Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:14]O)[C:11](=O)[CH2:10][CH:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>CO>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:11]2[NH:24][N:25]=[CH:14][C:12]=2[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(=CO)C(=O)CC1c1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 51 (310 mg, 1.02 mmol) from the previous step was dissolved in MeOH (3 ml). Hydrazine monohydrate (0.1 ml, 2.04 mmol) was added to the solution and then stirred at room temperature for 1 hour. Solvent was removed under reduced pressure to afford a yellow gel as the desired product. LCMS 300.2 (M+1)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was added portionwise, allowing for gas evolution, to a solution of 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5 mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete, benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9 g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[CH:9]([CH2:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN([CH:18]=[O:19])C>>[NH:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: C1=CCC2CCNC2=C1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Anhydrous DMF 20 mL in a 250 mL flask was cooled on ice bath and neat POCl3 4.6 mL (50 mmol) was added dropwise under Ar. After 10 min, a solution of tetrahydroindole 3.83 g (32.14 mmol) in anh DMF 10 mL was gradually added over 10 min (exothermic) followed by additional anh DMF 2×5 mL to wash the flask and the syringe. The cooling bath was replaced with ambient water bath and the reaction was stirred at RT under Ar for 13 hours (overnight). The reaction was quenched by addition of water 20 mL followed by 15% wt NaOH solution 40 mL. After 10 min, additional 15% NaOH 25 mL was added, followed by water 100 mL and the mixture was stirred vigorously for 30 min on ambient water bath. The precipitated product was collected by filtration, compressed on the Buchner funnel, washed thoroughly with water, dried by suction and on highvac. Y=4.282 g (90.5%) of light tan shiny flakes. 1H-NMR (d6-DMSO, 400 MHz): 11.609 (br s, 1H), 9.268 (s, 1H), 6.679 (s, 1H), 2.557 (t, 5.9 Hz, 2H), 2.446 (t, 5.9 Hz, 2H), 1.693 (m, 4H)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1F
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2cccc(Br)c2nc1NC(C)(C)C
Yield: 86.3 %

Procedure:
A solution of 5-bromo-3-fluoro-2-methylquinoxaline (Example 126f; 1.5 g, 6.22 mmol) and tert-butylamine (Aldrich; 3.27 mL, 31.1 mmol) in DMSO (15 mL) was stirred at 100° C. for 2.5 h. The mixture was subsequently diluted with DCM (150 mL), and washed with saturated aq. NaHCO3 (3×15 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude material was purified on a silica gel column (18-25% EtOAc in hexanes) to give 8-bromo-N-(tert-butyl)-3-methylquinoxalin-2-amine (1.58 g, 86% yield) as an amorphous pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79-7.86 (m, 1H), 7.71 (dd, J=8.1, 1.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.17 (s, 1H), 2.55 (s, 3H), 1.58 (s, 9H). m/z (ESI, +ve ion) 294.0/296.0 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(O[C@H]4CCNC4)cn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@H](Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 94 %

Procedure:
(S)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (50 mg, 94%) was prepared using a procedure analogous to that described in Example 20, substituting (S)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 1 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OCC)C.Cl.[N:25]([O-])=[O:26].[Na+]>O>[N:25]([N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:26]
Reactant: COc1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(4-chlorobenzyl)-4-methoxyaniline hydrochloride salt (141.4 g; 497.5 mmol), prepared as above, in 1500 mL water, 750 mL diethyl ether, and 525 mL aqueous 1N HCl was treated with a solution of sodium nitrite (37.7 g; 547 mmol) in 150 mL water. After stirring for 2 hours at ambient temperature the reaction mixture was extracted twice with diethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give N-nitroso-N-(4-chlorobenzyl)-4-methoxyaniline as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)#[N:12]
Reactant: NCCSCc1ccsn1
Reactant: CNC(SC)=C(C#N)C#N
Product: CNC(NCCSCc1ccsn1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 6-phenyl-1-hexanol (2.9 g, 16.27 mmoles), CH2Cl2 (30 ml), triethylamine (4.76 ml, 34.16 mmoles) and p-toluensulphonyl chloride (3.26 g, 17.08 mmoles) was kept under stirring at room temperature for 1 night, washed with water, 5% HCl and NaHCO3 and evaporated to give 5.4 g of the title compound (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][CH2:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O)[CH3:12].C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:20]/[C:16]2[N:15]([CH2:14][O:13][CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCOCn1cccc1C=O
Reactant: N#CCc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOCn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 4-chlorophenylacetonitrile (500 mg, 3.30 mmol), 1-ethoxymethyl-1H-pyrrole-2-carbaldehyde (520 mg, 3.39 mmol, 1.03 equiv.), and 18-crown-6 ether as a phase transfer catalyst (87 mg, 0.33 mmol) in toluene (30 ml) was added potassium hydroxide (185 mg, 3.30 mmol) and the mixture was heated to 80° C. for 3 h, then stirred at room temperature overnight. The solution was filtered through a small plug of silica and concentrated to afford an oil (705 mg). This is Compound 7 in Table 8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[BH4-].[Na+].CC(C)=O.[BH4-]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: OC1C(=Cc2cccnc2)N2CCC1CC2

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 140 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) stirred under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which when suspended in ether afforded 3-chloro-2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). The chloroquinuclidine (0.3 g, 1.3 mmol) was combined with 50 ml ethanol in a hydrogenation vessel, then wet Raney nickel (2.5 grams) was added in one portion. Hydrogenation (50 psig) was carried out for 6 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave the desired 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a white reside which easily recrystallized from ethanol-ether to give a white crystalline solid (0.21 g 70%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:17](=[O:18])[NH:16][CH3:15]
Reactant: CN=C=O
Reactant: Oc1ccc2oc3ccccc3c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 84 %

Procedure:
A solution of 2-hydroxydibenzofuran (5.0 g, 27 mmol), methyl isocyanate (1.9 mL, 32 mmol) and triethylamine (3.0 mL, 22 mmol) in 75 mL of methylene chloride was stirred under nitrogen at room temperature overnight. During this time a solid formed. Additional methylene chloride was added and the solid dissolved. The reaction was then extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 5.47 g of a yellow solid. Recrystallization from isopropyl ether gave 3.43 g (52%) of the title compound as a light brown crystalline solid, mp 155°-156° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) and diisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 3-hydroxyphenylacetate (6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([SeH:16])[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=C(C(C)C)[N:6]=1.[H-].[Na+].[CH2:19](OCCl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([SeH:16])[C:4]([CH:10]([CH3:15])[CH3:11])=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1
Reactant: Cc1nc(C(C)C)c(-c2ccccc2)n1[SeH]
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(C(C)C)n1[SeH]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a solution of 400 mg of 2-methyl-4-isopropyl-5-phenylselenyl-imidazole (1.4 mmol) in 4 ml of dry dimethylformamide is added 70 mg of 60% oil suspension of sodium hydride (1.8 mmol) under ice cooling and the mixture is allowed to stand for 5 minutes followed by the addition of 270 mg of benzyloxymethyl chloride (1.7 mmol). The mixture is stirred for 30 minutes under ice cooling, mixed with ice water and extracted with diethyl ether. The extract is washed with water, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:1). The product is recrystallized from n-hexane to give 297 mg of the objective 2-methyl-4-phenylselenyl-5-isopropyl-imidazole (I-87) and 1-benzyloxymethyl-4-isopropyl-2-methyl-5-phenylselenyl-imidazole (I-37). Yield, 52%; mp. 94°-96° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CO>O1CCCC1>[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OCC12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0° C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0° C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:26](I)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[OH-].[K+].C(O)CCC>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc(O)c(F)c3)s2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: CCCCCCOc1ccc(-c2nnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Temperature: 25 °C
Yield: 35.1 %

Procedure:
0.30 g (0.84 mM) of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole, 0.23 g (1.09 mM) of hexyl iodide, 0.08 g of 85%-potassium hydroxide and 6 ml of butanol were mixed, followed by refluxing for 5 hours under stirring. After the reaction, 10 ml of methanol was added to the reaction mixture, followed by cooling to room temperature and further cooling in a freezer to precipitate a crystal. The crystal was recovered by filtration and washed with methanol. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous magnesium sulfate. The magnesium sulfate was recovered by filtration and the filtrate was condensed into a solid. The solid was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (ethanol/hexane) to obtain 0.13 g of 2-(3-fluoro-4-hexyloxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole (Yield: 35.1%). ##STR23##
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C>C1COCC1>[C:6]([O:10][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)O
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(=O)C=C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Acrylic anhydride was synthesized in 70-80% yield as in the following example. Acryloyl chloride (2.7 g, 30 mmol) was added dropwise over 5 min to an ice-cooled solution of acrylic acid (2.0 g, 30 mmol) and triethylamine (2.8 g, 30 mmol) in THF (50 mL), and the solution was stirred at room temperature for 16 h. The NH4+Cl− precipitate was collected in a fritted glass filter, and the solvent was then removed from the filtrate by rotary evaporation. The residue was dissolved in CH2Cl2 (25 mL), washed twice with dilute aq. NaHCO3 (50 mL each) and once with satd. NaCl aq. soln. (50 mL), and dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, 2.8 g (80%) of acrylic anhydride was obtained as a light yellow liquid. It was used without further purification. 1H NMR (CDCl3, 77.23 ppm): 6.04 (m, ═CH trans to CO2), 6.14 (m, ═CH gem to CO2), 6.50 (d, ═CH cis to CO2). 13C NMR (CDCl3/DMSO-d6): 127.4 (═CH), 134.7 (′CH2), 161.2 (C═O).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.Br[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Water (0.6 mL), sodium carbonate (70 mg), 2-methoxyphenylboronic acid (40 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain 61 mg of tert-butyl 4-(2-methoxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=1.Cl.[CH3:25][NH:26][CH3:27].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:22])[N:26]([CH3:27])[CH3:25])[CH:15]=1
Reactant: CNC
Reactant: O=C(O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A mixture of 3-bromo-8-(3-carboxybenzoylamino)quinoline (200 mg), dimethylamine hydrochloride (65.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (100 mg) and 1-hydroxybenzotriazole (109 mg) in dimethylformamide (3 ml) was stirred for 3 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) and recrystallized from ethanol to give 3-bromo-8-[3-(dimethylcarbamoyl)benzoylamino]quinoline (120 mg) as pale yellow solid.