Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CCO>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:19][CH:18]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Product: Clc1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 4-chlorobenzylchloride (0.242 mg, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1C(=O)OC(C)(C)[O:8][C:7]1=[O:15].O.C(OCC)(=O)C>CN(C=O)C>[OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH2:5][CH2:6][C:7]([OH:15])=[O:8])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(O)cccc1CC1C(=O)OC(C)(C)OC1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)cccc1CCC(=O)O
Temperature: 90 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
To a solution of 5-(3-hydroxy-2-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (100 mg) in DMF (10 mL) was added water (1.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (50 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)C1CCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C1CCNC1=S
Reaction time: 1 h
Yield: 111.6 %

Procedure:
1.7 g of tert-butyl 2-oxopyrrolidine-3-carboxylate and 1.8 g of Lawesson's reagent were added to 20 ml of benzene and stirred at 50° to 60° C. for 1 hour. After filtering the insoluble matters the solvent was distilled off and the obtained residue was purified by silica gel chromatography to thereby give 1.0 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5](SC)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH3:49][NH2:50].C1COCC1>ClCCl.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5]([NH:50][CH3:49])[N:4]=1
Reactant: CN
Reactant: CNc1nc(SC)nc2c1C(=O)N(c1cccc(-c3nn(C)c(=O)o3)c1)C[C@@H]1CCCN21
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNc1nc(NC)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
(S)-5-[3-(7-Methylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (17.6 mg, 0.0388 mmol) obtained in Step 9 was dissolved in dichloromethane (2.5 mL), and the mixture was stirred at room temperature for 30 minutes after adding 3-chloroperbenzoic acid (20.5 mg, 0.0582 mmol). A saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in THF (2.0 mL), and the mixture was stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L methylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (Compound 156) (8.0 mg, 47%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][NH2:31])=[O:29])[N:27]=1)(=[O:21])=[O:20]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][N:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:29])[N:27]=1)(=[O:20])=[O:21]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1csc(CS(=O)(=O)Cc2ccco2)n1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1csc(CS(=O)(=O)Cc2ccco2)n1
Temperature: 100 °C
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-{[(2-furylmethyl)sulfonyl]methyl}-1,3-thiazole-4-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 32 mg of the title compound (63%) as a yellow solid in 99.3% purity by HPLC (Rt: 4.8, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)-phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C([C:36](OO)=[O:37])C=1.S(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([O:37][CH3:36])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
62.8 mg (0.153 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 52.7 mg (0.305 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol and excessive amounts of 295 mg (1.53 mmol) of sodium methoxide (28% methanol solution) was added at room temperature and stirred at 60° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17](OS(C)(=O)=O)[C:18]([F:21])([F:20])[F:19])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH2:17][C:18]([F:21])([F:19])[F:20]
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(OS(C)(=O)=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc(=O)c(O)c1CC(F)(F)F
Yield: 9.7 %

Procedure:
A mixture of methanesulfonic acid 1-(3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (2.80 g, 7.15 mmol) and 10% Pd/C (0.56 g) in ethyl alcohol was subjected to hydrogenation in a Parr apparatus under 50 psi hydrogen pressure for 90 min. The mixture was filtered through a pad of CELITE™, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of isopropyl alcohol and a conc. NH4OH solution (90/10, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness, thereby affording 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (first crop: 143 mg, 9.7% yield, second crop: 240 mg, 16.2% yield). 1H NMR (90 MHz, CD3OD) δ (ppm): 7.66 (d, J=7.2 Hz, 1H), 6.41 (d, J=7.4 Hz, 1H), 3.89 (q, J=10.2 Hz, 1H) and 3.82 (s, 3H); MS-ESI (m/z): 208 [M+1]+, 188.2, 168.2. HPLC purity (peak area percent) of both fractions are about 98% at λ=254 nm, RT=3.75 min (HPLC method is described in Part A above).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([OH:14])=O)[C:7]#[CH:8].C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:47](=[O:48])[N:32]2[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]3[S:40][CH:41]=[N:42][N:43]=3)[CH2:35][S:36][C@H:31]12>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH2:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([NH:29][CH:30]1[C:47](=[O:48])[N:32]2[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]3[S:40][CH:41]=[N:42][N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:14])[C:7]#[CH:8]
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
Phosphorus oxychloride (0.96 g.) was added at a time to a suspension of 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (1.13 g.) in dry tetrahydrofuran (10 ml.) at 2° C. and the mixture was stirred for 15 minutes at 2° to 4° C. Trimethylsilylacetamide (1.0 g.) was added dropwise thereto and the resulting mixture was stirred for 20 minutes at 2° to 6° C. Phosphorus oxychloride (0.96 g.) was added thereto and the mixture was stirred for 20 minutes. Dry dimethylformamide (0.45 g.) was added thereto at a time at 4° to 6° C. and the mixture was stirred for 1 hour to give a clear solution. On the other hand, trimethylsilylacetamide (4.6 g.) was added to a stirred suspension of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.65 g.) in dry ethyl acetate (20 ml.) and the solution was stirred for 30 minutes at 40° C. To this solution was added the above-obtained tetrahydrofuran solution at a time at -30° C., and the resulting mixture was stirred for 1 hour at -5° to -20° C. To the reaction mixture were added water (30 ml.) and ethyl acetate (20 ml.). An organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract was adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water to give 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.Cl.[F:12][C:13]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][NH:17]2>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[C:13]([F:12])[C:21]([F:22])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Product: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F

Procedure:
Analogously to (4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone this compound was prepared from 500 mg (3.17 mmol) 2-chloroisonicotinic acid and 1.0 eq 4,5-difluoroindoline hydrochloride.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:36])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([OH:35])[CH3:34])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:44]([Si:48](Cl)([CH3:50])[CH3:49])([CH3:47])([CH3:46])[CH3:45].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:36])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([O:35][Si:48]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:50])[CH3:49])[CH3:34])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 15 h

Procedure:
To a solution of 4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.86 g), triethylamine (1.1 mL) and 4-dimethylaminopyridine (0.15 g) in N,N-dimethylformamide (20 mL) was added tert-butyl(chloro)dimethylsilane (0.88 g), and the mixture was stirred for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.98 g, 86%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:4].I[CH2:30][CH3:31].[NH4+].[Cl-]>CN(C=O)C.CCCCCC>[CH2:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:3][CH3:4])[C:6]=1[C:13]1[CH:14]=[C:15]([O:27][CH3:28])[C:16]([CH:19]([O:20][CH2:30][CH3:31])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][N:18]=1)[CH3:12]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)c2ccccc2)cn1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(c1ccccc1)c1cnc(-c2c(CC)cccc2CC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% in mineral oil, 8 mg) is added to a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-phenyl-methanol (18 mg) in DMF (1 mL). The resulting mixture is stirred at room temperature for 15 minutes. The mixture is then treated with iodoethane (20 mg) and stirred at the same temperature for 1 hour. Aqueous NH4Cl solution (5 mL) and hexane (5 mL) are added to the mixture. The organic layer is separated, dried, and concentrated in vacuo. The crude product is purified by PTLC (4:1 hexane/EtOAc) to give 2-(2,6-diethyl-phenyl)-5-(ethoxy-phenyl-methyl)-4-methoxy-pyridine. 1H NMR (CDCl3) 8.66 (s, 1H), 7.45 (d, 2H), 7.35 (t, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 6.71 (s, 1H), 5.74 (s, 1H), 3.80 (s, 3H), 3.56 (q, 2H), 2.33 (m, 4H), 1.27 (t, 3H), 1.05 (m, 6H).
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]3=[N:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl>>[N:1]1([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2-n2cccn2)C1
Agent: Cl
Product: c1cnn(-c2nnc3n2CCNC3)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1,1-dimethylethyl 3-(1H-pyrazol-1-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I106) (24 mg, 0.083 mmol) and HCl (2 ml, 8.00 mmol) was stirred at room temp for 40 mins. The solvent was evaporated and the product was passed through SCX (elution with 2 M NH3 in methanol) to give the desired product as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography and ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (590 mg, yield: 75%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 81–82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][O:13][CH3:14])[NH:11][C:7]=2[C:6]([C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.O.NN.[OH-].[K+]>C(O)COCCO.ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][O:13][CH3:14])[NH:11][C:7]=2[C:6]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)Cc3ccncc3)c2[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: OCCOCCO
Product: COCc1nc2c(OC)ccc(CCc3ccncc3)c2[nH]1
Temperature: 100 °C
Yield: 108.1 %

Procedure:
A mixture of 1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone (0.92 g, Example 4), hydrazine hydrate (0.8 ml, 98%) and potassium hydroxide (1.6 g) in diethylene glycol (10 ml) was heated at 100° C. for 5 minutes. The resulting clear solution was the heated at 160° C. for 1 hour, then heated at 180° C. for 2 hours whilst removing water at intervals from an attached air condenser. The red solution was cooled to room temperature then poured into water (200 ml). The mixture was extracted three times with dichloromethane (100 ml). The combined extracts were dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (5:95, v/v). Fractions containing the required product were combined and evaporated. The resulting solid was combined with material similarly prepared from 0.47 g of 1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone and dissolved in dichloromethane (50 ml). The solution was washed with water (100 ml) then dried over magnesium sulphate and then evaporated. The residual white solid (1.03 g) was recrystallised from toluene to give the title compound (0.95 g) as a white solid, m.p. 154-156° C. [Elemental analysis:— C, 68.09; H, 6.43; N, 13.87%. Calculated:— C, 68.67; H, 6.44; N, 14.13%].
Reaction SMILES: [F:1][C:2]1[C:3]([N:19]2[C:28]3[C:23](=[C:24]([F:32])[C:25]([F:31])=[C:26]([F:30])[C:27]=3[F:29])[C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20]2)=[N:4][C:5]([NH:9]CC2C=CC(OC)=CC=2)=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>>[NH2:9][C:5]1[N:4]=[C:3]([N:19]2[C:28]3[C:23](=[C:24]([F:32])[C:25]([F:31])=[C:26]([F:30])[C:27]=3[F:29])[C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20]2)[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
To 1080 mg of ethyl 1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridine-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 4 ml of trifluoroacetic acid, and the mixture was allowed to stand at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and 4 ml of ethanol was added to the residue, and the solution was again concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol to obtain 960 mg of the title compound as a gray powder.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[OH:24][CH2:25][CH2:26][CH2:27][NH2:28].O.C(Cl)(Cl)Cl>O1CCOCC1>[OH:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1
Reactant: NCCCO
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(CCCNCCCO)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
3-(4-nitrophenyl)propyl p-toluenesulfonate (1 g) and 4.1 ml of 3-hydroxypropylamine were dissolved in 10 ml of dioxane and the solution was stirred at 80° C. for 30 minutes. To the solution was added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for separation. The chloroform-layer fraction was taken, washed with water and then dried over sodium sulfate anhydrous. The solvent was removed in vacuo and 0.7 g of an oil of N-(3-hydroxypropyl-3-(4-nitrophenyl)propylamine was obtained.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CCC[C@@H]1CO
Product: O=c1[nH]c(CCN2CCC[C@@H]2CO)cc2ccccc12
Yield: 11.6 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (4.975 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.0 g), (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (408.4 mg) was obtained.