Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]([O:24][CH2:25][CH:26]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:24][CH2:25][C@H:26]1[O:14][CH2:13][C@H:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH2:15][O:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CCOCc1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC([C@H]2CO[C@H](COCc3ccccc3)OC2)CC1

Procedure:
A solution of 100 mmol of trans-2-(4-pentylcyclohexyl)propane-1,3-diol, 100 mmol of benzyloxyacetaldehyde and 10 mmol of p-toluenesulfonic acid in 500 ml of toluene is heated at the boil on a water separator until the water separation is complete. Conventional work-up gives trans/trans-2-benzyloxymethyl-5- (4-pentylcyclohexyl)-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22]=1[CH3:31]>CCO>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)[CH:28]=2)[NH:23][C:22]=1[CH3:31]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1[nH]c2ccc(N)cc2c1Cl
Solvent: CCO
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(Cl)c5c4)c3s2)C1
Yield: 85.3 %

Procedure:
A solution of (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone (75 mg, 0.25 mmol) and 3-chloro-2-methyl-1H-indol-5-ylamine (45 mg, 0.25 mmol) in EtOH (10 mL) was heated to reflux. After 48 h the reaction mixture was concentrated onto silica gel (5 mL) and purified on silica gel by flash column chromatography CH2Cl2/MeOH/NH4OH (95/41) to afford the title compound as a yellow solid, (94 mg). MS: 441.2/443.2, 407.2 (MH+); HPLC Rf: 4.93 min.; HPLC purity: 98%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][CH2:15][C:16](=[O:23])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.N1CCCCC1>C(O)C>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:15]2[O:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:12][CH2:11]3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:25]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 12.8 %

Procedure:
To a stirred solution of ethyl 2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.31 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.018 g, y. 13%) as solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH2:18])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Reactant: CCCC(=O)Cl
Product: CCCCCOc1ccc2c(c1)C=C(CNC(=O)CCC)CO2

Procedure:
0.37 g (1.5 mmol) of the amine obtained in Step F of Example 55 is condensed with butanoyl chloride according to the same procedure as in Example 54. Purification on a silica column (eluant: ethyl acetate/petroleum ether 50/50) allows isolation of the title amide in the form of a yellowish solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>CN(C)C1C=CN=CC=1.CO>[CH2:11]([O:10][C:9]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:13])[CH3:12]
Reactant: CCOC(=O)OCC
Reactant: NCC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CCOC(=O)NCC1CCNCC1

Procedure:
The solution of 1.70 g (9.0 mmol) of 4-(ethoxycarbonylamino-methyl)-piperidine (obtained from 4-aminomethyl-piperidine and diethyl carbonate in the presence of 4-dimethylaminopyridine) in 18 ml of methanol was treated with 9.0 ml (9.0 mmol) of 1N methanolic hydrochloric acid. After addition of 0.53 g (3.0 mmol) of 8-methoxy-2-tetralone, the mixture was stirred for a further 5 minutes. 0.20 g (3.3. mmol) of sodium cyanoborohydride was then added and the mixture was stirred for 15 hours at room temperature, followed by standing for 18 days at about +4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].Cl.[N:26]1([C:32]2([C:35](O)=[O:36])[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:35]([C:32]2([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:33][CH2:34]2)=[O:36])[C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:10])=[O:11]
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 49 %

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light brown solid (49%). MS ISP (m/e): 523.4/525.3 (100/47) [(M+H)]+.
Reaction SMILES: [CH:1]1([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([NH:23][CH2:24][CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25][OH:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCBr)NC1CCCCCC1
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCN(CCO)Cc1ccccc1)NC1CCCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
N-cycloheptyl-5-bromopentanamide (4.15 g, 15 mmole) in solution in dimethylformamide (20 ml) is added dropwise to a hot solution (60° C.) of N-benzylethanolamine (2.27 g, 2.13 ml, 15 mmole) in dimethylformamide (25 ml) in the presence of potassium carbonate (4.15 g, 3 mmole). The reaction mixture is agitated for 2 hours at 60° C. then the solvent is evaporated under reduced pressure. The residue is taken up in dichloromethane (50 ml) and washed with water (3×30 ml). The organic phase is collected, dried over magnesium sulfate; the solvent is evaporated under reduced pressure. The product obtained is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (90/10) to give 3.04 g (50%) of the expected compound in the form of an oil.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:34]3[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)=[O:16])=[CH:19][CH:20]=2)[CH:2]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)cc1
Yield: 63.9 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (269 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (304.2 mg) was obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:28]([OH:29])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 0.72 mL, 1.44 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (435 mg, 1.02 mmol, 78%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C)C=O.O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reaction time: 3.5 h
Yield: 98.8 %

Procedure:
Add a solution of tert-butyldimethylsilyl chloride (5.0 g, 33.1 mmol) in dimethylforamide (DMF) (70 mL) dropwise over 15 minutes to a solution of 6-bromohexanol (5.0 g, 27.6 mmol) and imidazole (4.7 g, 69 mmol) in DMF (80 mL) at 0° C. under nitrogen protection and stir the mixture for another 3.5 hours. Dilute the mixture with water (400 mL) and extract with diethyl ether (3×150 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the crude product by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to provide (6-bromohexyloxy)-tert-butyldimethylsilane (8.05 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
A solution of 3.5 g (9.83 mmol) of 1,1-dimethylethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.1., in 20 ml of dichloromethane is admixed with 10 ml of trifluoroacetic acid and the solution is stirred at ambient temperature for 1 hour. It is evaporated to dryness and then the residue is taken up in 30 ml of toluene, which is evaporated again to dryness. The residue is subsequently washed with pentane and then taken up in a mixture of 60 ml of dichloromethane and 20 ml of 4N aqueous ammonia solution. It is stirred vigorously for 15 minutes and then the organic phase is decanted, dried over sodium sulfate and evaporated to dryness, to give 2.7 g of product in oil form, which is used as it is in the following step.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[NH:18])[S:14][CH:15]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[C:23]#[CH:24]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:25][CH2:22][C:23]#[CH:24])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[NH:18])[S:14][CH:15]=1)([O-:3])=[O:2]
Reactant: C#CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1

Procedure:
A mixture of the product of Step A (3.0 g; 8.61 mmoles) and propargylamine (6.0 ml) in acetonitrile (21 ml) was stirred and heated at reflux temperature under a positive pressure of nitrogen for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 70 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and evaporated, and the 480 mg of product was recrystallized from isopropanol to yield the title compound containing approximately 2/3 mole of isopropanol, mp 82°-90°. Thin layer chromatography on silica, using methylene chloride:methanol (90:10), gave Rf 0.25.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]=1[CH:4]=[N:17][OH:18]
Reactant: O=Cc1c(Cl)cccc1-c1ccncc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1c(Cl)cccc1-c1ccncc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
2-Chloro-6-(4-pyridyl)benzaldehyde (80 mg, 0.37 mmol) was dissolved in pyridine (2 mL) at room temperature. Hydroxylamine hydrochloride (26 mg, 0.38 mmol) was added and the mixture was allowed to stir overnight. The mixture was then concentrated under reduced pressure to obtain 2-chloro-6-(4-pyridyl)benzaldoxime (85 mg, 99% yield). MW=233 confirmed by LC-MS, tr=8.36 min (Method Y) MH+=231–235
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:37]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[O:21])=[C:11]([Br:37])[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCn2cc(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCn2c(Br)c(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8-(benzyloxy)-N-(3-chloro-4-fluorobenzyl)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxamide (0.23 g, 0.51 mmol) and sodium bicarbonate (0.52 g, 6.13 mmol) in dichloromethane (50 mL) at 0° C., a solution of bromine in dichloromethane (0.5 M, 1.1 mL, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([O:30][CH2:31][CH3:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:28][CH3:29].[Li+].[OH-]>>[CH2:31]([O:30][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:28][CH3:29])[C:3]([OH:33])=[O:2])[CH3:32]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH:17]([CH2:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:16][CH2:15][CH2:14][N:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].O>C(O)C>[C:29]([O:28][C:26]([N:13]1[CH2:12][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH:17]([CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[O:16][CH2:15][CH2:14]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(COCC(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 M Aqueous sodium hydroxide solution (0.32 mL) was added dropwise to a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-[(2-ethoxy-2-oxoethoxy)methyl]-1,4-oxazepane-4-carboxylate (150 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The obtained aqueous layer was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].O[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>[OH-].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]1[CH2:11][C:12](=[O:13])[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:6]1
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C2CC(=O)c3ccccc3O2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 86 %

Procedure:
A mixture of 3-methylbenzaldehyde (12 g, 0.1 mol), 2-hydroxyacetophenone (13.6 g, 0.1 mol), and 2 liters of 0.1 N NaOH was stirred at room temperature for 4 days. The reaction was extracted with ether and the ether dried and evaporated to give 20.5 g of 3'-methyl flavanone as an oil. The oil, not further purified but used directly, was converted in a similar manner as described in Example 1 into 8.2 g of the hydrochloride salt of 3'-methyl-3-dimethylaminomethyl flavanone, as a solid, m.p. 156°-158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1.[CH3:19][NH:20][CH3:21].O>CS(C)=O>[CH3:19][N:20]([CH3:21])[C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[O:18])=[CH:12][CH:13]=1
Reactant: CNC
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(N(C)C)cc1
Temperature: 150 °C

Procedure:
Ten grams of N-(2,6-dimethylphenyl)-4-fluorobenzamide were dissolved in 50 ml of dimethylsulfoxide in a high pressure/temperature bomb. Anhydrous dimethylamine (18.5 g) was added and the reaction vessel sealed and heated at 150° C. for 18 hours. The bomb was cooled and the contents poured into water. The mixture was extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was crystallized from methanol/water affording the desired title product in yield, m.p. 215-217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:32]2[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[N:21][C:20]=3[N:28]=[CH:29][N:30]=2)[CH:7]=1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 130 °C

Procedure:
The product from Example 6c (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (77 mg, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96 (t, J=7.4 Hz, 3H), 1.80 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 6.74 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 7.03 (m, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 8.53 (s, 1H), 8.78 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 403 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:8]1([C:6]2[CH:7]=[C:2]([C:16]3[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:21])[N:3]=[CH:4][N:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc(-c2ccccc2)ncn1
Yield: 23 %

Procedure:
Next, 1.6 g of 4-chloro-6-phenylpyrimidine synthesized in Step 1, 1.5 g of 2,6-dimethylphenylboronic acid, 1.8 g of sodium carbonate, 59 mg of PdCl2(PPh3)2, 20 mL of N,N-dimethylformamide (abbreviation: DMF), and 20 mL of water were put into a 100-mL round-bottom flask, and the air in the flask was replaced with argon. Then, heating was performed by irradiation with microwaves (2.45 GHz, 100 W) for 2 hours. An organic layer was extracted from the obtained mixture with the use of dichloromethane, and was washed with water and saturated brine. Magnesium sulfate was added and gravity filtration was performed. A solvent in the obtained filtrate was distilled off, and the given residue was purified by flash column chromatography using a mixed solvent of ethyl acetate and hexane (ethyl acetate: hexane=1:5) as a developing solvent, whereby 0.50 g of the objective substance, Hppm-dmp (abbreviation) was obtained (yield: 23%, a pale yellow oily substance). A synthesis scheme of Step 2 is shown in (a-2) below.