Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)=[O:3].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[NH2:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C

Procedure:
To a solution of 4-methylcarbonyl-2-nitro-benzenamine (500 mg, 2.775 mmol) in EtOAc (16 mL) was added SnCl2.2H2O (3.130 g, 13.88 mmol). The reaction mixture was refluxed for 2.5 h, cooled to rt, and diluted with H2O (130 mL). The pH of the mixture was adjusted to 7-8 by addition of saturated NaHCO3 solution and the aqueous phase was extracted with EtOAc (2×120 mL). The combined organic extracts were washed with brine (2×60 mL) and dried over MgSO4. After the removal of the solvent under vacuum, 142a was obtained as a red orange solid (418 mg).
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:26](=[O:27])[C:25](=[O:28])[NH:24][C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=3[S:21]2)=[CH:16][CH:15]=1.Cl>O1CCCC1>[OH:27][C@H:26]1[C:25](=[O:28])[NH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[S:21][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 83.9 %

Procedure:
A mixture of L-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (25 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to room temperature, and thereto is added tetrahydrofuran (25 ml). The mixture is cooled to -30° C., and thereto is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (997 mg). Each 139 μl of conc. hydrochloric acid (1.67 mmole as hydrogen chloride) is added at 1, 3, 5 and 22 hours after the beginning of the reaction, and the reaction is carried out for 45 hours. After confirming by HPLC that the starting compound is completely consumed, the mixture is evaporated under reduced pressure to remove the solvent, and water (70 ml) is added to the residue. The mixture is stirred at room temperature for one hour, and the precipitated crystal is collected by filtration and dried. The resulting residue is suspended in isopropyl alcohol (13 ml), and the mixture is refluxed for one hour. The mixture is cooled to 5° C., and allowed to stand overnight. The precipitated crystal is collected by filtration, and washed with cold isopropyl alcohol, and dried to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (842 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][C:27]1[C:34]([F:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([S:24][CH2:26][C:27]3[C:28]([F:36])=[CH:29][C:30]([C:31]#[N:32])=[CH:33][C:34]=3[F:35])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Reactant: N#Cc1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2c(F)cc(C#N)cc2F)n1-c1ccc(F)cc1
Temperature: 56 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
A mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (760 mg, 2 mmol), 4-(bromomethyl)-3,5-difluorobenzonitrile (464 mg, 2 mmol) and K2CO3 (414 mg, 3 mmol) in acetone (10 mL) was stirred at 56° C. for 4 h. After cooling, the solids were removed by filtration and rinsed with acetone. The combined filtrates were concentrated and purified by flash chromatography, eluting with EtOAc-Hexane (1:1) to afford the title compound (89 mg). 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J=4.2, 2H), 7.17 (d, J=6.5, 2H), 7.03 (d, J=2.2, 1H), 6.88-6.79 (m, 3H), 6.50-6.44 (m, 2H), 4.08 (d, J=9.1, 2H), 2.04 (s, 1H), 1.49 (s, 7H); MS (EI) m/z 432 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].[CH2:15]([N:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1F)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:15]([N:19]1[CH:23]=[C:22]([C:24]([CH3:26])([CH3:27])[CH3:25])[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=1[O:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1])[CH2:16][CH2:17][CH3:18]
Reactant: CN1CCC[C@H]1CO
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCCN1C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A solution of (S)-(1-methylpyrrolidin-2-yl)methanol (109 mg, 0.94 mmol) in THF (5 mL) was treated with 1 M solution of potassium t-butoxide (0.95 mL, 0.944 mmol) and stirred for 15 min. A solution of Example 9B (190 mg, 0.47 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo, partitioned between EtOAc and brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-15% methanol in dichloromethane) to afford the title compound (175 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.17-1.42 (m, 11H), 1.49-1.83 (m, 5H), 1.82-2.03 (m, 1H), 2.17 (q, J=8.7 Hz, 1H), 2.32 (s, 3H), 2.54-2.67 (m, 1H), 2.83-3.01 (m, 1H), 3.92-4.10 (m, 2H), 4.14 (t, J=7.3 Hz, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.72 (dd, J=9.0, 2.2 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/z 498 (M+H)+. Anal. calcd for C25H34F3N3O2S: C, 60.34; H, 6.99; N, 8.44. Found: C, 60.27; H, 7.09; N, 8.40.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: Cc1ccc(CN2CCN(C(=O)Nc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 4-methylbenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.35-7.00 (m, 9H), 6.32 (s, 1H), 3.50-3.48 (m, 6H), 2.49-2.46 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccnc3)c2cc1OC
Yield: 19.8 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 112.9 mg (1.2 mmol) of 3-amino-pyridine to give 60.6 mg (19.8%) of the product as an orange solid, m.p. 231-233° C., mass (electrospray, m/e): M+H 306.8.
Reaction SMILES: [C:1]([N:4]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@@H:11]2[C:6]([C:7]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:4]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C@@H:11]2[C:6]([C:7]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)[CH3:2]
Reactant: COc1ccc([C@H]2[C@H]3CCc4ccc(OC)cc4C3=NN2C(C)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1N=C2c3cc(OC)ccc3CC[C@@H]2[C@@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
To the solution of (141) (180 mg, 0.51 mmol) in THF (5 mL) was added LiAlH4 (2.056 mL, 2.056 mmol; 1M in THF) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then quenched with methanol followed by ice. The reaction mixture was extracted with ethyl acetate. Organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using 25% ethyl acetate-hexane as eluent to give (157) (30 mg, 17%): thick oil, 1H NMR (500 MHz, CDCl3): δ 1.40 (t, J=7.0 Hz, 3H), 1.72-2.04 (m, 2H), 2.62-2.85 (m, 2H), 3.87 (s, 6H), 4.15 (q, J=7.0 Hz, 2H), 4.75 (d, J=10.5 Hz, 1H), 6.75-6.77 (dd, J=8.0 and 3.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.44 (d, J=3.0 Hz, 1H). LRMS m/z 336.3 (calc for C21H24N2O2, M+, 336.2).
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1.[CH:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[OH:36][CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1
Reactant: CCCCCCCCCCCC=O
Reactant: CC[Si](CC)(CC)c1cc(CCC=C(Br)Br)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(O)C#CCCc1coc([Si](CC)(CC)CC)c1
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5M solution in tetrahydrofuran; 0.42 ml, 1.04 mmol) was added dropwise to a solution of 4-(4,4-dibromo-3-butenyl)-2-triethylsilylfuran (200 mg, 0.51 mmol) in tetrahydrofuran (8 ml) at -78 degrees under argon. After 2 hours, a solution of 1-dodecanal (102 mg, 0.56 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature. The mixture was quenched with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by a silica column with 15% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:18][CH2:17][CH2:16][C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: NCCc1[nH]c2ccccc2c1-c1ccccc1
Product: O=C(NCCc1[nH]c2ccccc2c1-c1ccccc1)C1CC1

Procedure:
3-Phenyl-1H-indol-2-ethanamine are reacted with cyclopropanecarboxylic acid chloride to give N-cyclopropylcarbonyl-3-phenyl-1H-indol-2-ethanamine, which is reduced with lithium aluminium hydride to N-cyclopropylmethyl-3-phenyl-1H-indol-2-ethanamine, which is reacted with chloracetyl chloride to give 2-chloro-N-cyclopropylmethyl-N-[2-(3-phenyl1H-indol-2-yl)ethyl]acetamide, m.p. 104°-106° (from ethanol/pentane).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl[O-].[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([Cl:11])=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: ON=CCc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: ON=C(Cl)Cc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Phenylacetaldehyde oxime (40.5 g, 300 mmol) was dissolved in acetonitrile (100 ml). To the solution, a 6.7% aqueous hydrochloric acid (145 g) and then an 8.5% aqueous sodium hypochlorite (262 g, 299 mmol) were added dropwise at -10° C. over 2.3 hours. The mixture was stirred at -5° C. for 30 minutes and then combined with toluene (200 ml) for extraction. The separated organic layer was washed twice with water (200 ml). Reversed phase HPLC revealed that the extract contained 40.3 g (238 mmol, yield 79%) of the desired compound. The solution was used in the next step without concentration.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:11]1[N:10]([CH2:23][O:24][CH3:25])[CH:9]=[N:8][CH:12]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCn1cncc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1-t-Butoxycarbonyl-4-[2-(t-butoxycarbonylamino)ethyl]imidazole (78.1 g) is dissolved in acetonitrile (500 ml), and thereto is added methoxymethyl chloride (22.2 g). The mixture is stirred at room temperature overnight, and poured into aqueous 10% sodium carbonate solution, and extracted with ethyl acetate. The extract is washed, dried and evaporated to give 5-[2-(t-butoxycarbonylamino)ethyl]1-methoxymethylimidazole (54.4 g) as an oil.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]([O:27][C:28]([CH:30]([CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:31]P(C)(=O)OCC1C=CC=CC=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:1]([P:5]([CH2:31][CH:30]([C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])[CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[PH](=O)O
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16mmol) in 80 mL of dry dichloromethane was cooled to 0C under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40w) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[N:12]1([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Yield: 89 %

Procedure:
1.84 g (11.6 mmol) of 2-chloro-5-nitropyridine are added to a solution of 2.05 g (8.62 mmol) of 2-(methylamino)-2-oxoethyl 1-piperazinecarboxylate hydrochloride, obtained in step 5.2., and 3.85 ml (22.4 mmol) of N,N diisopropylethylamine in 55 ml of 1,2-dichloroethane. This reaction mixture is maintained at 70° C. for 5 hours. The mixture is allowed to cool to room temperature and concentrated under reduced pressure, and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 2.48 g of product are obtained in the form of a pale yellow solid, and are used without further purification in the following step.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:34]([CH3:36])([CH3:35])[C@H:33]2[C@@:8]3([O:29][C:12]4[C:13]5[CH2:14][NH:15][C:16](=[O:28])[C:17]=5[CH:18]=[C:19]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:11]=4[CH2:10][C@:9]3([CH3:38])[C@@H:30]([CH3:37])[CH2:31][CH2:32]2)[CH2:7][C@@H:6]1[OH:39])(=[O:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(=O)([O-])O.[Na+]>CC(C)=O>[C:1]([O:4][C@H:5]1[C:34]([CH3:36])([CH3:35])[C@H:33]2[C@@:8]3([O:29][C:12]4[C:13]5[CH2:14][NH:15][C:16](=[O:28])[C:17]=5[CH:18]=[C:19]([O:20][CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:11]=4[CH2:10][C@:9]3([CH3:38])[C@@H:30]([CH3:37])[CH2:31][CH2:32]2)[CH2:7][C:6]1=[O:39])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@@H](O)C[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CNC5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C1(C)C
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=O)O[C@@H]1C(=O)C[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CNC5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C1(C)C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of Compound (49f) (Step-2 in Example 55) (116 mg, 0.22 mmol) in 5.0 ml of acetone was added dropwise 65 μl (0.26 mmol) of the Jones reagent under ice-cooling, and the mixture stirred for 30 min at the same temperature. To the reaction mixture was added 100 μl of isopropanol. The mixture was stirred for 5 min, neutralized with an aqueous saturated sodium hydrogen carbonate solution, and concentrated under reduced pressure to a half volume. After addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; toluene:ethyl acetate=1:1) to give 101 mg (87%) of Compound (52).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 2 h

Procedure:
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml) was treated with a M sodium hydroxide solution (1.65 ml) and stirring continued for a further 2 hours. The mixture was diluted with water (10 ml) and the resulting solution concentrated in vacuo. Water (20ml) was added and then a M hydrochloric acid solution (1.65 ml). On cooling to 4° C., a solid precipitated. This mixture was concentrated in vacuo, the solid collected and washed with ice-water, then dried to give the title compound, 320 mg, as a solid: m.p. 294°-296° C.; NMR (d6DMSO+TFA) δ8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)+ ; calculated for C19H21N3O4 : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C1(C)C(S(O[CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC1COC(C)(C)OC1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)OCC(COc2cnc(Cl)nc2)CO1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 74.1 %

Procedure:
To 2.53 g (19.4 mmol) of 2-chloro-5-hydroxypyrimidine, a solution of 5.95 g (19.8 mmol) of 5-(toluenesulfonyloxymethyl)-2,2-dimethyl-1,3-dioxane in 11 ml of N-methylpyrrolidone and 6.50 g (19.9 mmol) of cesium carbonate were added, and the reaction mixture was stirred at 70° C. for 3.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate twice. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. tert-Butyl methyl ether was added to the obtained residue, and the precipitate was obtained by filtration to provide 3.72 g of the title compound as a white solid (yield: 74%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[Cl:59][C:60]1[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc3)cc2C1=O
Yield: 92 %

Procedure:
The compound of example 133 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4-dichloro benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42](Cl)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.C[C:53]([N:55](C)C)=O>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:53]#[N:55])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 115 °C

Procedure:
To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (730 mg, 1.0 mmol), was added ZnCN2 (280 mg, 2.4 mmol), Zn (64 mg, 1.0 mmol), DMA (10 mL), and Pd(P-t-Bu3)2 (78 mg, 0.15 mmol). The reaction mixture was heated in a sealed vial at 115° C. for 2 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.