Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C=O)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A solution of 6-methoxy-3-pyridine carboxaldehyde (100 mg, 0.73 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.82 mmol, 339 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.69 mmol, 44 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the product (168 mg, 75%) as a colourless oil; δH (500 MHz, CDCl3) 1.47 (s, 9H, C(CH3)3), 2.00 (s, br, 2H, piperazine NCH2), 2.39 (t, J=4.7 Hz, 2H, piperazine NCH2), 3.43 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.45 (s, 2H, CH2), 3.94 (s, 3H, OCH3), 6.73 (d, J=8.4 Hz, 1H, methoxypyridine H-5), 7.57 (dd, J=8.5, 2.4 Hz, 1H, methoxypyridine H-4), 8.05 (d, br, J=2.3 Hz, 1H, methoxypyridine H-2);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[C:5]([F:12])=[CH:4][N:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:12])=[CH:4][N:3]=1
Reactant: CC(C)(O)c1cc(Br)ncc1F
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (24.7 g, 106 mmol) and methanesulfonic anhydride (55.1 g, 317 mmol) in DCM (250 ml) was added triethylamine (58.8 ml, 42.7 g, 422 mmol). The reaction mixture was stirred at rt for 20 h. Another 1 eq. (18 g) of methanesulfonic anhydride and 1.2 eq. (17 ml) of triethylamine were added and the reaction mixture was stirred an additional 20 h at rt. The reaction mixture was quenched with 1M aq. Na2CO3 sol. and diluted with DCM. The phases were separated and the aq. phase was reextracted twice with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (hexane:EtOAc 8:1) yielded the title compound as a clear colourless liquid. HPLC RtH4=1.12 min; ESIMS: 216, 218 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, 1H), 7.40 (d, 1H), 5.48-5.44 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]#[N:13])=[C:6]2[NH:5][CH2:4]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:31]>>[OH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]([NH2:13])=[O:31])=[C:6]2[NH:5][CH2:4]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2

Procedure:
The desired product was prepared form 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 364.9.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[I-].[CH3:11][S+](C)C.[OH-].[K+]>CC#N.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[CH2:11][O:9]2)[N:7]=1
Reactant: C[S+](C)C
Reactant: O=Cc1cccc(F)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1cccc(C2CO2)n1
Temperature: 67.5 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 6-fluoro-pyridine-2-carbaldehyde (1.88 g, 15 mmol), trimethylsulfonium iodide (3.3 g, 16.2 mmol) and KOH (crashed, 3.46 g, 61.9 mmol) in CH3CN (190 mL, containing 0.2 mL of water) was stirred at 65-70° C. under N2 for overnight. The mixture was cooled to rt and diluted with EtOAc (100 mL). After filtration, the filtrate was concentrated. The residue was portioned between H2O (100 mL) and EtOAc (80 mL), the aqueous layer was further extracted with EtOAc (4×80 mL). the combined EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (530 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12]CC2C=CC(OC)=CC=2)[C:6]=1[CH3:22])(=O)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[CH3:22][C:6]1[C:7]([SH:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[OH:4]
Reactant: COc1ccc(CSc2cc(C)cc(OC(C)=O)c2C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O)c(C)c(S)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a mixture of 3-((4-methoxybenzyl)sulfanyl)-2,5-dimethylphenyl acetate (509.1 mg) and anisole (1.5 mL) was added TFA (5.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and warmed to room temperature. Then the mixture was stirred at room temperature for 4 h. The mixture was concentrated. The residue was neutralized with 1N NaOH, and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (128 mg).
Reaction SMILES: [OH-].[Na+].[ClH:3].Cl.[CH3:5][N:6]([CH3:15])[CH2:7][CH:8]([CH3:14])[CH2:9][S:10]C(=N)N>O>[ClH:3].[CH3:5][N:6]([CH3:15])[CH2:7][CH:8]([CH3:14])[CH2:9][SH:10]
Reactant: CC(CSC(=N)N)CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CS)CN(C)C
Temperature: 95 °C
Yield: 73.1 %

Procedure:
A solution of sodium hydroxide (19.3 g) in water (20 ml) was added dropwise at 0° C. to a stirred solution of S-[3-(dimethylamino)-2-methylpropyl]isothiourea dihydrochloride (60 g) in water (100 ml). The stirred mixture was heated at 95° C. for 2 hours and allowed to cool. The product was extracted into ether (4×70 ml), the combined extracts dried over sodium sulphate and the solvent removed in vacuo. The residual oil was dissolved in ether and the solution saturated with hydrogen chloride. The resulting solid was collectedby filtration, washed with ether, and dried in vacuo over phosphorus pentoxide for 24 hours to give 3-(dimethylamino)-2-methylpropanethiol hydrochloride as a white solid (30 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:5]2[CH2:4]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCN1CCn2nc([N+](=O)[O-])cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 208a (1.4 g, 7.1 mmol), 10% palladium on carbon (50% wet, 208 mg), methanol (30 mL), and hydrogen gas. The mixture was stirred at room temperature under hydrogen atmosphere for 2 h. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 208b (1.0 g, 84%) as yellow oil. MS-ESI: [M+H]+ 167
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1>ClCCl.CO.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNc2ccc(F)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: O=c1cnc2ccc(F)cc2[nH]1
Yield: 47.7 %

Procedure:
A solution of 7-fluoro-3,4-dihydro-2(1H)-quinoxalinone (15.65 g, 92.88 mmol) in dichloromethane/methanol (1:1, 600 mL) was stirred with manganese dioxide (78.25 g) at room temperature for 1.5 h. The mixture was filtered through kieselguhr, washing through several times with 10% methanol/dichloromethane (˜1 L), and the filtrate was evaporated to give the product (7.27 g). Extraction of the residual filtration solids several times with dimethylformamide at 60-70° C., followed by filtration and evaporation of the extracts, gave more product (6.66 g), the total yield being 13.93 g (91.5%).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
The resulting ester compound and 0.07 g of 10% palladium-on-carbon were added to ethanol to conduct debenzylation in a hydrogen atmosphere to obtain 0.48 g of 1,1,1-trifluoro-2-octyl 4-hydroxybenzoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20]([O:22]C)=[O:21])[CH:11]=1)#[N:2].C(O)C.O1CCOCC1.[OH-].[Na+]>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A round-bottom flask was charged with dimethyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate (1.5 g, 4.4 mmol), ethanol (100 mL), 1,4-dioxane (20 mL), and a solution of sodium hydroxide (0.17 g, 4.4 mmol) in water (10 mL). The mixture was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure, and the residue was acidified with 1N aq. HCl to pH=4 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The residue was purified via flash chromatography to afford the desired product 2′-cyano-5-(methoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): 13.58 (br, 1H), 8.56 (t, J=1.3 Hz, 1H), 8.34-8.31 (m, 2H), 7.85 (s, 1H), 7.65 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 2.42 (s, 3H). 3-Ethyl 5-methyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate was also isolated as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]([NH2:7])[CH3:6].N1C=CC=CC=1.[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1COCC1>[Cl:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH3:2])=[O:19]
Reactant: O=C=NCCCl
Reactant: COC[C@@H](C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC[C@H](C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of (R)-1-methoxypropan-2-amine hydrochloride (500 mg, 3.98 mmol) and pyridine (315 mg, 3.98 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethylisocyanate (420 mg, 3.98 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, partitioned between EtOAc and brine and the organic layer dried over Na2SO4 and concentrated to dryness to afford (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 6.08 (s, 1 H), 5.93 (d, J=8.1 Hz, 1 H), 3.71 (m, 1 H), 3.56-3.51 (m, 3 H), 3.30-3.23 (m, 3 H), 3.22 (s, 3 H), 0.98 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][N:12]=[C:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C1CCOCC1
Product: Cc1ccc(S(=O)(=O)NN=C2CCOCC2)cc1
Yield: 40.2 %

Procedure:
A solution of 4-methylbenzenesulfonohydrazide (819 mg, 4.4 mmol) and dihydro-2H-pyran-4(3H)-one (487 μl, 5.28 mmol) was stirred in a Dean-Stark apparatus at 120° C. for 24 hours. The reaction mixture was cooled and evaporated at reduced pressure. The residue was purified by chromatography using a gradient of dichloromethane/ethyl acetate=100:0 to 80:20 as the eluent to give the 4-methyl-N′-(2H-pyran-4(3H,5H,6H)-ylidene)benzenesulfonohydrazide (475 mg, 40% yield) as an off white solid. MS (ISP): m/z=269.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][N:16](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:11]([F:14])([F:13])[C:4]1[CH:3]=[C:2]([C:15]#[N:16])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]cnc2c1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cc2nc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A red suspension of 7-Bromo-5-(trifluoromethyl)-1H-benzo[d]imidazole (270 mg, 1.02 mmol), zinc cyanide (1.12 mmol), and PdCl2(dppf) (0.06 mmol) in Water (3 ml) and dimethylformamide (10 ml) was heated with stirring under argon for 2 h. At the end, LC-MS analysis revealed completion of the reaction. The reaction mixture was cooled to ambient temperature and was subjected to preparative HPLC (8 injections using HPLC method 14). Fractions containing the required product were combined and evaporated in vacuo to give 97 mg (45% yield). 1H NMR (CD3OD, 500 MHz) δ 7.88 (s, 1H), 8.21 (s, 1H), 8.54 (s, 1H); IR (KBr) 2229 (CN stretching); LC/MS (HPLC method 9): tR=1.8 min, 212(MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1.CN1CCOCC1.[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31]>CN(C=O)C>[OH:31][CH2:30][C@@H:29]([NH:28][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C#N)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 67.4 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile (0.7 g, 2.19 mmol) in DMF (15 mL) were added N-methylmorpholine (0.66 g, 6.57 mmol) and (S)-(−)-2-amino-3-phenyl-1-propanol (0.40 g, 2.63 mmol). The reaction mixture was heated to 80° C. for 6 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (3% MeOH/CH2Cl2) to yield the title compound (0.59 g, 68%) as a yellow foam. 1H NMR (400 MHz, CD3OD) δ 7.74 (1H, s), 7.63 (1H, s), 7.12–7.27 (6H, m), 6.07 (1H, d, J=7.5 Hz), 3.97 (1H, m), 3.74 (2H, t, J=5 Hz), 3.14 (1H, dd, J=5.5, 14.0 Hz), 2.94 (1H, dd, J=7.9, 14.0 Hz), 2.60 (3H, s). LCMS (M+H)+ m/z 400 (t=1.71 min.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:18][C:19]1([CH2:22][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][O:20]1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Reactant: CC1(CCl)CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Temperature: 72.5 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
A mixture of N-(2-hydroxyphenyl)benzamide (159 mg; 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31])#[N:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31])#[N:25]
Reactant: N#Cc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C#N
Yield: 86.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-cyanocinnamic acid (2.1 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.2 g, 86%) as crystals.
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]1[CH:37]=[CH:36][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]3[C:19](=[O:30])[CH2:20][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])([CH3:23])[O:22][C:17]=3[C:16]=2[CH2:33][CH2:34][CH3:35])=[C:8]([CH2:38][CH2:39][CH3:40])[C:7]=1[OH:41])(=[O:5])[CH3:4]>O.O1CCCC1.CO>[C:3]([C:6]1[CH:37]=[CH:36][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]3[C:19](=[O:30])[CH2:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH3:23])[O:22][C:17]=3[C:16]=2[CH2:33][CH2:34][CH3:35])=[C:8]([CH2:38][CH2:39][CH3:40])[C:7]=1[OH:41])(=[O:5])[CH3:4]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)OC)CC3=O)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)O)CC3=O)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A solution of 0.5 g (9.5 mmole) of lithium hydroxide in 10 ml of water was added to a solution of 2.2 g (3.9 mmole) of the title compound of Example 6 in 25 ml of tetrahydrofuran and 20 ml of methanol. After the reaction mixture was stirred for 3 hours at room temperature, the solvent was evaporated and water was added to the residue. After extracting with a small amount of diethyl ether, the aqueous layer was acidified with dilute hydrochloric acid and allowed to stand in the cold overnight. The solid was filtered, washed with water and recrystallized from ethyl acetate/hexane to yield 1.83 g of the title compound, mp. 80°-83°. Structure assignment was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl3) loss of ester CH3 (compare Example 6)
Reaction SMILES: BrCCCCBr.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][Br:32])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][Br:32])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Solvent: BrCCCCBr
Product: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 1,4-dibromobutane as described for compound 58. M.p. 105°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1.[Cu]I>[CH:10]1([C:13]#[C:14][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: C#CC1CC1
Reactant: Nc1ccc(F)cc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(NC#CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is treated with PdCl2(PPh3)4 (177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane to afford 2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH2, 2H), 1.49 (m, 1H), 0.82 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][CH2:20][CH2:21][O:22][CH3:23])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][CH2:20][CH2:21][O:22][CH3:23])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: COCCSc1ncnc2cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: COCCSc1ncnc2cc(O)ccc12
Yield: 100.2 %

Procedure:
A solution of 7-benzyloxy-4-(2-methoxyethylsulphanyl)quinazoline (8 g, 24.5 mmol) in TFA (80 ml) was refluxed for 5 hours. After cooling and removal of the volatiles by evaporation, the residue was triturated with water, collected by filtration, washed with water and then ethyl acetate. The residue was resuspended in methylene chloride, filtered, washed with petroleum ether and dried under vacuum to give 7-hydroxy-4-(2-methoxyethylsulphanyl)quinazoline (5.8 g, quant.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]3=[O:16])=[CH:6][N:5]2[CH:17]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]=[C:26]=[S:27].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH3:24][NH:25][C:26]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:17]=[C:2]([CH3:1])[N:3]=3)[CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])=[S:27]
Reactant: CN=C=S
Reactant: Cc1cn2cc(C3CCCCC3=O)ccc2n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=S)C1(c2ccc3nc(C)cn3c2)CCCCC1=O
Yield: 78.4 %

Procedure:
In a nitrogen atmosphere, a solution of 35.79 g (0.157 mol) of the 2-(2-methylimidazo[1,2-a]pyridin-6-yl)cyclohexanone prepared in the Preparative Example 2 in 550 ml of tetrahydrofuran was cooled with ice, followed by the addition of 19.55 g (0.174 mol) of potassium t-butoxide. The obtained yellow solution was stirred under cooling with ice for one hour, followed by the addition of a solution of 11.8 ml (0.173 mol) of methyl isothiocyanate in 50 ml of tetrahydrofuran and 50 ml of N,N-dimethylformamide in this order. The obtained reaction mixture was stirred under cooling with ice for one hour, followed by the addition of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with chloroform. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. In the course of the concentration, a crystal began to precipitate. This crystal was recovered by filtration. 37.09 g of the title compound was obtained as a colorless crystal. Further, the mother liquor (14.5 g) was purified by silica gel column chromatography [solvent: dichloromethane/methanol (100:3)] and recrystallized from dichloromethane/ethyl acetate to give 3.21 g of the title compound as a pale-pink crystal. Thus. 40.3 g of the title compound was obtained in total (yield: 85%).