Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[K+:5].[C:6]([O:13]CC)(=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.C(=O)=O>CC(C)=O>[C:7]([O:9][CH2:10][CH3:11])(=[O:8])[C:6]([O-:13])=[O:12].[K+:5]
Reactant: CCOC(=O)C(=O)OCC
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)[O-]
Temperature: 40 °C
Yield: 96 %

Procedure:
A suspension of potassium bicarbonate (100 g; 1.00 mols) in diethyl oxalate (146.1 g; 1.00 mols) is added with water (26 g) and heated at a temperature of 50÷55° C. for 6÷8 hours until carbon dioxide evolution ceases. The suspension is cooled to 40° C., added with acetone (250 mL) and cooled to 15÷20° C. The resulting solid is filtered, washed with acetone (2×25 mL) and dried at 50° C. under vacuum to obtain potassium monoethyl oxalate (150.0 g, 99% purity, yield 96%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:23][CH:22]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Fc1cnccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cnccc2C(F)(F)F)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
To a solution of 3-fluoro-4-trifluoromethylpyridine (1 g, 6.1 mmol) and [2-(4-hydroxyphenyl)-ethyl]-carbamic acid tert-butyl ester (1.44 g, 6.1 mmol) in DMSO (10 mL) was added K2CO3 (5 g, 36.2 mmol), and the mixture was heated at 100° C. for 30 min. After cooling, the solids were removed by suction filtration and washed with Et2O. The pooled filtrates were diluted with Et2O (75 mL) and washed with 0.01 N HCl. The organic layer was concentrated in vacuo. The residue was dissolved in Et2O/hexane and washed with 10% NaOH. The organic layer was filtered and vacuum dried to provide 1.4 g (60% yield) of {2-[4-(4-trifluoromethyl-pyridin-3-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:32][CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH2:37])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.31) (188 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/dichloromethane) as a yellow solid (220 mg, 79%). MS (ISP) 555.3 [(M+H)+]; mp 300° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:10]=1[O:11][CH:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:8].C(O)(=O)C>CN(C=O)C>[CH:17]([C:12]1([C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:8])[C:9]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:10]=2[O:11]1)([CH3:19])[CH3:18]
Reactant: COC(=O)C(Oc1c(C=O)cccc1OC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(C)C)Oc2c(OC)cccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Potassium t-butoxide (5.62 g) was dissolved in DMF (150 ml) and the obtained solution was cooled to 0° C. To this solution, methyl 2-(2-formyl-6-methoxyphenoxy)isovalerate (11.10 g) solution in DMF (50 ml) was added dropwise for 40 minutes, and the resulting solution was stirred for another 30 minutes. Acetic acid (4 ml) was added to the reaction solution and the solution was concentrated. The resultant was poured into water layer (300 ml) and extracted twice with ethyl acetate (150 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (250 ml). To this solution, Celite (70 g) and pyridinium dichromate (23.55 g) were added and the solution was stirred at room temperature for 19 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the solution was stirred for 15 minutes. Ether (200 ml) was added to the solution and the solution was filtered through Celite, followed by washing the obtained precipitate with ether (100 ml twice). The filtrate was concentrated and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1-3/1) using silica gel to obtain the desired compound (7.26 g, yield: 66%).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[C:27](=[O:29])=[O:28]>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[C:27]([OH:29])=[O:28]
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-BuLi (26.7 mL of 2.5M solution in tetrahydrofuran (THF), 66.7 mmol) in THF (130 mL) at −78° C. was added 2,2,6,6-tetramethylpiperidine (22.5 mL, 133.4 mmol). The mixture was stirred at −78° C. for 30 minutes and then carefully lowered to −100° C. using liquid nitrogen. Neat 1-bromo-4-(trifluoromethyl)benzene (15 g, 66.7 mmol) was added. The mixture was kept at −100° C. for 6 hours and poured onto freshly crushed dry ice. The resulting mixture was stirred at room temperature for 16 hours. The residue solvent was removed by evaporation. Water (150 mL) was added and the mixture was extracted with diethyl ether (3×50 mL). The aqueous layer was acidified using concentrated hydrochloric acid (HCl), extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) (75 ml), dried with magnesium sulfate (MgSO4), filtered and concentrated to yield the title compound as a white solid (5.41 g). 1H NMR (400 MHz, CDCl3) δ 7.7 (dd, J=8.4, 2.3 Hz, 1 H) 7.9 (d, J=8.4 Hz, 1 H) 8.3 (d, J=2.0 Hz, 1 H). MS (ES+) Calc: 267.93, Found: 266.7 (M−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([C@@H:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([C@@H:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:7]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cc(Cl)nc(N4CCCC4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To 22 mg (0.1 mmol) 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine in 1 mL THF are added 17 μL (0.1 mol) DIPEA and 25 mg (0.1 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)ethyl]-acetamide (V.1). The mixture is stirred at rt over night. The solvent is removed in vacuo and the residue is purified using reversed phase HPLC (eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([NH2:14])[CH:3]=1
Reactant: Cc1nnnn1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cc1nnnn1-c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 1-(4-bromo-2-nitro-phenyl)-5-methyl-1H-tetrazole (1.13 g, 3.98 mmol) in methanol (40 mL, not completely dissolved in methanol even at hot conditions) was treated sequentially with ammonium chloride (3.19 g, 59.7 mmol), zinc dust (2.60 g, 39.8 mmol), and water (20 mL). Initially after the addition, the reaction was exothermic. The reaction mixture was then stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine (0.90 g, 97%) as a white solid: EI-HRMS m/e calcd for C8H8BrN5 (M+) 252.9963, found 252.9962.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(OC(=O)[NH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(C)(C)C.C(O)(=O)C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[NH2:27][CH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[OH:20])[N:3]=2)[CH2:30]1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCCNC1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.0 g, 3.46 mmol) was dissolved in 15 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled using an ice bath and (S)-piperidin-3-ylmethyl-carbamic acid tert-butyl ester/oxalic acid (1.16 g, 3.81 mmol) was added in portions, followed by triethylamine (1.05 g, 1.45 mL, 10.4 mmol). The reaction was allowed to warm to room temperature and was complete after 1.5 hour. The mixture was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to a yellow solid. This solid was suspended in 40 mL CH2Cl2 and 20 mL of TFA were added. The reaction was complete after 1 hour. The solvent and the excess TFA were removed in vacuo, the residue was re-dissolved in CH2Cl2, and the pH was adjusted to 7 using an aqueous 1 M solution of NaOH. The reaction was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71% overall yield) as a yellow solid. LC/MS: m/z 367.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[NH2:40])[O:5][C:6]1[C:7]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:36])[CH3:35])=[CH:8][C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:11][C:10]=2[CH:28]=1.[CH:41](O)=O>>[N:40]1[C:39]2[CH:38]=[CH:37][C:4]([O:5][C:6]3[C:7]([CH:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34](=[O:36])[CH3:35])=[CH:8][C:9]4[NH:13][C:12]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[N:11][C:10]=4[CH:28]=3)=[CH:3][C:2]=2[NH:1][CH:41]=1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(N)c(N)c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Reactant: O=CO
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc2nc[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
19 mg of 1-(2-(6-(3,4-diamino-phenoxy)-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 155 (step 2) was dissolved in 1 ml of formic acid, and the reaction liquid was stirred at 100° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:2]([OH:5])(=[O:4])=[O:3])=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(OC(=O)c2ccccc2)c1
Solvent: ClCCl
Product: COc1cc(OC(=O)c2ccccc2)ccc1S(=O)(=O)O
Yield: 13.9 %

Procedure:
A solution of 0.47 mL (7.01 mmol) of chlorosulfonic acid in 7 mL of dichloromethane was added drop by drop to a solution of 1.6 g (7.01 mmol) of 3-methoxyphenyl benzoate in 12 mL of dichloromethane at 0° C. Once the addition was completed, the mixture was left to react for 18 h at room temperature. The formed precipitate was filtered, giving 300 mg of 4-benzoyloxy-2-methoxybenzenesulfonic acid. Yield 15%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][Cl:22]>C(#N)C>[Cl:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: ClCCBr
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCCCl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 20 h

Procedure:
3-Methoxy-4-nitrophenol (0.6 g, 3.6 mmol) was dissolved in acetonitrile (15 ml). Potassium carbonate (1.3 g, 9.1 mmol) was added, followed by 1-bromo-2-chloroethane (5.1 g, 35.5 mmol). The reaction was stirred in a sealed pressure tube at 80° C. for 20 h. The reaction was cooled to room temperature, the solid was then filtered off and the solvent evaporated under reduced pressure. The residue was then taken up into ethyl acetate and washed with 1M sodium hydroxide, brine, and then dried over sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CC(C)=O>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: N#Cc1[nH]c(=O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(Br)c(C#N)n1

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), potassium carbonate (1.3 eq.), and 1-iodobutane (1.2 eq.) in acetone (0.3 M) was stirred at 70° C. overnight. The solvent was concentrated en vacuo, and the resulting residue was taken up in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by a COMBIFLASH® system (ISCO) using 0-30% ethyl acetate in hexane to give a colorless solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC([Si](C)(C)[O:29][C@H:30]1[CH2:34][NH:33][C:32](=[O:35])[CH2:31]1)(C)C>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:33]5[CH2:34][C@H:30]([OH:29])[CH2:31][C:32]5=[O:35])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Product: O=C1C[C@@H](O)CN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 252 (E252) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and (4R)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-pyrrolidinone (Tetrahedron, 2000, 56(39), 7705-7713) using the method described in E251; MS (ES+) m/e 394 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH2:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:30]4[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:32][CH:31]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CCc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)n2)c1
Yield: 50 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-ethyl-phenyl)-1H-pyridazin-4-one (A-4) and 4-(methylsulfonyl)phenylhydrazine according to the method described for Example 1 in 50% yield. MS: M=421.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16]CC3C=CC=CC=3)[C:10]2=[O:24])=[CH:5][CH:4]=1>O1CCOCC1.[C].[Pd]>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[C:10]2=[O:24])=[CH:5][CH:4]=1
Reactant: O=C1N(CCOCc2ccccc2)CCN1c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1N(CCO)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 57.3 %

Procedure:
To a solution of 38 g of α-{2-[1-(α,α,α-trifluoro-4-tolyl)-2-imidazolidinon-3-yl]ethoxy]toluene in 400 ml of 1,4-dioxane, 15 g of 7.5% palladium carbon were added, followed by stirring under a hydrogen gas stream at 50° C. and 30 atm for 15 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. Resulting crystals were collected by filtration and then washed with ether, whereby 16.4 g of the title compound were obtained (yield: 58%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51]>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:53])[CH3:52])=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C[Si](C)(C)CCOCOc1ccccc1CCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3OCOCC[Si](C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57 (c)] with 1-chloromethyl-(2-trimethylsilyl-ethoxymethoxy)-benzene [Example 17 (c)] there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-(4-{3-[2-(2-trimethylsilanyl-ethoxymethoxy)-benzyloxy]-propoxy}-phenyl)-piperidine-1-carboxylate as a colourless oil; MS: 746 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1.C(OC(C)C)(C)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][CH2:16][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: O=C1CC(CCN2CCCC2)=NC=C1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-vinyl-4-pyridone (2.90 g) and pyrrolidine (5.33 ml) was heated and refluxed for an hour. The mixture was cooled and diluted with tetrahydrofuran (20 ml) and diisopropyl ether (80 ml). After being stirred for an hour at ambient temperature, the resulting precipitate was collected by filtration, washed with diisopropyl ether and air-dried at ambient temperature to give 5-benzyloxy-2-[2-(1-pyrrolidinyl)ethyl]-4-pyridone (3.79 g).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:30])=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.C(O[CH:37](OCC(C)(C)C)[N:38]([CH3:40])[CH3:39])C(C)(C)C>O1CCCC1>[CH3:37][N:38](/[CH:40]=[N:29]\[C:27](=[O:28])[C:24]1[CH:23]=[C:22]([CH3:30])[C:21]([C:19]2[CH:18]=[N:17][C:12]3[NH:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]4)[C:11]=3[N:20]=2)=[CH:26][N:25]=1)[CH3:39]
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(=O)/N=C\N(C)C)cc4C)nc32)CC1
Temperature: 85 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide (0.412 g, 1.00 mmol), dimethylformamide dineopentylacetal (1.5 mL) and tetrahydrofuran (10 mL) were combined and heated at 85° C. for 3 h. Reaction was concentrated under a stream of nitrogen placed in reaction vessel. Crude product was used directly for next step (0.467 g, 1.00 mmol, 100% yield). MS (ESI) m/z 466.6 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1Br)=[O:5])[CH3:2].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1[C:39]1[C:34]([O:33][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1Br
Reactant: OB(O)c1cccnc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 75.3 %

Procedure:
step 2—A sealed tube containing 100 (150 mg, 0.36 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (125 mg, 0.56 mmol), Na2CO3 (116 mg, 1.1 mmol) and Pd(PPh3)4 (42 mg, 0.036 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 50% EtOAc/hexanes to afford 140 mg (84%) of (R)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester (102).