Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=O)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=NO)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(4-chloro-3-formyl-2-oxopyridin-1(2H)-yl)-3-fluorobenzonitrile obtained in Step C (2.70 g), hydroxylamine hydrochloride (814 mg), sodium acetate (1.60 g) and methanol (60 mL)/water (15 mL) was stirred at room temperature for 1 hr. The reaction solution was poured into ice water. The resulting solid was collected by filtration, and washed successively with water, 2-propanol and diethyl ether to give the title compound (2.39 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]=1.[C:32]([O-])([O-])=[O:33].[K+].[K+]>CO>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:7]3[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]=[C:4]2[CH2:3][CH2:2][O:33][CH3:32])=[CH:15][CH:14]=1)#[N:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc2nc(CCCl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: [K+]
Solvent: CO
Product: COCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 58.5 %

Procedure:
A mixture of methyl 2-(2-chloroethyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (1.0 g) and K2CO3 (0.25 g) in methanol (30 ml) was refluxed for 2 hours. The reaction mixture was concentrated to dryness to give a residue. The residue was dissolved to dryness to give a residue. The residue filtered off. The filtrate was concentrated to dryness and a resulting syrup was purified by column chromatography on silica gel to give a pale yellow syrup (0.45 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[NH:12]1)=[O:10].[C:29]1([C@@H:35]([O:39][Si](C)(C)C)[C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][NH:13][N:12]1[C:36](=[O:37])[C@H:35]([OH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NCc2cc(Cl)ccc2-n2cnnn2)N1
Reactant: C[Si](C)(C)O[C@@H](C(=O)Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCNN1C(=O)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}pyrazolidine-1-carboxylate (82 mg, 0.200 mmol) in DCM (2 mL) and pyridine (0.080 mL) was added a solution of (R)-2-phenyl-2-(trimethylsilyloxy)acetyl chloride (ca 0.3 M in DCM, 1 mL, 0.3 mmol, see Preparation 2). The resulting solution was stirred at rt over night. TFA (ca 1 mL) was added and the mixture was stirred for one more hour and then evaporated. The residue was purified using flash chromatography (DCM/MeCN gradient from 2:1 to 1:1) to give (3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide (52 mg, 59%) as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][C:27](=[O:37])[NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:46])C=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:26][C:27](=[O:37])[NH:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N+:19]=3[O-:46])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Solvent: ClCCl
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (119 mg, 0.24 mmol) in dichloromethane (DCM) (5 mL) stirred under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (122 mg, 0.71 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was then quenched with sat. aq. NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to provide the crude product, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (61 mg, 0.12 mmol, 50% yield) as a white solid. MS: 522 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:10][CH2:11][C:12]2[CH:31]=[CH:30][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.SCC(O)=O.[Li+].[OH-]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:31]=[CH:30][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(CCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1

Procedure:
To a solution of tert-butyl 4-[4-(2-{(4-methoxyphenyl)[(2-nitrophenyl)sulfonyl]-amino}ethyl)benzyl]piperazine-1-carboxylate in DMF (35 mL) was added mercaptoacetic acid (1.35 mL) and LiOH (1.63 g) at room temperature, then the reaction mixture was stirred over night. The reaction mixture was added mercaptoacetic acid (1.35 mL) and LiOH (1.63 g), and stirred for 5 hours. The reaction mixture was diluted with H2O, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/2) to afford tert-butyl 4-(4-{2-[(4-methoxyphenyl)amino]ethyl}benzyl)piperazine-1-carboxylate as a pale yellow amorphous (5.96 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[O:17][C:16]3=[O:25])[CH2:13][CH2:14]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4OC3=O)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN2CCC(N3Cc4ccccc4OC3=O)CC2)cc1OC
Reaction time: 3 h
Yield: 83.6 %

Procedure:
In this example, 3.0 g of 1-(3,4-dimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine obtained in Example 1 is mixed with 150 ml of methanol. While this mixture is stirred at 0°-10° C., 0.8 g of sodium borohydride is added thereto over a period of 3 hours. The reaction solution is stirred overnight at room temperature. Then, the solution is further mixed with 0.4 g of sodium borohydride and stirred at room temperature for 3 hours. The white crystals deposited are separated by filtration, washed with methanol and water and dried to obtain 2.77 g of a crude product. The crude product is recrystallized from ethanol to obtain 2.52 g of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:23]5[CH2:24][N:19]6[CH2:20][CH:21]([CH2:25][CH:17]4[CH2:18]6)[CH2:22]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:17]5[CH2:18][N+:19]6([O-:34])[CH2:20][CH:21]([CH2:22][CH:23]4[CH2:24]6)[CH2:25]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cc2cc(-c3cnc(OC4C5CC6CC4CN(C6)C5)s3)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: [O-][N+]12CC3CC(C1)C(Oc1ncc(-c4ccc5[nH]ccc5c4)s1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 28A (105 mg, 0.30 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 mmol; Aldrich) and stirred at ambient temperature for 4 hours. The resulting material was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.70-2.02 (m, 2H), 2.10-2.29 (m, 1H), 2.29-2.47 (m, 1H), 2.58-2.78 (m, 2H), 3.57-3.67 (m, 5H), 5.32 (t, J=3.3 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 7.27-7.31 (m, 2H), 7.36-7.42 (m, 1H), 7.66 (d, J=1.3 Hz, 1H), MS (DCI/NH3) m/z=368 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:34])[NH:29][CH2:30][CH2:31][CH2:32]O)([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([O:27][C:28]([NH:29][CH2:30][CH2:31][CH2:32][N:15]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:34])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1cccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To an ice cold solution of tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (500 mg, 1.611 mmol), tert-butyl(3-hydroxypropyl)carbamate (282 mg, 1.611 mmol) and triphenylphosphine (634 mg, 2.417 mmol) dissolved in THF (16 mL) was added DIAD (470 μl, 2.417 mmol) and stirred for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (600 mg, 80%). LCMS: Rt=1.02 min, m/z=468.4 (M+1) Method 2m_acidic.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]C(O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: O=C(O)Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccn1)c1c[nH]c2ncccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (200 mg, 1.13 mmol) and 2-pyridinyl-acetic acid hydrochloride (440 mg, 2.53 mmol) in anhydrous THF (10 mL) was added LiHMDS (1.0 M in THF, 10 mL, 10.0 mmol) at −78° C. The solution was stirred at −78° C. for 30 min and was allowed to warm up to RT. After stirring at RT for another 30 min, the reaction mixture was heated under reflux for 14 h. The solvent was then evaporated, the residue was taken up to ethyl acetate (50 mL), and washed with aq. NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was used directly for the next reaction.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-Boc-L-valine (3.72 g, 17.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.84 g, 18.86 mmol) were dissolved in anhydrous methylene chloride (50 mL) under nitrogen. Triethylamine (2.09 g, 20.64 mmol) was added to the mixture, followed by dropwise addition of diethyl cyanophosphonate (3.09 g, 18.92 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was then diluted with methylene chloride (150 mL) and washed with water (100 mL). The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was carried forward without further purification. 1H NMR (CDCl3): 5.28 (d, 1H), 4.61 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 2.09-1.85 (m, 1H), 1.43 (s, 9H), 0.99 (d, 3H), 0.90 ppm (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CC(C)NCCN
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: CC(C)NCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 16.7 %

Procedure:
Synthesised as in Example 26 using 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.500 g, Example 25b) and N-isopropylethylenediamine (0.186 g) to give the title compound as a solid (0.105 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Product: COC(=O)c1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloropyridine hydrochloride (0.22 g, 1.5 mmol) afforded, after purification by ion-exchange chromatography (SCX), 260 mg (73%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1.C(OCC)(=O)C>[C:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 39.3 mg (61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:29]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:17]([CH3:18])[C:10]=12.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12)[NH2:29]
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 90 °C

Procedure:
267 mg (0.59 mmol) of N-[3-fluoro-4-({3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)phenyl]acetamide are dissolved in 10 ml of ethanol. 5 ml of 20% strength aqueous sodium hydroxide solution are added, and the reaction mixture is heated at 90° C. overnight. Most of the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and shaken with sodium carbonate solution. The organic phase is washed with sodium chloride solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:1]
Reactant: NC(=O)c1cccc(C=O)n1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:36](=[O:37])[CH2:35][C:34]([CH3:39])([CH3:38])[CH2:33][C:32]2=[O:40])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[OH:51])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:52]1[CH:57]=[CH:56][CH2:55][CH2:54][CH2:53]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:32](=[O:40])[CH2:33][C:34]([CH3:39])([CH3:38])[CH2:35][C:36]2=[O:37])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[O:51][CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][O:52]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OC2CCCCO2)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Yield: 85 %

Procedure:
A mixture of methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β- D-glucopyranoside (500 mg, 0.6 mmol), 3,4-dihydro-2H-pyran (5 mL) and -p-toluenesulphonic acid (5 mg) in dry acetonitrile (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 7 with the addition of triethylamine and then evaporated to dryness. The residue was taken up in dichloromethane (30 mL), washed with water (2×10 mL) and the organic phase dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOA 2:1 as the mobile phase to give methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-4-O-tetrahydropyranyl-1-thio-β-D-glucopyranoside (5) (420 mg, 85%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[NH:11][C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:14]=2[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42]>C1COCC1>[CH:1]1([C:7]([C:9]2[CH:10]([C:27]3[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=3)[N:11]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[C:14]=2[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCBr
Reactant: CC1=C(C(=O)C2CCCCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)C2CCCCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Example 21 (780 mg, 1.67 mmol) in THF (25 ml) is added sodium hydride (60% dispersion in mineral oil; 653 mg, 2.53 mmol). The mixture is stirred for 1 hour at room temperature, then 2-bromo-N,N-diethylethanamine (653 mg, 2.53 mmol) is added, and the solution is stirred overnight (16 h) at room temperature. The reaction mixture is quenched with methanol (10 ml), concentrated, and the crude product is purified by preparative HPLC.