute THF and, at RT, add 24.8 ml (approx. 49.5 mmol) of phosphazene base P2-t-Bu in THF (approx. 2 M solution) dropwise. Stir the solution at RT for a further 30 min and then add dropwise to a mixture of 9.5 ml (64.6 mmol) of bromoacetic acid tert-butyl ester and add 10 ml of THF dropwise. Stir the mixture at RT overnight, then dilute with dichloromethane, and wash the organic phase successively with 1N hydrochloric acid, buffer solution (pH 7) and sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. Separate the crude product by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→1:1). 2.73 g (27.6% of theory) of the cis-configured target compound are isolated as a pure fraction.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[BrH:29].[NH+]1C=CC=CC=1>C1COCC1>[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:20]([Br:29])[CH:19]=1
Reactant: Br
Reactant: NCCOc1c(-c2ccc(N3CCCC3)cc2)[nH]c(=O)c2cc(F)ccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: NCCOc1c(-c2ccc(N3CCCC3)c(Br)c2)[nH]c(=O)c2cc(F)ccc12
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-(2-aminoethoxy)-7-fluoro-3-(4-pyrrolidin-1-yl-phenyl)-2H-isoquinolin-1-one hydrochloride [(I), cpd. 7, R=R1=R2=H, R3=4-pyrrolidin-1-yl, R4=H](15 mg, 0.037 mmol) in dry THF (0.3 mL), kept at room temperature, pyridinium hydrobromide perbromide (13 mg, 0.04 mmol) were added. The reaction mixture was stirred for 1 hour, the volatiles were then evaporated in vacuo and the resulting crude was purified through preparative HPLC on a Phenomenex Gemini C18 (21×250 mm, 10 μm) column, using a Waters FractionLynx System equipped with a 2996 PDA detector and ZQ2000 single quadrupole mass spectrometer, with electrospray ionization (positive and negative mode). Mobile phase A was 0.05% NH3/ACN 95/5, and mobile phase B was ACN. Gradient from 5 to 95% B in 25 min, hold 95% B 3 min. Flow rate 20 mL/min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](Cl)=[O:11]>O.C(OCC)C>[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:1]=[N+:2]=[N-:3])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)C1CCCS1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=NC(=O)C1CCCS1
Yield: 86.2 %

Procedure:
A solution of sodium azide (4.14 g.) in water (16 ml.) was added dropwise to a solution of 2-tetrahydrothiophenecarboxylic acid chloride (9.60 g.) in diethyl ether (24 ml.) with stirring under ice-cooling and stirred for further 15 minutes at the same temperature. After the mixture was stirred for 1 hour at ambient temperature, nitrogen gas was introduced to remove off diethyl ether. The resultant mixture was extracted with diethyl ether (50 ml.). The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give oily 2-tetrahydrothiophenecarboxylic acid azide (8.63 g.).
Reaction SMILES: [C:1]([Si:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:41][CH2:42][CH2:43][CH3:44]>C1COCC1>[C:1]([Si:5]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:44][CH2:43][CH2:42][CH2:41]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](OCCCCCCCCCCCCS(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a stirred solution of tert-butyldiphenyl(12-(phenylsulfonyl)dodecyloxy)silane (0.381 g, 0.675 mmol) in THF (2 mL) was added n-BuLi (2.5 M solution in hexanes, 0.297 mL, 0.742 mmol) at −78° C. under Argon. After stirring the resulting solution for 30 min, the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (2 mL) at −10° C. and the aqueous phase was extracted with DCM (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified by silica gel column chromatography using 5% ethyl acetate/hexane to afford the title product as a clear thick oil (0.16 g, 85%). 1H NMR (CDCl3): δ7.89-7.39 (m, 15H), 5.37 (m, 8H), 3.64 (t, 2H, J=6.5 Hz), 2.78 (m, 7H), 2.08 (m, 4H), 1.82 (m, 2H), 1.37-1.20 (m, 30H), 1.04 (s, 9H), 1.04 (t, 3H, J=6.7 Hz). m/z (ESI) 837.74 (M++1).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]C(Br)(Br)Br>ClCCl>[Br:34][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1Nc2ccccc2OC1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2OC1CCBr
Reaction time: 12 h
Yield: 79 %

Procedure:
580 mg of 2-(2-hydroxyethyl)-1,4-benzoxazin-3-one is stirred with 1 equivalent each of triphenylphosphine and tetrabromomethane in 50 ml of dichloromethane. After 12 hours at room temperature, the reaction is completed. The mixture is concentrated by evaporation, and all of this is put onto a column. After column chromatography, the title compound is obtained in a yield of 79%. [1H]-NMR (CDCl3): 8.35 broad 1H, 7.05 to 6.8 m 4H, 4.77 dd 1H, 3.67 m 2H, 2.5 m 2H.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]=[O:15])[CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:14]=[O:15])=[CH:10]2
Reactant: O=Cc1ccc2cc(O)ccc2c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(Br)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Step b) Bromine (7.45 mL, 145.3 mmol) was added dropwise to a cold (0° C.) solution of 6-hydroxy-2-naphthaldehyde (25.0 g, 145.3 mmol) in acetic acid (300 mL). After stirring for 30 minutes the mixture was poured into water (21), and the precipitated solid filtered and dried to yield a brown solid (34.5 g, 94% yield, m.p. 189-190).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: OCCCc1ccncc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of 0.070 g of 4-chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile, 0.062 g of 3-(4-pyridyl)-1-propanol and 0.235 g of triphenylphosphine in 3 ml of methylene chloride under nitrogen was cooled to 0° C. To this was added 0.14 ml of diethyl azodicarboxylate dropwise. After 30 minutes, the reaction mixture was warmed to room temperature and further stirred for 2 hours. The mixture was concentrated down to 1 ml and purified by silica gel chromatography, eluting with a solvent gradient of 1 to 2 percent methanol/methylene chloride, to provide 0.090 g of 4-chloro-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile as an off-white gum.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[CH:36]1[CH:41]=[CH:40][C:39]([C@H:42]([NH2:45])[CH2:43][OH:44])=[CH:38][CH:37]=1>C(Cl)Cl>[C:14]([NH:13][C@H:12]([C:11]([NH:45][C@H:42]([C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[CH2:43][OH:44])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (4.0 g; 9.22 mmol; see Example 4(a) above) and (S)-(+)-phenylglycinol (1.26 g; 9.22 mmol; 1 eq.) and CH2Cl2 (160 mL). The reaction mixture was stirred overnight and then washed with saturated aqueous KHSO4, saturated aqueous Na2CO3, brine, dried with Na2SO4, filtered and concentrated to dryness. The residue was triturated with ether to obtain 3.8 g of the sub-title compound as a white solid.