Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:8]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 20.0 g of 4,5-dichloro-2-nitroaniline and 16.0 g of 1-ethylpiperazine in 50 ml of dimethylsulfoxide, 20.0 g of potassium carbonate was added, followed by 2 hours' stirring at 120° C. Water was added to the reaction liquid, followed by extraction with diethyl ether. The diethyl ether layer was successively washed with water and saturated brine, dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from chloroform-diethyl ether, to provide 20.3 g of the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:7]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:10]=1[CH3:11]>CS(C)=O>[CH:12]1([C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1oc(C2CCCCC2)nc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(C2CCCCC2)nc1CC#N
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To 1.464 g of NaCN (29.88 mmol), dissolved in 20 ml of DMSO, was slowly added via dropping funnel 4.12 g of the above prepared 4-chloromethyl-2-cyclohexyl-5-methyl-oxazole (19.28 mmol) at such a rate that the internal temperature stayed at 25–30°. Stirring was continued for additional 2 h at 35°. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) gave 1.900 g of the title compound as colorless liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.CCOCC>C(O)(=O)C>[C:14]1([C:12]2[NH:27][C:21]3[C:26]([C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)[nH]c3ccccc23)cc1
Temperature: 130 °C

Procedure:
The mixture of 0.9 g (3.3 m mol) of 4-methylsulfonylphenyl-actophenone prepared in Example 97 and 0.5 g (3.3m mol) of phenylhydrazine hydrochloride were heated at 130° C. for 0.5 h. After cooling, 20 ml of acetic acid and 0.2 g of BF3.Et2O was added and heated to reflux for 1 h. Acetic acid was removed in vacuo, the resulting residue was suspended in water, filtered, dried and purified by column chromatography using petroleum ether/ethyl acetate 3:1 as elutant, 0.45 g of the title compound was obtained as white crystal, yield, 39.5%, m.p. 239-241° C. The data of Nuclear Magnetic Resonance shown that: 1HNMR (300 MHz, DMSO)δ: 3.24 (s, 3H, SO2CH3), 7.05-7.90 (m, 13H, Ar—H), 11.77 (s, 1H, N—H); Anal. Calcd for: C21H17NO2S: C 72.60, H 4.93, N 4.03; Found: C 72.35, H 5.03, N 4.25.
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[C:16]1([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][NH:31][C:32]=3[NH2:33])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[N:31]2[N:30]=[CH:29][C:28]([C:25]3[CH:26]=[N:27][C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][CH:24]=3)=[C:32]2[N:33]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C1
Temperature: 115 °C

Procedure:
A mixture of tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate (60.3 mg, 0.28 mmoL) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (67.8 mg, 0.28 mmoL) in toluene (5 mL) was heated at 115° C. overnight. Concentration afforded crude tert-butyl 8-amino-3-(6-phenylpyridin-3-yl)-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate, which was converted to 3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-8-amine by the treatment of 20% TFA/CH2Cl2 at room temperature: LCMS tR=0.38 Min (5 min run, UV254nm), Mass calculated for, M+328.1, observed LC/MS m/z 329.2 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>O1CCOCC1>[CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])([C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCCBr
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCCCC(=O)OC)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.50 g (52.22 mmol) of sodium hydride were added carefully to a solution of 2.00 g (69.62 mmol) of diallyl malonate in 700 ml of dioxane. After the evolution of gas had ended, the mixture was stirred at room temperature for 20 min, and a solution of 7.00 g (34.81 mmol) of methyl 5-bromovalerate in 120 ml of dioxane was added dropwise. The solution was stirred at 110° C. for 16 h. The resulting precipitate was filtered off, the solvent was removed and the residue was taken up in water. The mixture was extracted with diethyl ether, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromato-graphically (silica gel, cylcohexane/ethyl acetate 10:1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC)[C:3]([OH:5])=O.[Cl-].[CH2:21]([O:28][C:29](=[O:38])/[CH:30]=[CH:31]/[C@@H:32]([NH3+:37])[CH2:33][CH2:34][CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([NH:37][C@@H:32]([CH2:33][CH2:34][CH2:35][CH3:36])/[CH:31]=[CH:30]/[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:38])=[O:5]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCC[C@H]([NH3+])/C=C/C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(O)C(=O)N[C@H](/C=C/C(=O)OCc1ccccc1)CCCC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-hydroxyhexadecanoic acid (0.54 g, 2.0 mmol) and (E,4S)-1-(benzyloxy)-1-oxooct-2-en-4-aminium chloride (0.28 g, 1.0 mmol) in CH2Cl2 (5 mL), Et3N (0.3 mL) and subsequently WSCI (0.57 g, 3.0 mmol) and HOBt (0.32 g, 2.0 mmol) were added at 0° C. The reaction mixture was stirred for 1 h at 0° C. and at room temperature for 1 day. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (CHCl3/MeOH 98/2). Yield 0.33 g (75%); [α]D−10.3 (c 0.5 CHCl3);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][N:7]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 1.85 g (0.01 mole) of 3-cyclopentylamino-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.020 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 3.05 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-propanoic acid ethyl ester (IV-10)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][C:18](OCC)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of (R)-ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (574 g) in tetrahydrofuran (5.7 L) at about -78° C. was added boron trifluoride etherate (295.4 g) and then diisobutylaluminum hydride (1.5M in toluene, 3.91 L, 3.1 eq) added (over two hours) maintaining the temperature below -62° C. The resulting solution was stirred (between -78° and -62° C.) for three hours and then quenched into aqueous citric acid solution (2 kg citric acid in 5 L water plus 4 L ice) over about 40 minutes. The phases were separated and the aqueous phase extracted with ethyl acetate (2×2.1 L). The combined organic solution was dried (over magnesium sulphate) and evaporated, then the residual oil purified by chromatography through silica gel, eluting with mixed ethyl acetate/hexane (9:1 to 4:1) to give the-title compound as an oil (260 g), as produced in Example 12A (as an alternative, the residual oil can be purified by chromatography through silica gel eluting with ethyl acetate:hexane (1:1)).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Br>C(O)C>[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[N:4]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Nc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)nc(SCc2c(F)cccc2F)n1
Temperature: 22 °C

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimdine monohydrate (1.61 g, 10.0 mmol) is suspended in 50% ethanol (10 ml), then treated with solid sodium hydroxide (440 mg, 11.0 mmol) and stirred until the solid dissolved. 2,6-Difluoro-benzyl bromide (2.17 g, 10.5 mmol) is added and the reaction heated to reflux for 1.5 hrs. After cooling to 22° C., the solid is collected, washed with water, then air dried. The title compound is recrystallized from ethanol, mp 245-246° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[C:18]1[S:22][N:21]=[CH:20][C:19]=1[N+:23]([O-:25])=[O:24]>O1CCOCC1.C(OCC)(=O)C>[N+:23]([C:19]1[CH:20]=[N:21][S:22][C:18]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cnsc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1B2) (464 mg, 2.3 mmol) in dioxane (10 mL) at room temperature was added NaH (114 mg, 2.8 mmol). The mixture was stirred for 20 min and 5-bromo-4-nitroisothiazole (P) (400 mg, 1.9 mmol) was added. The mixture was stirred at 65° C. for 5 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-nitroisothiazol-5-yloxy)piperidine-1-carboxylate (1C3) (280 mg, 0.85 mmol).
Reaction SMILES: O.[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:4][CH3:5])[CH3:3].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=1)([CH2:4][CH3:5])[CH3:3]
Reactant: CCC(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: CCC(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 10.0 g of 4-sec-butylphenol was added dropwise, 7.5 ml of 61% nitric acid was added dropwise while cooling with ice. After, the temperature of the mixture was raised to room temperature and the reaction was continued for 4 days. The reaction mixture was extracted with 300 ml of ethyl acetate, washed with a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 14.71 g of 4-sec-butyl-2-nitrophenol.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC=CC=3OC)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:39][CH3:38])=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: COc1ccccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 441 (0.27 mmol). The crude product was used without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccc(F)c1
Product: CCC(CC)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 93.7 %

Procedure:
The title compound (93 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 138 mg of 3-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H24FN3, 301.20. found, m/z 302.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.30 (m, 4H), 3.92-3.85 (m, 1H), 3.51-3.43 (m, 2H), 3.38-3.33 (m, 2H), 3.30-3.24 (m, 2H), 2.86-2.78 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73 (m, 2H), 0.73 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([O:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][CH2:45][O:44][CH:41]([CH3:43])[CH3:42])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OCCCN
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)OCCCNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-isopropoxypropylamine (34 mg) according to Method B to give the title compound (34 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.28-7.17 (m, 5H), 7.03 (d, J=8.6 Hz, 1H), 4.80 (s, 2H), 4.50 (m, 1H), 4.24 (dd, J=5.1 Hz, J=9.3 Hz, 1H), 3.54 (t, J=6.1 Hz, 1H), 3.35 (m, 2H), 3.23 (m, 1H), 3.14 (m, 1H), 3.08-2.91 (m, 3H), 2.75 (dd, J=9.6 Hz, J=13.5 Hz, 1H), 1.63 (m, 2H), 1.35 (s, 9H), 1.12 (dd, J=2.0 Hz, J=6.1 Hz); IR (KBr) cm−1; HRMS m/z 629.2946 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.CN([CH:24]=[O:25])C>C1COCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>CC(O)=O.O.[Fe]>[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[C:10]([Cl:11])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1cc(Cl)c(Br)cc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 4-bromo-5-chloro-2-nitrobenzamide (900 mg, 3.2 mmol) in AcOH (20 mL) and water (5 mL) at 70° C., Fe powder (900 mg, 16.1 mmol) was added and the resulting mixture was stirred at 70° C. for 1 h. The mixture was allowed to cool to RT and poured into ice-water. The precipitate was collected by filtration and rinsed with water. This crude product was dissolved with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (770 mg, 97% yield). ESI-MS m/z: 250.1[M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2C=CN[CH:16]=2)[CH:14]=1.CI>O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:6][N:4]([CH3:5])[CH:3]=2)[CH:14]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc(-c2cc[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1ccc(-c2cncc(Br)c2)c1

Procedure:
Sodium hydride (60% in oil) (6 mg) was added to a DMF (1 ml) solution containing 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg), followed by stirring. Methyl iodide (9 μl) was added, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=30:1 to 3:1), and a white solid of 3-bromo-5-(1-methyl-1H-pyrrol-3-yl)pyridine (18 mg) was thus obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[CH:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1)([CH3:4])[CH3:3].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+]>>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[N:8]=[C:7]([CH:16]=[CH:17][C:18](=[N:29][OH:30])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]=1)([CH3:1])[CH3:4]
Reactant: NO
Reactant: CC(C)(C)c1nc(C=CC(=O)COc2ccccc2)nc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)c1nc(C=CC(COc2ccccc2)=NO)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
1-[4,6-Bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-4-phenoxy-1-butene-3-one (0.7 g, 1.9 mmol) is added to an ethanolic (50 mL) solution of hydroxylamine hydrochloride (1.3 g, 19 mmol) and sodium acetate (1.7 g, 20.9 mmol). The reaction mixture is stirred at room temperature under argon for 18 hours. The ethanol is evaporated under reduced pressure, and the remaining solid is partitioned between 20 mL of water and 20 mL of ethyl acetate. The layers are separated and the aqueous phase is washed with ethyl acetate (3×20 mL). The combined organic layers are washed with water (3×20 mL) and 20 mL of brine. Drying over MgSO4 followed by evaporation of solvent gives a yellow oil. Flash chromatography (silica, methylene chloride) followed by recrystallization from hexane gives 0.21 g (29%) of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-4-phenoxy-1-butene-3-one oxime, mp 130°-135° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:7].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[C@H:9]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Yield: 99.5 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzyl)-piperazine (360 mg), iron powder (360 mg), ammonium chloride (36 mg) and water (1.5 ml) in ethanol (6 ml) was heated under reflux for 40 minutes. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.34 g).