Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH3:7].P(Cl)(OCC)(OCC)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[C:6](/[S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])\[CH3:7])=[CH:26][CH:25]=1
Reactant: CCOS(=O)(=O)CC
Reactant: O=Cc1ccc(Cl)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOS(=O)(=O)/C(C)=C/c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
n-Butyllithium (35.0 mL, 1.6M solution in hexanes) was added dropwise during 25 min to a solution of ethyl ethanesulfonate (6.9 g, 50 mmol) (Synth. Comm. 1985, 15, 1057) in THF (100 mL) at −78° C. The reaction mixture was stirred for 15 min then diethyl chlorophosphate (4.35 ml, 30 mmol) was added dropwise. The solution was stirred at −78° C. for 30 min, allowed to warm to 0° C. and then cooled to −78° C. again. 4-Chlorobenzaldehyde (4.2 g, 30 mmol) in THF (30 mL) was then added dropwise during 15 minutes and the resulting mixture was stirred for 1 h at −78° C. and then allowed to slowly reach RT. Water (10 mL) was added to the mixture and the mixture was concentrated in vacuo. The residue was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using a gradient of 10% ethyl acetate/hexanes to 15% ethyl acetate/hexanes as eluent, afforded the title compound (4.5 g, 58%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[C:37][CH3:38])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([S:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:22]([O:21][C:19]([CH:18]1[C:11]2([CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[S:14][CH2:15][CH2:16][N:24]1[S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]#[C:37][CH3:38])=[CH:32][CH:33]=1)(=[O:26])=[O:27])=[O:20])[CH3:23]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OCC)C2(SCCO)CCN(Cc3ccccc3)CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCSC3(CCN(Cc4ccccc4)CC3)C2C(=O)OCC)cc1

Procedure:
A mixture of ethyl {1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate (5.0 g, 8.9 mmol), tributylphosphine (4.04 g, 20 mmol) and 1,1-(azodicarbonyl)-dipiperidine (5.04 g, 20 mmol) was stirred in dry THF at room temperature for 6 h. The reaction sure was quenched with water, extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel column chromatography eluting with 60% ethyl acetate/hexane to give ethyl-9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-thia-4,9-diazaspiro[5.5]undecane-5-carboxylate as a pale yellow oil; Yield: 4.2 g (87.5%); Electrospray Mass Spec: 543 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: Nc1cc2cc(Cl)ccc2cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc2ccc(Cl)cc2cc1N

Procedure:
To 0.025 mole of the 2-amino-7-chloro-3-nitronaphthalene (prepared in Example 2) in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the relfuxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 4.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[CH:14]=[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[CH:11][N+:10]=2[CH:9]=[CH:8][CH:7]=1.COC1C=CC(CN2C=CC(C(C3C=CN(CC4C=CC(OC)=CC=4)N=3)=C)=N2)=CC=1>[N+](C)([O-])=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][N+:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c[n+]3ccccc3cc2c1
Agent: C=C(c1ccn(Cc2ccc(OC)cc2)n1)c1ccn(Cc2ccc(OC)cc2)n1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C[N+](=O)[O-]
Product: c1ccc2c(c1)Cc1cccc[n+]1C2

Procedure:
A reaction mixture containing benzo[b]quinolizinium perchlorate (9.5 g; 6.8 mmol)and 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene (14.9 g; 0.034 mol) in 300 mL of nitromethane was refluxed for 16 h under nitrogen. The reaction mixture was concentrated in vacuo, the residue was triturated with 400 mL of methanol, and the solid was filtered, and dried (60° C.) to afford 22.1 g (85.6%) of 6,11-ethano-12,12-di-[(1-p-methoxybenzyl) -pyrazol-3-yl)]-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R1 =R2 =R3 =R4 =R7 =H; R5 =R6 =1-p-methoxybenzyl-3-pyrazolyl; X- =ClO4-), as a solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:29]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c3c2)cc1
Yield: 65.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (110 mg, 0.28 mmol) and glycine (275 mg, 2.82 mmol) in a solution of sodium methoxide (0.5 M in methanol; 5.7 mL) was refluxed overnight. Reaction mixture was concentrated and dissolved in water (50 mL). It was washed with ethyl acetate (10 mL). Aqueous layer was acidified by 1 N HCl to pH=3-4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Crude product was triturated with methanol (3 mL) and solid was collected and dried to give the title compound (72 mg). MS-(+)-ion: M+1=394.32.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1.[Cl-]>O1CCCC1.CN1CCCC1=O.C(OCC)C>[CH2:9]([C:13]1[CH:12]=[C:11]([CH:10]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CN1CCC(OC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)c2nc3ccccc3s2)CC1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
80A To a mixture of trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester (110 mg) and ferric acetylacetonate (4 mg) in a mixture of tetrahydrofurane (4.5 mL) and N-methylpyrrolidone (0.25 mL) cooled at 0° C. is added a 2M solution of butylamgnesium chloride in tetrahydrofurane (150 μL). The mixture is stirred at room temperature for 25 min, then warmed at 30° C. for 15 min. A second addition of butylamgnesium chloride in tetrahydrofurane (150 μL) is performed. The mixture is then diluted with diethyl ether and quenched with 0.5N hydrochloric solution. The aqueous phase is extracted with diethyl ether, then ethyl acetate. Organic phases are pooled, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradiant heptane/ethyl acetate from 99/1 to 90/10). The product is then refluxed in methanol and concentrated to give 2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]2[O:10][CH2:11][O:12][C:5]2=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([CH2:21][CH:22]=1)=[CH:19][CH:18]=[C:17]([N:23]([CH3:25])[CH3:24])[CH:16]=2.N1C=CC=CC=1.[CH2:32]([O:34][C:35](Cl)=[O:36])[CH3:33].CCCCCC.[CH3:44][CH2:45][O:46][C:47](C)=[O:48]>C(Cl)Cl>[C:8]([C:7]1[C:2]([N:1]([C:47]([O:46][CH2:45][CH3:44])=[O:48])[C:35]([O:34][CH2:32][CH3:33])=[O:36])=[C:3]([C:13]2[O:14][C:15]3[C:20]([CH2:21][CH:22]=2)=[CH:19][CH:18]=[C:17]([N:23]([CH3:25])[CH3:24])[CH:16]=3)[CH:4]=[C:5]2[O:12][CH2:11][O:10][C:6]=12)#[N:9]
Reactant: CCOC(C)=O
Reactant: CN(C)c1ccc2c(c1)OC(c1cc3c(c(C#N)c1N)OCO3)=CC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)N(C(=O)OCC)c1c(C2=CCc3ccc(N(C)C)cc3O2)cc2c(c1C#N)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 2-amino-3-cyano-7-dimethylamino-4-(methylenedioxy)phenyl-4H-chromene (53 mg, 0.16 mmol) in methylenechloride (3 ml) was added pyridine (0.06 ml, 0.74 mmol), followed by ethylchloroformate (0.045 ml, 0.47 mmol). The mixture was stirred at room temperature overnight, then diluted with 1:1 hexane/EtOAc (45 ml), washed with water, 2N HCl, water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (3:1 hexane/EtOAc) to yield the title compound as a yellow solid (5 mg, 7%). 1H NMR (CDCl3): 6.84-6.61 (m, 4H), 6.49-6.42 (m, 1H), 6.30 (m, 1H), 5.93, 5.92 (2s, 2H), 4.74 (s, 1H), 4.36 (m, 4H), 2.93 (s, 6H), 1.31 (t, J=7.2, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:11].[K+].[OH2:16]>>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([C:8]([OH:11])=[O:16])[CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: O
Agent: [K+]
Product: O=C(O)c1cnc(Cl)c(Br)c1

Procedure:
3-Bromo-2-chloro-5-methylpyridine (30 g) in water (650 ml) containing potassium permanganate (60 g) was stirred and heated under reflux for 3 hours. Further potassium permanganate (20 g) was then added and the mixture heated and stirred for another 21/2 hours. The mixture was steam-distilled to remove unchanged starting material, and then filtered while hot. The residue was washed with hot water. The filtrate and washings were cooled and acidified with concentrated hydrochloric acid. The solid which separated was extracted with ether. The ether extract was dried and evaporated to give 3-bromo-2-chloropyridine-5-carboxylic acid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3CC[O:14][C:15]4[CH:22]=[C:21](C=C)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N+]1([O-])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.S([O-])([O-])=[O:34].[Na+].[Na+]>CC(C)=O.C1COCC1.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:31][CH2:30][O:29][C:28]4[CH:27]=[C:21]([CH:22]([OH:34])[CH2:15][OH:14])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Reactant: O=S([O-])[O-]
Reactant: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C(O)CO)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (1.28 mmol) in acetone, THF and water (15 mL, 1:1:1) was treated with N-methylmorpholine-N-oxide (299 mg, 2.56 mmol) then potassium osmate dihydrate (14 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight. Solid sodium sulfite was added and the reaction mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate, concentrated and the residue purified by reverse phase HPLC to give 286 as a colorless solid (222 mg, 46%). LCMS: 373.1. 1H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.04 (s, 1H), 5.82 (dt, J=13.3, 6.5 Hz, 1H), 5.26 (d, J=4.4 Hz, 1H), 4.70 (t, J=5.8 Hz, 1H), 4.54 (dd, J=10.4, 5.6 Hz, 1H), 4.36 (t, J=5.0 Hz, 2H), 3.53-3.35 (m, 4H), 1.55 (d, J=6.6 Hz, 6H)
Reaction SMILES: [C-:1]#[N:2].[Na+].COS([O-])(=O)=O.CO[N+:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>O>[C:1]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][N:12]=1)#[N:2]
Reactant: CO[n+]1cc(C)cc(C)c1
Reactant: [C-]#N
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C#N)c(C)c1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a cooled (0° C.) solution of NaCN (49.0 g, 0.999 mol, 3.0 eq.) in 135 mL of water (air free) was dripped 1-methoxy-3,5-dimethyl pyridinium methyl sulfate (83.0 g, 0.33 mol) in 100 mL water (air free) in 1.25 hr., keeping the temperature below 3° C. The reaction mixture was stored at about 3° C. overnight. The mixture was filtered and washed with water to give 40 g of the title compound. An analytical sample was recrystallized from isopropyl ether and pentane (4:1) (m.p.: 61-62° C.).
Reaction SMILES: [Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][CH2:15][OH:16].[CH3:18][O:19][C:20](=[O:25])[C:21]([CH2:23]Br)=[CH2:22].[Cl-].[NH4+]>[Zn].O1CCCC1>[Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][C@H:15]([OH:16])[CH2:23][C:21]([C:20]([O:19][CH3:18])=[O:25])=[CH2:22].[Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][C@@H:15]([OH:16])[CH2:23][C:21]([C:20]([O:19][CH3:18])=[O:25])=[CH2:22]
Reactant: C[C@H](CCO)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Reactant: C=C(CBr)C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C[C@@H](O)C[C@@H](C)[C@H]1CCC2C(=CBr)CCC[C@@]21C)C(=O)OC
Product: C=C(C[C@H](O)C[C@@H](C)[C@H]1CCC2C(=CBr)CCC[C@@]21C)C(=O)OC
Reaction time: 1 h

Procedure:
A 105 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanol was taken in a 50 ml eggplant-shaped flask, then 8 ml of dried tetrahydrofuran was then added to dissolve the same. The solution was cooled by an ice cooled bath, then 84 μl of methyl-2-bromomethylacrylate was added dropwise. Further, 35 mg of zinc powder and 10 ml of a saturated aqueous solution of ammonium chloride were added, then the solution was stirred at the same temperature for 1 hour. The reaction solution was extracted by ethyl acetate, the organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 166 mg. This was purified by a silica gel column (Merck gel, hexane/ethyl acetate=9/1) to obtain (4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene in an amount of 43 mg and (4R,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene in an amount of 55 mg.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)=[O:16])=[CH:9][CH:8]=1)=O)C.N1C=CC=CC=1.[OH-].[NH4+].Cl>O.CC(C)=O>[OH:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=2)=[O:16])=[CH:11][CH:12]=1
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(O)cc2)cc1
Yield: 96 %

Procedure:
7.65 g (23.45 mmol) 4-pentoxyphenyl (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylate, 70 ml pyridine and 40 ml acetone were mixed. A solution of 12.5 ml ammonium hydroxide 25% in water and 30 ml acetone were added dropwise. The reaction mixture was subsequently allowed to react for 18 h at 25° C. and acidified to pH=1 with hydrochloric acid 7 N. The product was filtered off, washed with water and dried under vacuum to give 7.35 g 4-pentoxyphenyl (2E)-3-{4-hydroxyphenyl}acrylate as colourless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[O:3]1.[Li]C(C)(C)C.CN([CH:29]=[O:30])C>C1COCC1.CCCCC.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[O:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-chrom-3-ene (Compound P, 480 mg, 1.45 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution, 1.1 mL) and the mixture was stirred for 30 minutes. DMF (200 mg, 2.9 mmol) was added, the mixture was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with ethyl acetate (150 mL), washed with brine (10 mL), dried and the solvent was removed by evaporation. Purification by chromatography on silica gel column gave the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:37][CH3:38])([O:35][CH3:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:44]([O-:48])([O-])(=[O:46])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:44]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:37][CH3:38])([O:35][CH3:36])[C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:48])=[O:46])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(OC)(OC)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(C(OC)(OC)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.55 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.43 g of 3-ethylsulfanyl-N-[4-(2,2,2-trifluoro-1,1-dimethoxyethyl)phenyl]picolinamide (Compound of Present Invention 58) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.43 g of 3-ethylsulfonyl-N-[4-(2,2,2-trifluoro-1,1-dimethoxyethyl)phenyl]picolinamide (hereinafter, referred to as Compound of Present Invention 42).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[CH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:47].C(O)(C)C>C(#N)C>[ClH:47].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([CH2:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Reactant: ClC(Cl)Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC#N
Product: Cl
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
Dissolve 1-(2-{4-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-piperidine in 20 mL acetonitrile and chill in an ice bath. Add 1.5 mL of boron tribromide with swirling and allow to warm to room temperature. Pour this mixture into a two-phase mixture of saturated sodium bicarbonate solution and a 3/1 mixture of chloroform/isopropanol. Wash the organic layer with water and dry over 3 Å molecular sieves. Concentrate the organic layer and purify on a silica gel column, eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent and convert the compound to the salt with HCl to give 369 mg (82%) of the title compound: 1H-NMR (CDCl3, 300 MHz) δ7.77 (d, J=8.7 Hz, 1H); 7.61 (d, J=8.1 Hz, 1H); 7.28-7.25 (m, 1H); 7.11-6.94 (m, 4H); 6.89-6.83 (m, 1H); 6.74 (d, J=8.7 Hz, 2H); 6.57-6.54 (m, 2H); 4.31-4.10 (d, 2H); 4.04 (t, J=6.0 Hz, 2H); 2.80-2.80 (m, 2H); 2.59-2.59 (m, 4H); 1.68-1.65 (m, 4H); 1.48-1.46 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24]O>ClCCl>[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24][O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](CC(F)(F)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](CC(F)(F)COS(=O)(=O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The mixture of pyridine (124 μl) and trifluoromethanesulfonic anhydride (206 μl) in dichloromethane (5 ml) was stirred at -20° C. under argon atmosphere for 5 min. To this solution the alcohol (7) (400 mg, 1.02 mmol) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 40 min. The usual work-up (dichloromethane for extraction) gave the triflate (8) (612 mg), which was used in the next step without further purification. 1H-NMR δ: 0.73 (3H, s, 18-H3), 1.00 (3H, s, 19-H3), 1.15 (3H, d, J=6 Hz, 21-H3), 3.56 (2H, m, THP), 3.85 (1H, m, 3-H), 4.50 (2H, t, J=12 Hz, 24-H2), 4.70 (1H, m, THP), 5.37 (1H, m, 6-H). 19F-NMR δ: +12.2 (3F), +41.3 (2F).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:29]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCCCC
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 68.4 %

Procedure:
1.15 g (3.5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 1.29 g (10 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.04 g (68%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).