Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].S(=O)(=O)(O)O.N[C:11]1[NH:15][N:14]=[C:13]([N+:16]([O-:18])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20]>>[N+:1]([C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13]([N+:16]([O-:18])=[O:17])[NH:14][N:15]=1)([O-:3])=[O:2]
Reactant: Nc1[nH]nc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1n[nH]c([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
650 mg of sodium nitrite are added rapidly at 0-10° C. to a 20% solution of sulfuric acid (5 mL) containing 145 mg of 5-amino-3,4-dinitropyrazole. The mixture is left to react at this temperature for 1 hour and then the cold mixture is poured into 40 mL of 10% strength aqueous sodium nitrite which is maintained at 20° C. The mixture is subsequently heated at 50-60° C. for 30 minutes until the effervescence disappears completely. The excess sodium nitrite is then neutralized by addition of concentrated sulfuric acid. The reaction mixture is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a brine, dried over magnesium sulfate, filtered and then concentrated. 3,4,5-Trinitropyrazole is obtained in the form of an orange gum with a crude yield of 80%. The NMR and IR analyses are in accordance with those obtained with the product of Example 3.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 1 h

Procedure:
A mixture of 25 g of 1-chloro-7-methoxy-4-nitro-9H-thioxanthen-9-one, 32.1 g of anhydrous aluminum chloride, and 300 ml of 1,2-dichloroethane is heated under reflux for 1.5 hours. The mixture is concentrated, then treated with 640 ml of concentrated HCl. After 1 hour, the slurry is filtered, and then washed with 500 ml of water followed by 300 ml of 2-propanol, to afford the title compound as a gold solid, mp>300° C.
Reaction SMILES: [CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>C1COCC1>[CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Reactant: CC(C)CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCN1CCCN(C2CCCc3ccccc32)CC1
Yield: 74.2 %

Procedure:
A 250 mL flask was charged with a solution of 1-(1,2,3,4-tetrahydronaphthyl)homopiperazine (2.68 g, 11.6 mmol) in THF (105 mL). Triethylamine (2.20 ml, 3.03 g, 29.9 mmol) and 1-bromo-3-methylbutane (2.00 ml, 1.59 g, 10.5 mmol) were added. The solution was immersed in a 60° C. oil bath for 16 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography using diethyl ether:hexane:methanol (5:5:1) to obtain the title compound as a yellow oil (2.34 g). 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, 6H), 1.39 (m, 2H), 1.54-1.79 (m, 5H), 1.92-2.15 (m, 2H), 2.50 (m, 2H), 2.60-2.80 (m, 10H), 3.90 (m, 1H), 7.02-7.18 (m, 3H), 7.77 (d, 2H); m/s: M+H+ 301.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H].C>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Nc1ccc(Cl)c(Cl)c1Br
Yield: 86.1 %

Procedure:
A solution of 2-bromo-3,4-dichloronitrobenzene (23.5 g) in toluene was treated at 25°-35° C. for 1.25 hours with hydrogen in the presence of charcoal containing 5% platinum. The solution was then filtered and the filtrate was evaporated to dryness. The brown solid thus obtained was dissolved in diethyl ether and the solution was treated with decolourising charcoal and filtered. Evaporation to dryness of the filtrate gave 2-bromo-3,4-dichloroaniline (18.0 g), m.p. 78°-80° C. in the form of a brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([O:20][CH3:21])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:22][CH:23]=1
Reactant: CONCc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(Cl)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-chlorobenzyl)-O-methyl-hydroxylamine (Kawase, M.; Kikugawa, Y. J. Chem. Soc. Perkin Trans.1, 1979, 643-645) as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 129-130° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.69 (3H, s, OCH3), 4.79 (2H, s, NCH2), 6.39 (1H, s, CH), 7.4 (4H, s, aromatics). Anal. calcd. for C15H16ClNO5: C, 55.31; H, 4.95; N, 4.30. Found: C, 55.32; H, 4.95; N, 4.27.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]1.C([Li])CCC.O.Cl>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@H]1CC[C@H](CCCC)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A solution of 162.1 g of trans-1-(2,2-dibromovinyl)-4-butylcyclohexane in 1.3 l of absolute tetrahydrofuran was cooled to -75° C. under nitrogen gasification and treated dropwise within 1 hour with 690 ml of a 1.6M solution of butyl lithium in hexane. The mixture was subsequently stirred at -70° C. for a further 2 hours, then poured into 1.5 l of water, neutralized with concentrated hydrochloric acid and extracted twice with 1 l of hexane each time. The combined organic phases were washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness on a rotary evaporator. Distillation of the resulting light yellow crude product in a high vacuum gave in the main run 75.9 g (92.4%) of trans-1-ethynyl-4-butylcyclohexane as a colourless liquid; b.p. 41°-43° C./0.4 Torr.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]([CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cl)ncc2ncn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml). Cs2CO3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently. The reaction is stirred at room temperature overnight, poured into water. After extraction with CH2Cl2, the organic layer is washed with H2O and brine, dried (Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([S:18][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:16][CH:17]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[C:23]([O:22][C:20](=[O:21])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([CH2:12][CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=2)[N:14]=1)([CH3:28])[CH3:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)O)cc2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)benzoic acid methyl ester (7.0 g) obtained in Example 60-1 was dissolved in methanol (50 mL) and tetrahydrofuran (30 mL), 1 mol/L aqueous sodium hydroxide solution (24 ml) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.8 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:3]1=[O:18].OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:24]([O-:26])=[O:25])[CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:3]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC1C(=O)N(C2CCN(C)CC2)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1C(=O)N(C2CCN(C)CC2)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 3-methyl-1-(1-methylpiperidin-4-yl)indolin-2-one(0.18 g, 0.736 mmol) in con. H2SO4 (2 mL) was treated with fuming HNO3 (0.034 mL, 0.736 mmol) at −5 to −10° C. (ice+salt) and resulting solution was stirred for 30 min. at this same temperature. The reaction was quenched with addition of crushed ice, and then basified with 1 N NaOH and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5) to obtain compound 3-methyl-1-(1-methylpiperidin-4-yl)-5-nitroindolin-2-one (0.13 g, 61%) as a solid. 1H NMR (DMSO-d6) δ: 1.39 (d, 3H, J=7.5 Hz), 1.55-1.62 (m, 2H), 2.01 (t, 2H, J=11.4 Hz), 2.20 (s, 3H), 2.31-2.39 (m, 2H), 2.87 (d, 2H, J=11.4 Hz), 3.63 (q, 1H), 4.06-4.16 (m, 1H), 7.39 (d, 1H, J=9.3 Hz), 8.18-8.22 (m, 2H); ESI-MS (m/z, %) 290 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:22]([O:25]CC=C)[CH:23]=[CH2:24].C(C1C=C(C(C)C)C=C(Br)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:3]2[O:11][CH:23]([CH2:22][OH:25])[CH2:24][C:4]=2[CH:5]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:7]=1
Reactant: CC(C)c1ccc(O)c(Br)c1
Reactant: C=CCOCC=C
Agent: C=CCc1cc(C(C)C)cc(Br)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: CC(C)c1cc(Br)c2c(c1)CC(CO)O2
Yield: 17 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(C)=O>CN(C=O)C>[NH:38]([C:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)CC(=O)NC1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)Nc3ccccc3)cc2)nc1N(C)CC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
A solution of methyl {2-(4-aminobenzyl)-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)-amino]pyrimidin-5-yl}acetate (0.050 g, 0.11 mmol) in DMF (2 mL) was treated with phenyl isocyanate (0.022 mL, 0.20 mmol). After stirring at room temperature for 18 hours, EtOAc was added and the organic phase was washed with 8% NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product thus obtained was triturated with CH2Cl2 and diisopropyl ether to give methyl {2-{4-[(anilinocarbonyl)amino]benzyl}-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)amino]pyrimidin-5-yl}acetate (0.055 g, 87% yield) as a white powder.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].C[Si]([NH-])(C)C.Cl[Si](C)(C)C.[C:22]1([CH2:28][CH2:29][S:30][CH:31]([C:35]([OH:37])=O)[C:32]([OH:34])=[O:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K+].[Br-]>O>[OH:37][C:35]1[CH:29]=[C:28]([C:22]2[CH:27]=[CH:26][C:25]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:24][CH:23]=2)[O:34][C:32](=[O:33])[C:31]=1[S:30][CH2:29][CH2:28][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[NH-]
Agent: [Br-]
Solvent: O
Product: O=c1oc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using the corresponding benzenesulfonamide (3.0 g, 10.91 mmol), lithium bis(trimethylsilylamide (3.65 g, 21.82 mmol), chlorotrimethylsilane (3.68 mL, 21.82 mmol) and diethyl ester of [(phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 89°-91° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.78 (t, 2 H), 3.03 (t, 2 H), 6.86 (s, 1 H), 7.25 (m, 6 H), 7.72 (t, 3 H), 7.86 (m, 5 H); IR (KBr) 3443, 3335, 1725, 1632, 1543, 1383, 1171, 912, 729, 581, 552 cm-1 ; Analysis calc'd for C25H21N1S2O5.H2O: C, 60.35; H, 4.66; N, 2.81; found: C, 60.13; H, 4.47; N, 3.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:36].CO>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:28])([CH3:29])[C:25]([NH2:36])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)(C(=O)O)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C(N)=O)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
An 250-mL round bottom flask was charged with 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoic acid (0.33 g, ˜0.40 mmol) in dichloromethane (10 ml). To this mixture at 0° C. was added oxalyl chloride (0.17 mL, 2.00 mmol) followed by DMF (1 drop). After stirring for 3 h, the volatile material was removed under reduced pressure to afford crude acid chloride. The residue was dissolved in dichloromethane (20 mL), cooled to 0° C. and 7N ammonia in methanol (14.0 mL, 98 mmol) was added. After stirring for 1.25 h the volatile material was removed under reduced pressure. The residue was absorbed onto silica (5 g). Purification by chromatography on silica using hexanes/ethyl acetate as eluent afforded 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanamide (0.128 g, 79%) as a white solid. MW=404.93. 1H NMR (CDCl3, 500 MHz) δ 7.92-7.90 (m, 1H), 7.80-7.77 (m, 1H), 7.37-7.31 (m, 4H), 7.24 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 5.32 (br s, 1H), 5.16 (br s, 1H), 3.96 (s, 2H), 3.09 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H), 1.57 (s, 6H). Treatment with 1.25M HCl in methanol (0.72 mL, 0.90 mmol) afforded the title compound (0.124 g, 94%) as a white solid. MW=441.39. M.p. 180-182° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.88 (br s, 1H), 7.58-7.52 (m, 2H), 7.29-7.22 (m, 4H), 6.83 (s, 2H), 5.50 (br s, 1H), 4.03 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.39 (s, 6H); APCI MS m/z 405 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH:18]C(OCC2C=CC=CC=2)=O)[CH2:14][CH:15]([F:17])[F:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH2:18])[CH2:14][CH:15]([F:17])[F:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of 168 mg 4-((S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyryl)-piperazine-1-carboxylic acid ethyl ester in 15 ml ethyl acetate were added 100 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 1 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethyl acetate and concentrated. Yield: 100 mg colorless oil
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N[C@@H](Cc4ccc(-c5ccccc5)cc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the (2S)-2-amino-3-biphenyl-4-yl-N,N-dimethylpropanamide (19 mg, 0.070 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=10) to afford the desired product (3 mg, 20%) as a white solid. Analytical LCMS (M+H)+: m/z=538.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([O:31]COC)[C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([OH:31])[C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COCOc1ccc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(O)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxy-3-methoxymethoxyphenyl)-L-phenylalanine methyl ester (165 mg) was dissolved in MeOH (5 mL) and HCl in dioxane (4 M, 1 mL) was added to the mixture. The mixture was stirred at room temperature for 3 h. The mixture was evaporated and the residue was taken up with water (40 mL) and extracted with CH2Cl2. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexane and AcOEt 3:1 to 1:1) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-hydroxyphenyl)-L-phenylalanine methyl ester (145 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[C:17]1([C@@H:15]([NH:14][C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:7][CH:6]=3)[CH:9]=[N:10][CH:11]=2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Nc1cncc(-c2ccc(NS(C)(=O)=O)cc2)n1)c1ccccc1
Temperature: 0 °C
Yield: 73.3 %

Procedure:
To a stirred solution of 6-(4-aminophenyl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine (58 mg, 0.2 mmol) in dry THF (3 mL) was added triethylamine (70 μL, 0.5 mmol). The solutions was cooled to 0° C. and methanesulphonyl chloride (18.6 μL, 0.24 mmol) was added dropwise. The mixture was allowed to warm to RT and stirred overnight, before dilution with water (15 mL). The product was extracted into ethyl acetate (2×15 mL) and the combined extracts washed with 10% aqueous Na2CO3 and brine, and then dried (Na2SO4). The solvent was removed under reduced pressure and the product purified by chromatography eluting with ethyl acetate-hexane (3:2) to afford the product as a pale yellow solid (54 mg, 73%).