Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:19]([F:22])([F:21])[F:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=3[F:16])[NH:9][C:8](=O)[NH:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].NC(N)=[S:31]>P(Cl)(Cl)(Cl)=O>[CH:1]1([C:4]#[C:5][C:6]2([C:19]([F:22])([F:21])[F:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=3[F:16])[NH:9][C:8](=[S:31])[NH:7]2)[CH2:3][CH2:2]1
Reactant: NC(N)=S
Reactant: O=C1Nc2ccc(F)c(F)c2C(C#CC2CC2)(C(F)(F)F)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc2c(c1F)C(C#CC1CC1)(C(F)(F)F)NC(=S)N2
Temperature: 95 °C
Yield: 42.7 %

Procedure:
A solution of (+/-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (0.32 g, 1.0 mmol) in phosphorous oxychloride (5 mL) containing Na2CO3 (160 mg, 1.5 mmol) was heated at 95° C. overnight. After cooling to room temperature, the phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in ethanol (5 mL) and thiourea (0.44 g, 5.7 mmol) was added. The resulting mixture was heated at reflux for 24 hours, cooled to room temperature and concentrated. The material was dissolved in EtOAc (75 mL) and washed sequentially with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL). The organic extract was dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (38% EtOAc/hexanes) to afford the title compound as a white solid (142 mg, 43%): mp 241-243° C.; 1H NMR (300 MHz, acetone-d6) δ 7.52-7.43 (m, 1H), 7.06-7.03 (m, 1H), 1.43-1.40 (m, 1H), 0.89-0.86 (m, 2H), 0.79-0.74 (m, 2H); 19F NMR (282 MHz, acetone-d6) δ -83, -136, -145; Analysis calc'd for C14H9F5N2S: C, 50.60; H, 2.73; N, 8.43; found: C, 50.46; H, 2.78; N, 8.31.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18][NH2:19])=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[CH:23]=[CH:22][N:21]=1.C(O)(=O)C>C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18]/[N:19]=[CH:30]/[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][N:21]=[CH:20]4)=[O:17])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc2cnccc12
Reactant: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(N/N=C/c1cccc2cnccc12)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a room temperature solution of 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) in ethanol (20 mL), was added isoquinoline-5-carbaldehyde (122 mg, 0.77 mmol) and acetic acid (0.5 mL). The reaction mixture was then heated at 80° C. for 3 h, concentrated in vacuo and the residue diluted with water and extracted with EtOAc (2×20 mL). The layers were separated and then the combined organic layers were washed with a saturated NaHCO3 solution, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via column chromatography eluting with 2% MeOH in dichloromethane to afford (E)-2-(4-cyclohexylphenyl)-N′-(isoquinolin-5-ylmethylene)cyclopropanecarbohydrazide (100 mg, 33%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:41])[N:8]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:19][CH2:18]4)[N:14]=[C:13]([CH3:33])[N:12]=3)[C:5]=2[NH:4][N:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[NH2:1][C:2]1[C:6]2[C:7](=[O:41])[N:8]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)[N:14]=[C:13]([CH3:33])[N:12]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cc1nc(-c2cn(-c3ccccc3C)c(=O)c3c(N)n[nH]c23)cc(N2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn(-c3ccccc3C)c(=O)c3c(N)n[nH]c23)cc(N2CCN(CCO)CC2)n1
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-7-(6-(4-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step C (195 mg) in tetrahydrofuran (2.0 mL) was added tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.679 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol/dichloromethane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (50.0 mg).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-bromoethyl)-1-nitrobenzene (1 eq) in tetrahydrofuran was added morpholine (3 eq) and stir for 16 h at ambient temperature. Concentrating and passing through a plug of silica gave 4-[2-(4-nitrophenyl)ethylmorpholine. MS: MH+=236.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:8]2)=[C:4](C)[CH:3]=1.[Cl:23]C1C=C(Cl)C=CC=1CN1C2C(=CC=CC=2)C(C(OCC)=O)=N1>>[Cl:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:8]1
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Reactant: Cc1cc(Cl)ccc1Cn1nc(C(C)(C)O)c2ccccc21
Product: CC(C)(O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12

Procedure:
The product was obtained using the method described for the preparation of compound 10b, but using as starting material compound 11a (0.4 mol) instead of compound 10a.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1

Procedure:
Ethyl 3-benzylamino-5 -dimethylsulphamyl-4-phenoxy-benzoate (1 g) was heated on a steam bath with 1N sodium hydroxide (15ml) for 6 hours. From the resulting solution, the 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoic acid was precipitated by addition of 4N hydrochloric acid until a pH of 2.5. After isolating and recrystallizing from aqueous ethanol, the compound was obtained with a melting point of 205°-206° C.
Reaction SMILES: CC1N=CN(C2C(=O)N3CC[N:14]([C@H:17]([C@@H:19]4[CH2:23][CH2:22][C@H:21]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[O:20]4)[CH3:18])C(=O)C3=CC=2)C=1>O1CCCC1>[F:32][C:30]([F:31])([F:33])[C:27]1[CH:26]=[CH:25][C:24]([C@@H:21]2[O:20][C@H:19]([C@@H:17]([NH2:14])[CH3:18])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)[C@@H]2CC[C@H](c4ccc(C(F)(F)F)cc4)O2)C3=O)cn1
Solvent: C1CCOC1
Product: C[C@H](N)[C@@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)O1

Procedure:
Palladium hydroxide on carbon (˜50% water, 10 wt % palladium, 7.1 g, 5 mmol) was added to a slurry of C40 (22.0 g, 50.3 mmol) and ammonium formate (80.2 g, 1.27 mol) in methanol (500 mL), and the reaction mixture was stirred for 2.5 hours at room temperature, then combined with similar reactions run on C41 (24.5 g, 56.0 mmol) and filtered through Celite, rinsing with methanol (1 L). The filtrate was concentrated in vacuo and treated with aqueous sodium hydroxide solution (0.2 M, roughly 800 mL), while keeping the pH at approximately 9. This was extracted three times with ethyl acetate (0.5 L, 1 L and 0.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to afford the product as a light yellow oil. Hydrogenation was assumed to have occurred on the less hindered face; the assigned stereochemistry was also supported by the IC50 obtained on the final product 8, which indicated that the tetrahydrofuran moiety bore the substituents in a cis orientation (see Table 1). Yield: 26.3 g, 101 mmol, 95%. 1H NMR (400 MHz, CDCl3) δ 7.53 (br AB quartet, JAB=8 Hz, ΔνAB=50 Hz, 4H), 4.96 (dd, J=7.4, 7.0 Hz, 1H), 3.70-3.77 (m, 1H), 2.93-3.01 (m, 1H), 2.33-2.43 (m, 1H), 2.00-2.10 (m, 1H), 1.66-1.85 (m, 2H), 1.12 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[N:13]([CH2:2][C:3]3[CH:7]=[CH:6][O:5][N:4]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reactant: ClCc1ccon1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1Cc1ccon1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A compound of 3-(chloromethyl)-isoxazole (1.2 g) was added dropwise at a temperature of 20° to 30° C. under stirring to a mixture of 7-fluoro-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.16 g), acetonitrile (50 ml) and potassium carbonate (1.5 g). The reaction mixture was heated under refluxing for 3 hours, cooled to room temperature, and filtered. The filtrate was concentrated under a reduced pressure to dryness. The resultant residue was mixed with toluene (150 ml) to form a suspension, which was then filtered to remove the undissolved materials therefrom. The filtrate was concentrated under a reduced pressure so as to obtain a viscous material, which was thereafter dissolved in a minimum amount of ethanol. The ethanol solution was cooled to precipitate a crystalline product. This product was separated by filtration and dried, so that the aimed compound, i.e. 7-fluoro-4-(isoxazol-3-ylmethyl)-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.3 g) was obtained. m.p. 206°-210° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Fc1ncccc1-c1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(-c2cccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-2′-(trifluoromethyl)-3,4′-bipyridine (200 mg, 0.83 mmol), 4-(pyridin-2-ylamino)phenol (185 mg, 0.99 mmol) and cesium carbonate (323 mg, 0.99 mmol) in DMSO (3.3 mL) was heated to 80° C. for 4 h. The mixture was cooled to room temperature, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The solids were suspended in sat aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (EtOAc/Hexanes=0→40%) to give the title compound. MS (ESI, pos. ion) m/z: 409 (M+1). IC50 (uM) 0.022.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[B+3].[Na+].[OH-].[OH-].[OH-].S(=O)(=O)(O)O>[OH-].[Na+]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(N2CCC(=O)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Agent: [B+3]
Agent: [Na+]
Product: Cc1c(N2CCC(O)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
1-Cyclopropyl-7-(4-oxo-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.25 g) is dissolved in 1% aqueous sodium hydroxide (28 ml), and thereto is added sodium boron hydroxide (0.1 g) at room temperature. The mixture is stirred at the same temperature for 30 minutes, and the resulting mixture is poured into ice water and then acidified with conc. sulfuric acid. The mixture is extracted with dichloromethane, and the solvent is distilled off. The resulting residue is crystallized by adding thereto ethyl acetate, and then recrystallized from chloroform-methanol to give 1-cyclopropyl-7-(4-hydroxy-1-piperidyl)-6-fluoro-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylic acid (0.16 g), as pale yellow crystals, m.p. 234°-236° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (18.6 g, 164 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)benzonitrile (20 g, 136 mmol) and triethylamine (20.6 g, 204 mmol) in DCM (200 mL) at 0° C. The reaction mixture was stirred at rt until the reaction was complete (as indicated by tlc). Water (200 mL) was added and the organic layer was separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [C:1]([OH:4])#[C:2][CH3:3].[CH2:5]([OH:8])[C:6]#[CH:7].[C:9]1([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:5]([OH:8])[C:6]#[C:7][C:3]#[C:2][CH2:1][OH:4].[C:9]1([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC#CO
Reactant: C#CCO
Agent: CCOC(=O)Nc1ccccc1
Product: OCC#CC#CCO

Procedure:
The monomer 2,4-hexadiyn-1,6-diol-monophenylurethane is synthesized by the unsymmetrical coupling reaction of propyne-1-ol and 2-propyne-1-ol-phenylurethane and is purified by recrystallization of the crude product from ethyl acetate/petroleum ether. Recrystallization of a 0.4 gm sample from 100 ml of a 10:90 acetone/petroleum ether solvent mixture by slow evaporation at room temperature gives approximately 5 cm long needle-like crystals which turn pink upon exposure to light.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16]CC)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:20]>CO>[CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH2:20])=[O:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(Cc2ccccc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(N)=O)nn1Cc1ccccc1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-benzyl-5-methyl-1H-pyrazole-3-carboxylate (57.57 g, 0.236 mol), concentrated ammonium hydroxide (114 mL), and methanol (114 mL) was heated at 125° C. for 39 hours in a pressure vessel. After cooling to ambient temperature, the vessel was placed in an ice bath and the reaction solution was stirred for 30 minutes until a precipitate formed. The precipitate was isolated by filtration and washed with water to yield 28.22 g of 1-benzyl-5-methyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH:33]5[N:35](C(OC(C)(C)C)=O)[CH:30]([CH2:31][CH2:32]5)[CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:30]12[NH:35][CH:33]([CH2:32][CH2:31]1)[CH2:34][CH:28]([C:25]1[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=1)[CH2:29]2
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
tert-Butyl 3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.911 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (1 mL) was added and the reaction was stirred for 45 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (438 mg, 0.870 mmol, 95.5% yield).
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCOCC2)cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 3.0 g (9.1 mMol) (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-carbamic acid methyl ester in 15 ml toluene was added at room temperature over 15 minutes to a solution of 13 ml (46 mMol) Red-Ale® (70% in toluene) and 15 ml toluene. After 2 hours at 50° C., the reaction mixture was cooled to 0° C. and 25.5 ml aqueous NaOH 1N were added over 10 minutes (very exothermic). The phases were separated and the aqueous phase extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated. The residue was crystallized from n-heptane at −10° C. to yield 2.3 g (88%) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine as a light beige powder of m.p.=73.5-76° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1C=C(NC2C=CC=CC=2)C=CC=1.N1C=CC=CC=1C=O>>[CH2:19]([C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:20]
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: CCc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-methylphenylaniline (32.1 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH3:25])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1)(=[O:25])=[O:24]
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.30 g) and pyridine (8 mL) was added 2-methylbenzenesulfonyl chloride (0.26 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.38 g, yield 73%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 255-256° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(OC(F)(F)F)ccc2nc(Cl)sc12
Temperature: 60 °C

Procedure:
10 g of 2-chloro-6-trifluoromethoxybenzothiazole are added dropwise over one hour to a mixture, cooled to 10° C., of concentrated sulphuric acid (50 cm3) and concentrated nitric acid (25 cm3). The mixture is then heated for one hour at 60° C. After cooling, the mixture is poured into an ice/water mixture (1/1 by weight) and extracted with 3 times 100 cm3 of chloroform. The organic phases are dried over magnesium sulphate and concentrated under vacuum (2.7 kPa). The residue is purified by flash chromatography with a chloroform/cyclohexane mixture (4/6 by volume) as eluent. 6.4 g of 2-chloro-7-nitro-6-trifluoromethoxybenzothiazole are thus obtained, melting at 64° C.