Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH3:35][C:32]([CH3:36])([CH2:31][NH:30][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][C:14]=3[C:17]3[CH:21]=[N:20][NH:19][CH:18]=3)[N:9]=2)=[CH:29][CH:28]=1)[CH2:33][OH:34]
Reactant: CC(C)(CN)CO
Reactant: O=Cc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(CO)CNCc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzaldehyde (1-3) (0.11 g, 0.29 mmol) in NMP (10 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.030 g, 0.29 mmol) and acetic acid (0.026 g, 0.43 mmol). After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.092 g, 0.43 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave 2,2-dimethyl-3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol (1-4) as a off white solid. HRMS (M+H)+: calculated 464.2207; found 464.2194
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].O1CCCC1>CO>[CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCO[C@H]1CC[C@H](C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCO[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate (D11) (39.1 g), 40% w/w sodium hydroxide solution (150 mL), tetrahydrofuran (200 mL) and methanol (150 mL) was stirred for approx. 72 hours. The solvent was partially removed then the resulting mixture was treated with ethyl acetate and water. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether layer was washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds as oil (15.42 g).
Reaction SMILES: C1(C2[N:12]=[C:11]([C:13]([O:15]CC)=O)[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)C=CC=CC=1.[CH3:28]NCCNC.C[Al](C)C.[C:38]1([CH3:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]2[N:12]=[C:11]([C:13](=[O:15])[CH3:28])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: Cc1ccccc1
Reactant: CNCCNC
Agent: C[Al](C)C
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, 6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid ethyl ester (Compound 25, 49 mg, 0.13 mmol) in toluene (3 ml), N,N′-dimethylethylenediamine (DMEDA, 13 mg, 0.15 mmol) and trimethylaluminum (0.2 ml, 2.64 mmol, 2 M in toluene) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichlorofluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH2:10][NH:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([N:11]([OH:12])[CH2:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: ONC[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N(O)C[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of N-[(trans-2-phenylcyclopropyl)methyl]-N-hydroxylamine (3.26 g, 20 mM) in methylene chloride (50 ml) was added chloroacetyl chloride (4.52 g, 40 mM) and triethylamine (4.04 g, 40 ml) at room temperature. After stirring for 5 hours, it was poured into saturated aqueous sodium bicarbonate. The whole was extracted with chloroform (2×100 ml). The extracts were washed with water and brine, then were added and evaporated in vacuo. Chromatographic purification (eluent chloroform:ethanol=15:1) of the residue provided 2 g (41.8% yield) of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[O:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:9][CH2:8][CH2:7][C:6]2[O:5][C:4]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)=[N:3][C:2]=2[CH3:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2nc(C)c(CCO)o2)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(-c2nc(C)c(CCOS(=O)(=O)c3ccc(C)cc3)o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the solution of 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethanol (2.93 g, 10 mmol) in 30 ml of pyridine 4-toluenesulfonyl chloride (1.9 g, 10 mmol) was added portionwise at room temperature. Subsequently, the reaction mixture was stirred for 5 h at room temperature, and then poured into 200 ml of water and extracted (3×) with 50 ml of dichloromethane. The combined extracts were washed with 1M HCl, an aqueous solution of sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated, to obtain a product, 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethyl 4-toluenesulfonate having the purity of ca. 95%.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].C(=O)([O-])[O-].[K+:19].[K+]>>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O-:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[K+:19]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
The inclusion complex (100 g) of clavulanic acid with heptakis-(2,3,6-tri-O-acetyl)β-CD, which was prepared in the same way as in Example 4, was suspended in a 3% aqueous potassium carbonate solution (200 ml), in which methyl-β-CD (53.6 g, 40.9 mmol) was dissolved. The suspension was stirred for 5 min at ambient temperature, the solid particles were filtered off and the filtrate was frozen in liquid nitrogen and then freeze-dried. There was obtained a yellowish microcrystalline inclusion complex (56.7 g, 91.9%) of potassium clavulanate with methyl-β-CD. The complex contained 14.9% of potassium clavulanate as it was determined by the HPLC method.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[O:8][C:9]1[N:10]=[C:11]([O:28][CH2:29][CH2:30][CH3:31])[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]C)=[C:20]([CH3:27])[CH:19]=3)[O:15][C:13]=2[N:14]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[O:8][C:9]1[N:10]=[C:11]([O:28][CH2:29][CH2:30][CH3:31])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:27])[C:21]([OH:25])=[C:22]([CH3:24])[CH:23]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(Oc2ccccc2F)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1nc(Oc2ccccc2F)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
1.0 ml of a 1 M solution of boron tribromide in dichloromethane was slowly added to an ice-cooled solution of 145 mg of 5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine in 8 ml of dichloromethane. The mixture was stirred for 2 h while maintaining ice cooling, and another 1 h at room temperature. Then a saturated solution of sodium hydrogencarbonate was carefully added. Extraction with dichloromethane, drying over sodium sulfate, filtration and removal of the solvent in vacuo gave 126 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:23][CH:24]([CH2:28]O)[CH:25]([CH3:27])[CH3:26])=[O:22])[C:17]=3[CH:30]=2)[C:3]1=[O:31].S(Cl)([Cl:34])=O>C(OCC)C>[Cl:34][CH2:28][CH:24]([NH:23][C:21]([C:18]1[C:17]2[CH:30]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[N:2]([CH3:1])[C:3]3=[O:31])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)=[O:22])[CH:25]([CH3:27])[CH3:26]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(CO)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: CCOCC
Product: CC(C)C(CCl)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 89.8 %

Procedure:
To 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-N-[1-(hydroxymethyl)-2-methylpropyl]-1,2-benzisothiazole-3-carboxamide(1.89 g, 4.14 mmol) at 0° C. is added thionyl chloride (5.00 ml). The resultant mixture is stirred one hour at 0° C. and two hours at room temperature. Anhydrous diethyl ether is added and the resultant suspension stirred vigorously for 1.75 hour. The suspension is filtered to afford the title compound as a cream-colored solid (1.77 g, 89.8%, mp>220° C.) which is identified by NMR spectral analysis.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([OH:63])(C)([CH3:61])[CH3:60].[CH2:64]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[N:89]=[C:88]([O:90][CH2:91]CC=C)[C:87]3[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=3)[N:81]=2)[CH2:76][CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+]>O>[CH2:64]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[N:89]=[C:88]([O:90][CH2:91][CH2:60][C@H:59]([OH:63])[CH2:61][OH:22])[C:87]3[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=3)[N:81]=2)[CH2:76][CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: C=CCCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OCC[C@H](O)CO)c3ccccc3n2)CC1

Procedure:
To a mixture of AD-mix-α (manufactured by Aldrich Co.) (29.74 g), t-butanol (106 ml) and water (106 ml) is added 2-[4-(benzyloxycarbonyl)piperazin-1-yl)-4-[(3-buten-1-yl)oxy]-quinazoline (8.88 g) with stirring under ice-cooling, and the mixture is stirred under ice-cooling for 22 hours. To the reaction mixture is added sodium sulfite (31.8 g), and the mixture is stirred at room temperature for 35 minutes. The reaction mixture is separated into an organic layer and an aqueous layer, and the aqueous layer is extracted with ethyl acetate. The organic layer is combined with the ethyl acetate extract, and washed with water. The ethyl acetate solution is dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=50:1, v/v), and the resulting crystalline product is recrystallized twice from acetone-diethyl ether to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(3S)-(3,4-dihydroxybutan-1-yl)oxy]quinazoline (2.15 g) as crystals.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O[CH2:22][C:23]1[C:24](CO)=[C:25]([CH3:31])[C:26]([OH:30])=[CH:27][C:28]=1[CH3:29]>C1(C)C=CC=CC=1.C(O)(=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([CH2:22][C:23]2[CH:24]=[C:25]([CH3:31])[C:26]([OH:30])=[CH:27][C:28]=2[CH3:29])=[C:4]([OH:5])[CH:3]=1
Reactant: Cc1cc(O)c(C)c(CO)c1CO
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cc2ccc(O)cc2O)c(C)cc1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
22.02 g of resorcinol, 1.90 g of p-toluene sulfonic acid, and 44.04 g of water are put in a 100 ml 4-necked flask, and 7.61 g of 4-hydroxymethyl(hydroxymethyl)-2,5-Xylenol is partly added thereto for one hour while maintaining at room temperature of 25° C. The mixture is reacted for 3 hours at the same temperature. Then, 50 g of acetic acid and 50 g of toluene are added to the reaction mass, separating a phase. The obtained organic layer is washed and concentrated. The obtained precipitate is filtered. The filtered product is rinsed with toluene, dried under reduced pressure for 24 hours, and treated through liquid chromatography, obtaining 7.94 g of 1,3-dihydroxy-4-(4-hydroxy-2,5-dimethyl benzyl)benzene having a purity of 99%.
Reaction SMILES: [Na].[Br-].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:5])=[O:4].[C:29]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CS(C)=O>[C:29]1(=[CH:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCCCCCCCCC1
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCC=C1CCCCCCCCCCC1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
Dry dimethylsulfoxide (50 ml, distilled from calcium hydride) and 24.1 ml (0.06 mole) of the sodium salt of dimethylsulfoxide (2.49 M in dimethylsulfoxide, Fieser and Fieser, "Reagents for Organic Synthesis", 1:310 [1967]) were mixed together and cooled in an ice-water bath. Then 13.29 g (0.03 mole) of (4-carboxybutyl) triphenylphosphonium bromide (Aldrich Chemical Co.) was added thereto and the mixture was stirred for 30 min. Cyclododecanone (3.64 g, 0.02 mole; Aldrich Chemical Co.: Beilstein 7[2],36) was dissolved in 10 ml of dry dimethylsulfoxide and added to the above mixture and the mixture was stirred for 15 hr at room temperature. The resulting mixture was then poured into 500 ml of water. This aqueous mixture was extracted with 900 ml (3×300 ml) of ether-ethyl acetate (1:1 V/V). The aqueous phase was acidified (pH 1 to 2) with 30 ml of concentrated hydrochloric acid. The aqueous phase was then extracted with 900 ml (3×300 ml) of ether-hexane (1:1 V/V). The ether-hexane extract was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo. The resultant product was recrystallized from ethanol-water to yield 2.0 g (36.2%) of 5-cyclododecylidenepentanoic acid (mp 70°-72° C.) having the following physical characteristics:
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CCCCCC>[C:15]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CN(C)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 94 %

Procedure:
Using a THF solution of phenylmagnesium bromide (1.19 mL, 1.01 M, 1.2 mmol) and 3-chloro-N,N-dimethylaniline (155.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=50 and 100% in hexane), the above compound was obtained as a colorless liquid (0.185 g, yield=94%, purity=>98% (GC analysis)).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:18][CH2:17][O:16][CH2:15]2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].CC1C=CC=C(C2CCOC2)C=1OCC(OC)=O.NN>CCO>[O:16]1[CH:17]=[CH:18][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:2]([CH3:1])[C:3]=2[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7])=[CH:15]1
Reactant: Cc1cccc(C2CCOC2)c1OCC(=O)NN
Agent: COC(=O)COc1c(C)cccc1C1CCOC1
Agent: NN
Solvent: CCO
Product: Cc1cccc(-c2ccoc2)c1OCC(=O)NN
Temperature: 100 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
Synthesis of 2-(2-methyl-6-(tetrahydrofuran-3-yl)phenoxy)acetohydrazide: methyl 2-(2-methyl-6-(tetrahydrofuran-3-yl)phenoxy)acetate (141 mg, 0.56 mmol) and hydrazine (0.03 mL, 0.6 mmol) were dissolved in EtOH 2 mL, followed by stirring at 100° C. for 12 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 2-(2-(furan-3-yl)-6-methylphenoxy)acetohydrazide (127 mg, 90%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:2]=[N-:3].C1C=C(Cl)C=[C:22]([C:27]([O:29]O)=O)C=1.[OH:31][S:32]([O-])=[O:33].[Na+]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][S:32]([CH2:22][CH2:27][OH:29])(=[O:33])=[O:31])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCS(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of sulfide 3 (8.41 g, 44 mmol) in CH2Cl2 (100 ml) was cooled in an ice bath. mCPBA (84% purity, 27.1 g, 3 equiv.) was added portion wise and the resulting solution was stirred at RT for 16 h. An aqueous 1 M NaHSO3 solution (20 ml) was added, and the resulting suspension was vigorously stirred at RT for 30 min. The white m-chlorobenzoic acid precipitate was filtrated over a celite pad. The organic layer was washed with a saturated aqueous NaHCO3 solution (3×20 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 1:1 then 3:7 then pure AcOEt) afforded sulfone 5 as a colorless liquid (8.41 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>[Cu]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
4-Methoxyphenol (25 g, 0.20 mol) was heated under a nitrogen atmosphere to 70° C. during which time the solid melted. Eighty-five percent potassium hydroxide (12.4 g, 0.19 mol) was added all at once and the mixture stirred at 70° C. for 1 hour. 1-Bromo-4-nitrobenzene (33 g, 0.16 mol) and copper powder (0.1 g, 1.57 mmol) were added and the mixture stirred at 190° C. for 3 hours. After cooling to room temperature, the residue was partitioned between benzene and water. The organic layer was then extracted two times with 5% KOH, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. Purification by HPLC (hexane-methylene chloride) gave 4-methoxy-4'-nitrodiphenyl ether as a yellow crystalline solid (19.05 g, 49%), mp 107°-109° C.
Reaction SMILES: [N:1]([C@H:4]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:5][O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[N:1]([C@H:4]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:5][OH:6])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@H](CO)N=[N+]=[N-]

Procedure:
A solution of (R)-(2-azido-3-(hexadecyloxy)propoxy)(tert-butyl)dimethylsilane (1 eq), and 1M TBAF in THF (1.1 eq) in THF (0.2 M) was stirred at 25° C. for 20 minutes. The reaction was diluted with Et2O and washed with saturated NH4Cl, H2O, and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hex to give (S)-2-azido-3-(hexadecyloxy)propan-1-ol as a colorless oil.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.Cl.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2([C:5]#[N:6])[CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: O=C1CCC1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NC2(C#N)CCC2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 22 %

Procedure:
Trimethylsilyl cyanide (0.4 g, 4 mmol) was added dropwise to a mixture of 4-methanesulfonylphenylamine hydrochloride (0.415 g, 2 mmol), cyclobutanone (0.28 g, 4 mmol) and sodium sulfate (1 g) in DMF (3 ml). The mixture was stirred for 15 hours at 120° C. After filtration to remove the sodium sulfate, the filtrate was washed with brine and extracted with ethyl acetate. The organic layer was concentrated and chromatographed (dichloromethane:acetone, 90:10) to yield 1-(4-methanesulfonylphenylamino)cyclobutanecarbonitrile (45a) (0.116 g, 0.44 mmol, 22%) as a yellowish solid. 4-methanesulfonylphenylamine (0.201 g, 1.17 mmol, 59%) was also recovered.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.[S:22]([OH:26])([OH:25])(=[O:24])=[O:23].CS[C:29](=[NH:31])[NH2:30]>C(O)C.O.CCOCC>[S:22]([OH:26])([OH:25])(=[O:24])=[O:23].[NH:1]([CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:29]([NH2:31])=[NH:30].[NH:1]([CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:29]([NH2:31])=[NH:30]
Reactant: NCCN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: N=C(N)NCCN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 112.6 %

Procedure:
To a solution of 2'-(2-aminoethyl)spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (3.6 g) in ethanol (15 ml) is added a solution of 2-methyl-2-thiopseudourea sulfate (1.8 g) in water (25 ml). After stirring at reflux (110°) for 20 hours, the mixture is cooled and diluted with ether (100 ml). The resultant precipitate is collected, washed with ether and dried to yield product (4.0 g, 83%). Recrystallization from methanol/ether yields the analytical sample as an off-white solid, mp 234°-239° (dec.).