Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:14]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:24][CH:23]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccnc1
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of imidazole (170 mg) and triethylamine (350 ml) in DMF (1 ml), a solution of methyl 2-bromo-2-(4-chlorophenyl)-acetate (657 mg) in DMF (3 ml) was added. After stirring for an overnight, water was added to the reaction liquid, followed by extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate. The reaction liquid was condensed under reduced pressure and the resulting residue was purified on silica gel column chromatography (methanol/chloroform=1/10) to provide methyl 2-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-acetate (400 mg) as a yellow oily substance.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([O-])(O)=O.[Na+].[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:23]([C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([CH2:13][C:4]3[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:11][C:10]([CH3:12])=[C:9]4[C:5]=3[CH:6]=[CH:7][NH:8]4)=[N:15][C:16]=2[CH:22]=1)#[N:24]
Reactant: Cc1cc(CN)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-((5-(aminomethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.063 mmol) in CH2Cl2 (1 mL)/5% aq. NaHCO3 (2 mL) was added acetyl chloride (45 μL, 0.634 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction was quenched by methylamine in EtOH (33%, 2 mL), and then stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with H2O and brine, dried over Na2SO4, and filtered. After concentration the residue was purified by silica gel flash column chromatography (CH2Cl2/2M NH3 in MeOH=94/6) to give the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.16 (br. s., 1H), 8.47 (t, J=5.31 Hz, 1H), 8.10 (s, 1H), 7.69 (d, J=8.30 Hz, 1H), 7.65 (dd, J=1.00, 8.30 Hz, 1H), 7.30 (dd, J=2.80, 3.00 Hz, 1H), 6.91 (s, 1H), 6.49 (dd, J=1.80, 3.00 Hz, 1H), 4.64 (s, 2H), 4.42 (d, J=5.31 Hz, 2H), 2.45 (s, 3H), 1.79 (s, 3H). HRMS calcd. for C21H19N5O (M+H)+ 358.1662. found 358.1660.
Reaction SMILES: O1CCCC1.[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Li+:26]>O>[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)[CH2:8][C:9]([O-:11])=[O:10].[Li+:26]
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a tetrahydrofuran (350 ml) solution of Example 34A (5 g, 18.17 mmol) is added lithium hydroxide (435 mg, 18.17 mmol) in water (150 ml). The solution is stirred at room temperature for 4 hours, and then concentrated to afford a white solid. The product is used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[C:22](O)=[O:23]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: COc1cc(OC)cc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)c1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,5-dimethoxybenzoic acid
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][CH2:18][C:19](O)=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][CH2:18][C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1cccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 18.8 %

Procedure:
To a solution of 1-aminopyrrole (2.46 g) and carbobenzyloxyglycine (6.28 g) in 120 ml of dry DCM and 10 ml of dry dimethylformamide was added DDC (8.00 g). The reaction mixture was stirred at room temperature over a period of 64 hours. The precipitate was removed by filtration and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) yielding a first fraction (2.97 g) which was contaminated by DCU. A second fraction recrystallized from ethyl acetate afforded 1.54 g of the product as crystals, m.p. 146°-147° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([CH2:12]Cl)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[Cl:2][C:3]1[N:4]([CH2:12][S:21][C:19]2[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cc(O)nc(S)n1
Reactant: ClCn1nc2ccccc2c1Cl
Agent: [Ag+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCn2nc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
3-chloro-2-(chloromethyl)-2H-indazole hydrochloride (285 mg, 1.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (142 mg, 1.0 mmol), and silver carbonate (550 mg, 2.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. The solid was filtered. The solution was evaporated, and the crude product was purified by column chromatography to provide the titled final product (15 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.34 (s, 3H), 6.05 (s, 1H), 6.22 (s, 2H), 7.25 (t, 1H), 7.48 (t, 1H), 7.67 (d, 1H), 7.74 (s, 1H); M+307.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:12]3=[C:11]([C:28](=[O:39])[NH:29][C@@H:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:31]([NH:33][CH3:34])=[O:32])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][NH:17][CH2:18][C:12]3=[C:11]([C:28]([NH:29][C@@H:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:31]([NH:33][CH3:34])=[O:32])=[O:39])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CN(C(=O)OC(C)(C)C)CC(C)(C)C2)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CNCC(C)(C)C2)C(C)(C)C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
The product from step 1 above (128 mg, 0.23 mmol) was dissolved in 2 mL of DCM and carefully treated with 2 mL of TFA. The mixture was stirred for 45 minutes and concentrated in vacuo. The residue was suspended in 5 mL of toluene and concentrated in vacuo. The residue was dried in a vacuum oven overnight to give the title compound (182 mg, 99%) as a poly-TFA salt. LCMS (+ESI) m/z: 448.3 [MH]+1
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Nc2ccccc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(Nc2ccccc2)nc1-c1ccc(C)cc1
Yield: 62.6 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(phenylamino)-6-p-tolylpyrimidin-5-yl)pentanoate (0.058 g; 0.149 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.035 g (62%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1>>[CH2:12]([CH:11]([NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:28])[N:3]=[C:4]([S:16][CH3:17])[N:5]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O
Product: CCC(CC)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title compound 4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.92 (m, 6H), 1.54-1.71 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 4.28 (m, 1H), 6.63-7.05 (m, 2H), 7.21 (m, 1H), 9.05 (br s, 1H), 10.50 (s, 1H). LC MS (m/e)=348 (MH+).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH2:11][CH2:12][CH3:13])[CH:20]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 44.4 %

Procedure:
The title compound (0.273 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.2 mmol) and 3-propoxyphenylboronic acid (0.521 g, 2.9 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.44-7.39 (m, 3H), 7.27 (t, J 7.9, 1H), 7.16-7.10 (m, 2H), 5.51 (s, 2H), 3.97 (t, J 6.5, 2H), 1.75-1.70 (m, 2H), 0.98 (t, J 7.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(Cl)Cl.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18].[OH-].[Na+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:29]([NH:28][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:17]([O:16][CH3:15])=[O:18])(=[O:27])=[O:26])=[O:30])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture containing 1.6 g of 2-amino-4,6-dimethoxypyrimidine, 30 ml of anhydrous methylene chloride and 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate was stirred at ambient temperature and pressure for 16 hours. It was then filtered to remove unreacted amine and the filtrate evaporated at temperatures up to 40° and reduced pressure. The residue thus obtained was stirred in 25 ml of water, the pH adjusted to 10 by the addition of 50% aqueous sodium hydroxide and the solution filtered. Acidification of the filtrate to pH 3 caused the formation of a precipitate. Filtration and drying the precipitate yielded 1.7 g of the desired product, melting at 185°-190°. Its infrared absorption peaks at 1700 and 1710 cm-1 are consistent for the desired structure and the nuclear magnetic resonance absorption peaks at 3.8 and 3.85 are consistent for the two different types of methoxy groups brought together in this product.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].C1(O)C=CC=CC=1.[BrH:26]>C(O)(=O)C>[BrH:26].[CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2]
Reactant: CC[C@H]1COCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: CC[C@H]1COCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-ethyl-4-tosylmorpholine (220 mg, 0.82 mmol) and phenol (150 mg, 1.6 mmol) were dissolved in 4.1 M of hydrogen bromide in acetic acid (2.4 mL) and the solution was stirred at room temperature overnight. The reaction was poured on ether and the solid was collected by filtration and washed with ether to give (S)-3-ethylmorpholine hydrobromide (j-1) as a white solid: 1H NMR (400 MHz, CDCl3) δ 3.77-3.60 (m, 3H), 3.60-3.44 (m, 2H), 3.44-3.19 (m, 3H), 1.67 (dtd, J=28.6, 14.0, 7.4 Hz, 2H), 1.31-1.12 (m, 2H), 0.97-0.84 (m, 3H).
Reaction SMILES: C[Mg]I.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.O>ClCCCl>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]I
Solvent: ClCCCl
Solvent: O
Product: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium iodide (3 M in diethyl ether, 30.7 mL, 92.02 mmol) was added over 20 min to a solution of 1H-indole (7.19 g, 61.35 mmol) in DCE (25 mL) under nitrogen at 0° C. 2,4-Dichloro-5-methylpyrimidine (10 g, 61.35 mmol) in DCE (20 mL) was then added slowly to the reaction mixture over 20 min at 0° C. and the reaction mixture was stirred for an additional 30 min at 0° C. The reaction mixture was then allowed to warm up to RT and stirred at 30 min. The reaction mixture was then cooled to 0° C. and water (50 mL) was slowly added. The resultant yellow solids were collected by vacuum filtration. The solids were then suspended in 10% aqueous citric acid solution (150 mL) and stirred for 10 min, filtered, then washed with water and diethyl ether to give the title product. (8.10 g, 54.2%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.Cl>CN(C=O)C.CCOCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: Fc1ccccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Oc1ccc2cc(OCc3ccccc3F)ccc2c1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A stirred solution of 15.0 g (94.0 mM) of 2,6-dihydroxynaphthalene in 60 mL of DMF was treated with 3.21 g (80.0 mM) of NaH under nitrogen. The resulting dark solution was treated dropwise with a solution of 5.94 g (31.0 mM) of 2-fluorobenzyl bromide in 20 mL of Et2O over 0.75 h. The mixture was stirred an additional 2 h then treated cautiously with 200 mL 1N HCl. The mixture was stirred 8 to 16 hours then filtered. The solid was washed thoroughly with water and dried. Flash chromatography produced a solid which was recrystallized from i-PrOH to afford 4.51 g (56%) of product as gray crystals mp 143-144° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])C1C=CC=CC=1>[Pd].C(O)C>[CH2:13]([O:12][C@H:10]([CH3:11])[CH2:9][OH:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCO[C@H](C)COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCO[C@H](C)CO
Yield: 72.5 %

Procedure:
A mixture liquid of the above (R)-1-benzyloxy-2-hexyloxy-propane (25 g),palladium/carbon catalyst (2.0 g) and ethanol (200 ml) was subjected to hydrogenolysis. After completion of the reaction, the catalyst was filtered off, followed by concentrating the mother liquor, and distilling the concentrate under reduced pressure to obtain (R)-2-hexyloxy-1-propanol (b.p. 67°-68° C./4 mmHg) (11.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15]O)[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:15][C:13]1[CH:12]=[C:11]([O:17][CH3:18])[C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([Cl:1])[CH:14]=1
Reactant: CCOC(=O)COc1c(Cl)cc(CO)cc1OC
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCOC(=O)COc1c(Cl)cc(CBr)cc1OC
Yield: 77 %

Procedure:
The compound was prepared according to general procedure G with ethyl 2-(2-chloro-4-(hydroxymethyl)-6-methoxyphenoxy)acetate (1.3 mmol) in dichloromethane (12 ml) and PBr3 (1.3 mmol). 338 mg of compound were obtained (78% yield). This compound was used without further purification. 1H NMR (250 MHz, CD3OD): δ 1.29 (m, 3H), 3.83 (s, 3H), 4.15 (m, 2H), 4.55 (s, 2H), 4.94 (s, 2H) 6.80 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H). MS (ESI): m/z 336.9 [M−H]−, 360.8 [M+Na]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=[O:25].C[O-].[Na+:29]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([O-:26])=[O:25].[Na+:29]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(CC(=O)[O-])c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.33 h

Procedure:
5-fluoro-2-methyl-1-(ρ-methylsulfonylbenzylidene)-3-indenylacetic acid (1.79 g.) in methanol (10 ml.) is added to a solution of sodium methoxide (0.27 g.) in methanol (5 ml.). The reaction mixture is stirred for 20 minutes and evaporated to dryness to yield sodium 5-fluoro-2-methyl-1-(ρ-methylsulfonylbenzylidene)-3-indenylacetate.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:11]=1)=[O:14]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(S(C)(=O)=O)cc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(C)(=O)=O)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (90 mg, 0.250 mmol), DMSO(2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70.9 mg, 0.376 mmol), N-methylmorpholine (0.110 mL, 1.002 mmol), 1-hydroxy-7-azabenzotriazole (68.2 mg, 0.501 mmol) and EDC (96 mg, 0.501 mmol). The final product was collected as 106 mg (85%). LCMS E-S (M+H)=494.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=5.6 Hz, 6 H), 2.13 (br. s., 3 H), 2.23 (br. s., 3 H), 4.42 (m, 2 H), 5.36 (br. s., 1 H), 5.91 (br. s., 1 H), 8.11 (d, J=7.3 Hz, 2 H), 8.27 (br. s., 1 H), 8.39-8.64 (m, 3 H), 9.01 (br. s., 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])[CH2:13][N:12]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:10])[CH2:3]1.[ClH:55]>O1CCCC1.O>[ClH:55].[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([OH:24])=[O:23])[CH2:13][NH:12]2)=[O:10])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C[C@H](C)N1

Procedure:
The whole of the 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-(cis-3,5-dimethyl-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate prepared as described in step (a) above was dissolved in 4 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 261 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 0.2 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 27 mg of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]#[N:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([NH:23][C:24]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Cl:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([C:11]#[N:12])=[C:5]2[CH2:10]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#Cc1c(-c2ccccc2)c(Cl)n2c1CNCC2
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 34 g (119 mmol) of 6-chloro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in 300 ml of dichloromethane are added 16.3 ml (143 mmol) of tert-butyl isocyanate (CAS1609-86-5). After stirring for 4 hours at room temperature, the solvent is evaporated off under reduced pressure to give an orange-coloured solid, which is crystallized from acetonitrile to give 40.0 g of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in the form of a yellow powder after filtering off and drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[N:11]=1)[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[N:11]=1)[C:8](=[O:13])[N:7]([CH3:16])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Cl)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,8-dichloro-2,7-naphthyridin-1(2H)-one (215.0 mg, 1.0 mmol) in dry DMF (10 mL) was added NaH (100 mg, 60% in mineral oil, 2.5 mmol) at 0° C. under N2. After the reaction mixture was allowed to be warmed to room temperature and stirred for 20 minutes, CH3I (0.25 mL, 568.08 mg, 4.0 mmol) was added via syringe. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NH4Cl solution (2×50 mL), water (30 mL) and brine (20 mL), and concentrated to afford the crude title compound. ESI-MS m/z 229.0 (MH+).