Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:27]1[CH2:34][NH:33][S:30](=[O:32])(=[O:31])[CH2:29][CH2:28]1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[O:31]=[S:30]1(=[O:32])[CH2:29][CH2:28][CH2:27][CH2:34][N:33]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1
Reactant: O=S1(=O)CCCCN1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(N4CCCCS4(=O)=O)ccc3c2n1CCCOC(C)C
Temperature: 110 °C
Yield: 55.5 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g), 1,4-butanesultam (0.29 g), copper(I) iodide (68 mg), (±)-trans-1,2-diaminocyclohexane (42 μL), potassium phosphate (0.79 g) and dioxane (4 mL) were added to a scintillation vial. The vial was flushed with nitrogen, sealed with a Teflon-lined cap, placed in an oil bath, and heated at 110° C. for 30 hours. The reaction was cooled to ambient temperature, diluted with chloroform and filtered through a bed of CELITE filter agent. The solvent was evaporated and the residue was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 90:10. Additional purification by recrystallization from acetonitrile provided 0.47 g of 7-(1,1-dioxo-[1,2]thiazinan-2-yl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as pale yellow crystals, mp 172-174° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2′-Ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester (0,172 g, 0.5 mmol) and diisopropylethylamine (0.18 mL, 1.0 mmol) were combined in CH2Cl2 (2.5 mL) and cooled to 0° C. Benzyl chloroformate (0.1 mL, 0.7 mmol) was added, and the reaction was stirred for 1 hour. The mixture was purified by silica gel chromatography, and then further purified by preparative HPLC to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.Cl.[CH3:14]O>O1CCOCC1>[CH3:14][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: O=C(O)Cc1cc(Br)ccc1F
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2-fluoro-phenyl)-acetic acid (2.3 mmol) in MeOH (15 mL) was added 4N HCl in 1,4-dioxane (2 mL), and the reaction was stirred at 90° C. for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]([NH2:21])=O>P(Cl)(Cl)(Cl)=O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[N:5][CH:4]=[C:3]1[C:19]#[N:21]
Reactant: CC(C)COc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)COc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Yield: 56.2 %

Procedure:
A mixture of 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)pyrimidine-5-carboxamide (7.4 g.) and phosphorus oxychloride (150 ml.) was heated under reflux for 3.5 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water (150 ml.). The mixture was stirred briefly, cooled, and filtered. The collected solid was recrystallized from 50% aqueous acetic acid to give the title compound (3.9 g., 58% yield), m.p. 186°-187°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[CH:13]>>[CH3:11][C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(C#Cc2cnc3cc(C)nn3c2)cc1

Procedure:
The title compound, brown solid, MS: m/e=248.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynyltoluene.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:7]=[C:6]([C:8](OCC)=O)[NH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].S(Cl)([Cl:34])=O>ClCCl.O1CCCC1>[Cl:34][CH2:8][C:6]1[NH:5][N:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:7]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)n[nH]1
Reactant: O=S(Cl)Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CCl)[nH]n1

Procedure:
To a tetrahydrofuran solution (4 mL) of ethyl 3-(trifluoromethyl)-1H-pyrazol-5-carboxylate (104 mg, 0.50 mmol), diisobutylaluminum hydride (1.75 mL, 1.75 mmol, toluene solution) was added at 0° C. and the resultant solution was stirred for 2 hours. To the reaction solution, saturated sodium sulfate aqueous solution was added and the resultant mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Subsequently, to a dichloromethane solution of the obtained residue (28 mg), thionyl chloride (39.4 mg, 0.33 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was used in the next reaction as it was.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CO)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(O)c1cccc(Br)n1
Reaction time: 0.5 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)-2-hydroxyethanone (2.2 g, 10.18 mmol) in ethanol (127 mL) was charged with sodium borohydride (0.385 g, 10.18 mmol). After 30 minutes, the reaction was concentrated to dryness and then partitioned between ethyl acetate (50 mL) and 3:1 saturated aqueous sodium bicarbonate:water (25 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (600 MHz, DMSO): δ 7.69 (m, 1H), 7.46 (m, 2H), 5.50 (d, J=5.0 Hz, 1H), 4.69 (m, 1H), 4.49 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][O:30][C:31](=[O:34])[C:32]#[CH:33]>>[CH3:29][O:30][C:31]([C:32]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10](=[O:11])[C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])=[CH:14][C:13]=3[Cl:27])[CH:9]=2)[CH:33]=1)=[O:34]
Reactant: C#CC(=O)OC
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: COC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.50 mmol) and propynoic acid methyl ester (0.50 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]#[CH:27].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:27][C:26]#[CH:25])[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.17 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 4 ml of DMF. 7 mg (0.18 mmol) of sodium hydride was added, to the obtained solution, and they were stirred at room temperature for 30 minutes. 30 mg (0.25 mmol) of 3-bromopropyne was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl.N1C=CC=CC=1>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2c(c1)c(-c1cncc(N[C@H](C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
To a solution of N2-[5-(5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (1.5 mL) and pyridine (0.2 mL) was added acetic anhydride (9.23 μL, 0.098 mmol) and the mixture was stirred for 2 h. The reaction was concentrated and the residue 5-2a was carried on without further purification.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.O1CCCC1.[O:14]=[C:15]([CH3:23])[CH2:16][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19].C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1>O>[N+:33](=[C:16]([P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])[C:15](=[O:14])[CH3:23])=[N-:34]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.32 g, 13.2 mmol) in 100 mL 6/1 benzene/tetrahydrofuran was added dimethyl 2-oxopropylphosphonate (2.0 g, 12 mmol) dropwise at 0° C. After the addition, the mixture was stirred at 0° C. for 1 hour and p-toluenesulfonyl azide (13% in toluene, 19.2 g, 12.6 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. Water was added and extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated to provide the crude title compound which was used in the next step without purification. MS (DCI/NH3) m/z 193 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>CC(O)C.CCOCC.[Fe]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:32])([F:31])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 50.8 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (17.26 mmol, 8 g) and iron (143 mmol, 8 g) in 2-propanol was added 2M hydrochloric acid. The reaction was refluxed for 3 hours. The reaction was filtered through celite washing with 2-propanol and concentrated under reduced pressure. Water and ethyl acetate was added. Solid potassium carbonate was added until the aqueous layer was basic. The organic phase was separated and the water layer was extracted with dichloromethane. The combined organic phases were combined, dried (sodium sulfate) and concentrated under reduced pressure. The crude material was chromatographed on silica eluting with ethyl acetate. The brown solid obtained was stirred in ether and filtered to give the title compound (3.8 g). MS (ESI) m/z 434.1 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:32]3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](N)CC1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (3.98 g, 11.8 mmol) and t-butyl trans-3-(4-aminocyclohexyl)propionate (2.70 g, 1 1.8 mmol) were condensed to give 5.04 g of t-butyl trans-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl]propionate as a colorless solid (78%). In the same manner as in Example 85, this solid (4.90 g, 8.95 mmol) was subjected to hydrogen reduction to give 3.52 g of compound (161) as a colorless solid (95%), which was treated with methanesulfonic acid (0.82 g, 8.52 mmol) in tetrahydrofuran solvent to give 3.82 g of methanesulfonate of compound (161) as a colorless solid (88%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2ocnc2c1
Reactant: Cc1nc2cc(O)ccc2s1
Product: Cc1nc2cc(OCC3CO3)ccc2s1

Procedure:
Compound 33 was prepared in the manner of compound 6 substituting 2-methyl-benzothiazol-5-ol for compound 8 in partC-5 of Example 1.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([NH:20][C@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:20]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:21]([C:23]([NH:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:25])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
One equivalent of EDC [1-(3-dimethylaminopropyl)3-ethylcarbodiimide.hydrochloride] (1 g, 5.3 mmol, Aldrich) is added into a cold stirred solution of 1 g (5.3 mmol) Boc Alanine (Sigma), 1.07 g of (5.3 mmol) of Gly-OBzl (Sigma), 0.71 g of HOBT (Aldrich), and 0.5 ml of NMM in 50 ml DCM. The reaction mixture is stirred at 0° C. for 3 h and at ambient temperature for 22 h. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The organic layer is washed with 10% aqueous citric acid, water, saturated NaHCO3, water, and saturated brine. The organic layer is dried over anhydrous Na2SO4 and the solid is decanted from the mixture. The organic solvent is evaporated and the residue is recrystallized using petroleum ether to give a colorless solid of Boc-Ala-Gly-OBzl (11). 1H-NMR (CDCl3): 1.35 (3H,d, J=6 Hz), 1.42 (9H, s), 4.05 (2H, d, J=5 Hz), 4.25 (1H, m), 5.15 (2H, s), 5.28 (1H, d, J=5 Hz), 7.02 (1H, br), 7.33 (5H, s). FABMS: 337 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[N:17][CH:18]=1>ClCCl.C(N(C(C)C)CC)(C)C>[C:4]1([CH2:3][CH2:2][C:1]([NH:12][C:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
Hydrocinnamoyl chloride (0.037 mL, 0.25 mmol) in dichloromethane was added to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.20 mmol) in dichloromethane (2 mL) and diisopropylethylamine (0.087 mL) at 0° C. The mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the title compound was obtained in 7.6% yield (7.3 mg) after column purification. 1H NMR (300 MHz, CDCl3) δ 7.99, 7.80, 7.71, 7.56, 7.27, 6.91, 6.61, 3.91, 3.57, 3.43, 3.27, 3.04, 2.64. MS (ES+) m/z 483.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C(O)(=O)C.N1CCCCC1>C(O)C>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([NH2:19])=[O:18])#[N:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(N)=O

Procedure:
A solution containing 1.3 g of 3,4-dihydroxy-5-nitro-benzaldehyde, 0.73 g of cyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. The solvent was evaporated in vacuo and the residue was recrystallized water-DMF. Yield 0.84 g (48%), m.p. 296-298° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:12])=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(Cl)ncnc1Cl
Temperature: 25 °C

Procedure:
A solution of 4,6-dichloro-5-pyrimidinecarbaldehyde (15.0 g, 84.8 mmol) in DMF (360 mL) was charged with potassium monopersulfate (38.9 g, 254 mmol) and stirred over night at rt. The reaction mixture was filtered through a pad of celite and partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with water (2×), brine, and dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ=9.02 (s, 1H).
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[N:6]12[CH2:9][CH2:10][C:3]([CH2:1][NH2:2])([CH2:8][CH2:7]1)[CH2:4][CH2:5]2
Reactant: N#CC12CCN(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC12CCN(CC1)CC2
Temperature: 23 °C
Reaction time: 3 h

Procedure:
A solution of 4-cyanoquinuclidine (0.30 g, 2.2 mmol) in diethyl ether (5 mL) was slowly added to a suspension of LAH (0.167 g, 4.41 mmol) in diethyl ether (15 mL) at 0° C. The reaction was stirred at 23° C. for 3 h, then quenched with sodium sulfate decahydrate and stirred for 30 more minutes. Ethyl acetate was then added and, after 30 minutes, celite was added and the suspension was filtered on celite. The filtrate was concentrated to dryness to give an oil (0.310 g, quant.). The compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 1.31-1.40 (6H, m), 2.43 (2H, s), 2.86-2.94 (6H, m).
Reaction SMILES: [C:1]([CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:19]([O:21]CC)=O)[CH3:4])#[N:2]>C(O)C.[Pt]=O>[CH3:4][CH:3]1[N:5]2[C:13]3[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6]2[C:19](=[O:21])[NH:2][CH2:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2c1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)C(C)CNC3=O
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of diethyl 1-(1-cyanoethyl)-1H-indole-2,6-dicarboxylate (3.9 g, 12.4 mmol) in ethanol (500 mL) is added platinum oxide (2.0 g, 8.8 mmol). The reaction mixture is then shaken under 50 psi of H2 for 4 h. Additional platinum oxide (700 mg, 3.1 mmol) is added along with more ethanol (10 mL) and the mixture is shaken under 50 psi of H2 for another 16 h. The reaction mixture is filtered through Celite under a flow of N2 and the Celite is rinsed with EtOAc. The filtrates are combined and concentrated to afford the title compound (3.2 g, 95%) which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)cc(F)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
3-Chloro-5-fluoro-2-hydroxybenzaldehyde (2.5 g., 0.014 mole) was taken into 25 ml. of acetone. Potassium carbonate (2.48 g., 0.018 mole) and methyl iodide (2.55 g., 0.018 mole) were added in sequence and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between methylene chloride and water. The organic layer was washed in sequence with fresh water, 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated to yield 3-chloro-5-fluoro-2-methoxybenzaldehyde (1.83 g., 69%; m.p. 59°-62° C.).