Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([NH2:13])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1>CC(OC)(C)C>[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([N:13]=[CH:1][C:2](=[O:3])[CH3:4])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(=O)C=O
Solvent: COC(C)(C)C
Product: CC(=O)C=NC1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.68 mL, 3.16 g, 17.5 mmol) in 30 mL of TBME at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (2.0 mL, 2.19 g, 14.0 mmol). After 30 min, the solution was diluted with 50 mL of TBME and washed with 3×25 mL of water and 25 mL of brine. The solution was concentrated in vacuo to yield 2.1 g (71%) of the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.64 (1H, s), 3.70 (1H, tt, J=3.9, 11.6 Hz), 2.34 (3H, s), 1.61 (2H, dd, J=3.9, 13.0 Hz), 1.32 (2H, t, J=12.2 Hz), 1.21 (6H, s), 1.14 (6H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([CH2:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([CH2:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CCc1nn2c(N)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
0.33 ml (3 mmol) of 1-methyl-piperazine was added to a solution of 0.4 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-pyrazolo[1,5-a]pyrimidin-7-ylamine in 5 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.24 g (50%) of 3-benzenesulphonyl-2-ethyl-5-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-7-yl-amine as colorless crystals, m.p.>250°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1.[NH:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:25]([O:24][C:22]([N:14]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:8]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrCc1ccc(-c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2nccs2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a solution of 4-(thiazol-2-yl)benzyl bromide (1.25 g, 4.92 mmol) obtained in Reference Example 4-(b) in N,N-dimethylformamide (16 ml) were added di-tert-butyl iminodicarboxylate (1.28 g, 5.89 mmol) and potassium carbonate (1.35 g, 9.76 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (2.05 g) substantially quantitatively as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([C:16]2[CH2:17][CH2:18][N:13]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(=O)Nc1cccc(C2=CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1

Procedure:
The reaction of tert-butyl N-(3-bromopropyl)carbamate and N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide in refluxing dioxane with catalytic Bu4NI and base as described in Scheme A gave tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11-12) gave the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[NH4+].[Cl-]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.O>[CH3:40][O:39][C:35](=[O:38])/[CH:36]=[CH:37]/[C:24]1[CH:23]=[CH:22][N:21]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)[N:19]=[C:20]2[CH:25]=1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 150 °C
Yield: 83.8 %

Procedure:
To a mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (534 mg, 1.03 mmol), methyl acrylate (0.19 mL, 2.06 mmol, 2.0 equiv), triethylamine (0.16 mL, 1.17 mmol, 1.1 equiv), palladium(II) acetate (17 mg, 0.08 mmol, 7 mol %) and tri (2-tolyl)phosphine (53 mg, 0.18 mmol, 17 mol %) in acetonitrile (7 mL) was heated at 150° C. for 2 h. in a microwave apparatus. The reaction mixture was mixed with water (10 mL), a saturated aqueous NH4Cl solution (10 mL) and CH2Cl2 (25 mL) with vigorous stirring at room temperature for 30 min. The resulting organic phase was washed with a saturated aqueous NaCl solution, dried (Na2SO4 anh), and concentrated under reduced pressure to give (E)-3-{2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-acrylic acid methyl ester (452 mg, 75%):
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][N:21]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:28][CH:29]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 5 °C
Yield: 75.3 %

Procedure:
Lithium aluminium hydride (256 mg) was added to absolution of methyl 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinate (1.4 g) in THF (50 ml) with stirring at 5-10′ under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 4 hours. The reaction mixture was cooled at 5° C. and water (0.26 ml), 15% NaOH solution (0.26 ml) and water (0.72 ml) was added, the resultant mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (85:15). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}methanol (0.96 g)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cl
Reaction time: 0.05 h
Yield: 72.1 %

Procedure:
To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from methylene chloride to give 525 mg of the desired product as a white crystalline solid, m.p. 228°-230° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC#CCN1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC/C=C/CN1CCCC1
Temperature: 60 °C
Yield: 70.6 %

Procedure:
A solution of 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 31 mmol) in THF (20 ml) was added dropwise to a suspension of lithium aluminum hydride (2.35 g, 62 mmol) in anhydrous THF (8 ml) and the mixture stirred and heated at 60° C. for 2 hours. The mixture was cooled to 5° C. and 2M aqueous sodium hydroxide solution (28 ml) was added dropwise. The resulting suspension was filtered and the volatiles removed from the filtrate by evaporation. The residue was dissolved in a mixture of methylene chloride/ethyl acetate, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on aluminum oxide eluting with methylene chloride/methanol (97/3) to give (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.09 g, 70%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]3[N:11]([C:13]([CH:16]=[CH2:17])=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CCO.[Pd]>[CH2:16]([C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]2=[N:15][CH:14]=1)[CH3:17]
Reactant: C=Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Reaction time: 2 h

Procedure:
100 mg 4-(6-phenyl-3-vinylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under intermediate example 13) were dissolved in a mixture of 5 mL THF and 5 mL EtOH. 10 mg 10% Pd/C were added and the mixture stirred under an atmosphere of hydrogen for 2 h. The mixture was filtered through Celite, the solvent was evaporated and the crude product was purified by chromatography on silica gel (dichloromethane/methanol).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=[N:12]2)[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(OCC3CCCC3)cc2=O)n1
Yield: 10 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (Intermediate 59) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (22.2 mg, 10%); ES+-HRMS m/e calcd for C25H37N5O4 [M+H+] 472.2919, found 472.2922. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.05 (m, 1H), 1.25-1.97 (m, 18H), 2.26 (m, 1H), 3.89 (s, 2H), 3.90 (d, J=5.8 Hz, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.2, J=11.2 Hz, 1H), 6.27 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.8 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and o-anisoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) and filtered. The solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-methoxy-benzamide (0.8 g, 94%) as a white solid: mp 236-238° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 3.88 (s, 3H, OCH3), 4.39-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.9 and 13.1 Hz, 1H, CH), 7.02 (t, J=7.4 Hz, 1H, Ar), 7.16 (d, J=8.3 Hz, 1H, Ar), 7.44-7.72 (m, 5H, Ar), 8.77 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.60, 31.17, 46.20, 51.55, 55.82, 111.93, 120.41, 121.51, 123.10, 128.24, 130.22, 130.43, 131.57, 132.17, 134.89, 139.94, 156.87, 165.34, 168.09, 171.00, 172.83; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.59; H, 5.01; N, 10.17.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11]1)=[O:7])(C)(C)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: CN(CCCCN1CCC(CNC(=O)OC(C)(C)C)C1)C(=O)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN(C)C(=O)c2ccccc2)C1

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-N-methylbenzamide (0.57 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.30 g) to give 4-amino-N-(1-(4-(N-benzoyl-N-methylamino)butyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])OC)([CH3:3])[CH3:2].C([Si](C(C)C)(C(C)C)OCCCC)(C)C.[ClH:28]>>[CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[Cl:28])([CH3:3])[CH3:2]
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cl
Agent: CCCCO[Si](C(C)C)(C(C)C)C(C)C
Product: CC(C)[Si](Cl)(C(C)C)C(C)C
Yield: 99 %

Procedure:
The procedure of Example 13 was repeated except that triisopropylmethoxysilane was replaced by 83.3 g (0.2 moles) of triisopropyl-n-butoxysilane. The latter was reacted with 35% hydrochloric acid. There was obtained 38 g of triisopropylchlorosilane (yield; 99%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.CN(C)P(N(C)C)(N(C)C)=O.C(NC(C)C)(C)C.[Li].Br[CH2:47][CH2:48][Cl:49].Cl>C1COCC1>[Cl:49][CH2:48][CH2:47][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: ClCCBr
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of diisopropylamine (88 mL, 0.62 mol) in anhydrous THF (500 mL) was added n-butyl lithium (240 mL, 0.6 mol, 2.5 M solution in hexane) over 20 minutes at −78° C. The mixture was stirred at 0° C. under nitrogen for 30 min. To a mixture of dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added lithium diisopropylamine (freshly prepared above) over 30 min at −40° C. After stirring for 1 h at this temperature, 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1 h. The mixture was stirred for 3 h at −78° C., then warmed to room temperature and stirred overnight. To the reaction mixture was added aqueous hydrochloric acid (3 N, 420 mL) and the mixture was stirred for 10 min. The solvent was removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×200 mL), and the combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration under reduced pressure afforded dimethyl 1-(2-chloroethyl)cyclohexane-1,4-dicarboxylate (116 g, 88% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (s, 3H), 3.65 (s, 3H), 3.46-3.42 (m, 2H), 2.33-2.21 (m, 3H), 2.05-1.85 (m, 4H), 1.58-1.42 (m, 2H), 1.25-1.15 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[OH:30][N:29]=[CH:1][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(C=NO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Yield: 96 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g), hydroxylamine hydrochloride (580 mg) and sodium acetate (1.6 g) are dissolved in ethanol (20 ml) and water (10 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue. The mixture is extracted with chloroform, dried with sodium carbonate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:2) and recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxyiminomethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) as white powder, m.p.: 222°-224° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)(=[O:18])=[O:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].C1(C)C=CC(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH3:29][S:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([C:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=2)(=[O:14])=[O:13])=[N+:39]=[N-:40])(=[O:17])=[O:18])=[CH:20][CH:21]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OS(C)(=O)=O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)c2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
The bis(4-methylsulfonyloxyphenylsulfonyl)methane in Synthesis Example 3, 9.7 g (0.02 mol), was dispersed in 97 g of dichloromethane. To the dispersion was added 4.6 g (0.03 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring at room temperature, 5.9 g (0.03 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to the dispersion, and after 5 minutes, 150 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 14 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 40 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 3.0 g (yield 29%) of fine yellow crystals.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][C:17](OCC)=[O:18].[H-].[Na+].[NH4+].[Cl-]>CCOCC.CCO.CO.CCCCCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][C:17]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8])=[O:18]
Reactant: CCOC(=O)COC1CCCCO1
Reactant: O=C1CCCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: O=C1CCCCCC1C(=O)COC1CCCCO1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 2.80 g (25 mmol) of cycloheptanone and 4.71 g (25 mmol) of ethyl (tetrahydropyranyloxy)acetate (Ireland, R. E.; Wipf, P. Tetrahedron Lett., 1989, 30, 919-22) in 20 mL of Et2O was added over the course of 1 h to an ice-cold, stirring mixture of hexane-washed NaH and 0.12 mL (2 mmol, 0.092 g) of absolute EtOH in 10 mL of Et2O under N2. The light brown mixture was allowed to warm to room temperature and was stirred overnight. MeOH (5 mL) was added and the solution was poured onto 200 mL of saturated aqueous NH4Cl. After acidification to pH 2 with 1N aqueous HCl, the mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 5.61 g of crude 2-[(tetrahydropyranyloxy)acetyl]cycloheptanone as a light brown oil.