Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:46]=[O:47]>O1CCCC1>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:46]=[O:47])=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(C=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) (332 mg) in tetrahydrofuran (10 ml) at −78° C. under an atmosphere of nitrogen was added n-butyllithium in hexanes (0.69 ml of 1.6M). Dimethylformamide (86 μl) was added dropwise to the solution after 20 minutes of stirring at −78° C. After a further 20 minutes of stirring at −78° C., the mixture was quenched with saturated ammonium chloride solution (2 ml). The mixture was diluted with ammonium chloride (50 ml), extracted with ethyl acetate (50 ml), dried over magnesium sulphate, filtered and the filtrate was evaporated to dryness. Purification of the residue by column chromatography on silica gel (32 g), eluting with an ethyl acetate:hexane gradient (1:1 to 3:1) yielded the title compound as a cream solid (52 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:12])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:12][C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)O)sc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
4-Methyl-2-thiophenecarboxylic acid ethyl ester (3.4 g) synthesized in accordance with the method of Reference Example 140 was dissolved in acetonitrile (30 ml), and sulfuryl chloride (2.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room-temperature for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g). 5-Chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) was dissolved in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml), and 1N aqueous sodium hydroxide (40 ml) was added. The mixture was stirred at 60° C for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][NH2:30]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:30][CH3:29])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (50 mg, 0.16 mmol) in DCM (1.5 mL) was added oxalyl chloride (0.042 mL, 0.48 mmol) followed by 1 drop of DMF. After 30 minutes, methylamine (2M in THF, 1 mL, 2 mmol) was added to the reaction. The reaction was stirred for 14 h. The crude reaction was loaded directly onto a column and purification (FCC, SiO2, 0-10%, MeOH/DCM) afforded the title compound as a white solid (19 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 9.17 (d, J=2.3 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.49 (d, J=2.7 Hz, 2H), 7.38-7.31 (m, 4H), 6.28-6.22 (m, 1H), 5.21 (s, 2H), 3.10 (d, J=4.7 Hz, 3H). [M+H]=327.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>CN(C)C=O>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])[CH:7]=[CH:6][CH:5]=3)=[CH:9][N:10]=[C:11]2[CH:16]=1
Reactant: Cc1ccn2c(-c3cccc(N)c3)cnc2c1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2c(-c3cccc(Nc4ccccc4[N+](=O)[O-])c3)cnc2c1
Temperature: 120 °C
Yield: 10.3 %

Procedure:
3-(3-Aminophenyl)-7-methylimidazo[1,2-α]pyridine (1.0 g, 4.5 mmol) and 1-fluoro-2-nitrobenzene (0.55 ml, 5.2 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 ml) and heated at 120° C. for 2 days. The cooled reaction mixture was poured into water (25 ml), extracted with ethyl acetate (2×20 ml) and the combined organic phases dried over anhydrous magnesium sulphate and concentrated in vacuo. Purification by flash chromatography eluting with 5% methanol in dichloromethane gave the title compound as an orange oil (160 mg, 10%). 1H NMR (400 MHz, d4-methanol) δH 2.61 (3H, s), 6.89-6.93 (1H, m), 7.33-7.35 (1H, m), 7.40-7.42 (1H, m), 7.47-7.52 (2H, m), 7.55-7.57 (1H, m), 7.62-7.69 (2H, m), 7.74 (1H, s), 8.06 (1H, s), 8.24 (1H, d, J 7), 8.67 (1H, d, J 8); m/z (ES+) 345 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])N(OC)C)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[C:30]([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])[CH3:30])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 4-[3-chloro-5-(methoxy-methyl-carbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (1.0 g, 2.6 mmol) in anhydrous THF (20 mL) was added MeMgBr (2.6 mL, 3M solution in Et2O, 7.8 mmol, Aldrich) with stirring at 0° C. The reaction mixture was stirred at room temperature for 4 h and poured into satd. aq. NaHCO3 solution (20 mL). After the addition of EtOAc (50 mL), the mixture was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (70% EtOAc in hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 340 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:7]1([C:6]2[C:2]([O:1][S:13](=[O:16])(=[O:15])[NH2:14])=[N:3][S:4][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1nsnc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NS(=O)(=O)Oc1nsnc1-c1ccccc1

Procedure:
A slurry of 3-hydroxy-4-phenyl-1,2,5-thiadiazole (15.0 g, 0.084 mole) in acetonitrile (100 ml) was treated by the simultaneous dropwise addition of a sulfamoy l chloride solution in acetonitrile (0.20 mole, 66 ml of 3M) and a diisopropylethylamine solution (0.22 mole in enough 1:1 acetonitrile/methylene chloride to make 66 ml). High Pressure Liquid Chromatography analysis indicated a maximum of 85% conversion of starting material to product. The reaction was worked up by concentration of the reaction mixture and partitioning the residue between ethyl ether and water. Concentration of the ether fraction gave a white paste from which desired product was separated by dissolving in a small amount of acetonitrile. The product was crystallized from the acetonitrile to give 2.8 g (13%) of the title compound as a white powder, mp 128°-130° C.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=C[C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.CS(O)(=O)=[O:15]>C(OCC)C>[O:15]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]1=[O:12]
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: CS(=O)(=O)O
Solvent: CCOCC
Product: O=c1ccc2ccccc2o1
Yield: 5 %

Procedure:
To a mixture of 2,7-dihydroxynaphthalene (0.20 g, 1.3 mmol) and 1 (0.20 mg, 0.83 mmol) was added methanesulfonic acid (1.3 mL, 21 mmol) at 0° C. The clear brown solution gradually became dark orange within 4 h after which time the reaction mixture was diluted with cold (−30° C.) ethyl ether (10 mL), centrifuged (3000 rpm) at 4° C. for 20 minutes. After removing the ether by aspiration, the residual orange solid was dried under high vacuum, dissolved in H2O (3 mL), and purified by RP-HPLC using an appropriate linear gradient of acetonitrile containing 10% de-ionized water (A) and 0.1% (v/v) TFA/H2O (B) (3-50% A over 20 min. followed by a steep gradient to 100% A and equilibrium back to 3% A). The fractions containing the product were collected, concentrated, and lyophilized to give Mini401 as a white solid (5%). 1H NMR (DMSO-d6, 400 MHz): δ 10.21 (1H, s), 8.08 (1H, d, J=8.9 Hz), 7.94 (1H, d, J=8.8 Hz), 7.84 (3H, bs), 7.72 (1H, s), 7.33 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.8, 2.0 Hz), 6.44 (1H, s), 3.54 (2H, t, J=6.8 Hz), 3.32-3.29 (2H, m). 13C NMR (DMSO-d6, 75 MHz): δ 159.2, 157.6, 155.1, 153.0, 133.9, 131.5, 130.8, 125.3, 117.0, 115.2, 114.0, 111.9, 1079, 37.2, 33.9. LRMS (APCI+): Calc'd for C15H13NO3 255.1 m/z, measured 256.2 (MH+).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].P([O-])(OCC)(SCC)=[S:18]>C(O)C.O>[NH2:1]/[C:2](/[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3](/[C:4]#[N:5])\[C:6](=[S:18])[NH2:7]
Reactant: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOP([O-])(=S)SCC
Solvent: CCO
Solvent: O
Product: N#C/C(C(N)=S)=C(/N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A suspension of Example 96C (2.1 g, 9.8 mmol) and 90% diethyl dithiophosphate (1.8 mL, 10.8 mmol) in ethanol (15 mL) and water (15 mL) was heated to reflux for 24 hours, cooled to room temperature, poured into ice water (300 mL), and filtered. The filter cake was dried to provide 2.3 g (95% yield) of the desired product. MS(ESI(−)) m/e 247 (M−H)−.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:7]([O:9][N:10]=[CH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1)[CH3:8]>>[CH2:7]([O:9][N:10]=[CH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH2:5][CH2:4][CH2:3][C:2]#[CH:1])=[C:14]([CH3:20])[CH:13]=1)[CH3:8]
Reactant: CCON=Cc1cc(C)c(O)c(C)c1
Reactant: C#CCCCO
Product: C#CCCCOc1c(C)cc(C=NOCC)cc1C

Procedure:
Condensation of 4-pentyn-1-ol and 4-hydroxy-3,5-dimethylbenzaldehyde O-ethyloxime using Mitsunobu Reaction conditions (see for example J. Med. Chem., 36, 3240, 1993 and references cited therein) gave 3,5-dimethyl4-(4-pentyn-1-yloxy)benzaldehyde O-ethyl oxime in good yield.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>>[CH2:31]([O:30][C:28]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)=[CH:34][CH:33]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(Nc2nc(Nc3ccc(C(=O)OCC)cc3)c3nc[nH]c3n2)cc1
Yield: 54.1 %

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 660 mg of ethyl 4-aminobenzoate in place of trans-1,4-diaminocyclohexane. 181 mg of the expected product are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:22]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of 3-(4-methoxy-phenyl)-7-trifluoromethyl-1H-indazole (59 mg, 0.2 mmol) in 0.5 ml DMF were added 72 μl of benzyl bromide (0.6 mmol). The reaction mixture was heated overnight at 120° C. After cooling to room temperature, ethyl acetate was added and the solution was washed three times with brine. The organic layer was dried over MgSO4 and concentrated. Column chromatography (n-heptane/ethyl acetate, 70:30 as eluent) afforded 61 mg of pure product.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO.O>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2cccnc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

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 (1.0 g, 4.7 mmol) was combined with 50 ml methanol and 0.2 g palladium on charcoal (5% w/w) in a hydrogenation vessel. Hydrogenation (50 psig) was carried out for 4 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one as white semisolid, which dissolved in ethanol give a white crystalline solid upon cooling (0.82 g 88%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ncc(C#Cc3ccccc3)cc2F)C(=O)O1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (12.5 mg, 17.9 μmol, 0.05 equiv.) was dissolved in 1 ml DMF. (120 mg, 357 μmol) 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (Example 1, step 2) and phenylacetylene (72.9 mg, 78.4 μl, 714 μmol, 2 equiv.) were added at room temperature. Triethylamine (108 mg, 149 μl, 1.07 mmol, 3 equiv.), triphenylphosphine (2.81 mg, 10.7 μmol, 0.03 equiv.) and copper(I)iodide (2.04 mg, 10.7 μmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 3-(3-fluoro-5-(phenylethynyl)pyridin-2-yl)-5,5-dimethyloxazolidin-2-one (96 mg, 309 μmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=311.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:29][C:26]1[N:25]=[C:24]([CH2:23][N:17]2[C:16](=[O:19])[N:14]3[CH:15]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)[CH:11]=[CH:12][C:13]3=[N:18]2)[O:28][N:27]=1
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reactant: Cc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1noc(Cn2nc3ccc(-c4ccc(OC(F)(F)F)cc4)cn3c2=O)n1
Temperature: 110 °C

Procedure:
A mixture of 90 mg 6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.30 mmol), 40 mg 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (0.30 mmol) and 23 mg potassium carbonate (0.17 mmol) in 2 mL DMA was heated at 110° C. for 2 h. The reaction mixture was then filtered and the filtrate concentrated. The residue was column purified on 12 g silica, eluting with 36 mL 5% ethyl acetate in hexanes, then 5-50% over 60 mL, and then 50% 120 mL. 2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was isolated as a yellow solid. m/z (ESI)=392.0 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 7.95 (dd, 1H) 7.54 (d, 2H), 7.40 (dd, 1H), 7.32 (d, 2H), 7.20 (dd, 1H) 5.43 (s, 2H), 2.40 (s, 3H)
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:16]=1)=[N:11][CH:12]=[CH:13][C:14]=2[CH3:15])[CH2:4][CH2:5][CH3:6].[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24]([C:39]2[N:43]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]=[N:41][N:40]=2)[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33]OS(C)(=O)=O)=[CH:29][CH:28]=2)[CH:26]=1)=[O:21])[CH3:18]>CS(C)=O.[Cl-].[Na+].O>[CH2:3]([C:7]1[N:16]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([N:25]3[CH:26]=[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:23]=[C:24]3[C:39]3[N:43]([C:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:42]=[N:41][N:40]=3)=[CH:32][CH:31]=2)[C:10]2=[N:11][CH:12]=[CH:13][C:14]([CH3:15])=[C:9]2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2nccc(C)c2[nH]1
Reactant: CCOC(=O)c1cc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)n(-c2ccc(COS(C)(=O)=O)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Sodium hydride (10 mg) (60% in oil) was added to a stirred solution of 2-butyl-7-methylimidazo[4,5-b]pyridine (48 mg) in dimethyl sulfoxide (5.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. To this mixture was added a solution of 4-ethoxycarbonyl-1-(4-methanesulfonyloxymethylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)pyrrole (193 mg) in dimethyl sulfoxide (2 ml). The mixture was stirred for 3 hours at ambient temperature and poured into brine. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography to afford 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1-trityl-1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (123 mg) as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)(=[O:9])=[O:8].[O-:28][C:29]#[N:30].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1/[CH:5]=[CH:6]/[S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][C:29]([NH2:30])=[O:28])[CH:12]=1)(=[O:9])=[O:8]
Reactant: N#C[O-]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Nc2ccc(OC)c(NC(N)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)-sulfonamide (1 mmol) in glacial acetic acid (10 mL) is added an aqueous solution of potassium cyanate (1 mmol in 2 mL of de-ionized water). The reaction mixture is stirred for 3 h at room temperature. The reaction mixture is then poured into de-ionized water (100 mL) and extracted with ethyl acetate for 3 times. The combined organic layer is then washed with sodium bicarbonate to neutralize acetic acid and then with brine. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under vacuum to yield the title compound which is purified by column chromatography.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH3:37])[C:34](Cl)=[O:35])[CH3:32]>C(O)CO>[I-:1].[CH2:31]([N:33]([CH3:37])[C:34]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:35])[CH3:32]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: OCCO
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1

Procedure:
Mix 7.9 g (0.02 mol) (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, let it react at 20° C. for 16 hours. Filter it and reduce the pressure to recover 9.8 g of red-brown liquid to be directly used in the next reaction.