Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](OC(C)(C)C)=[O:21])=[N:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1.Cl.[CH3:29][O:30][C@H:31]([CH3:41])[C@H:32]([NH:36][C:37]([O:39][CH3:40])=[O:38])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](=[O:21])[C@@H:32]([NH:36][C:37](=[O:38])[O:39][CH3:40])[C@H:31]([O:30][CH3:29])[CH3:41])=[N:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: CC(C)(C)OC(=O)N1C(c2ncc(-c3ccc(Br)cc3F)[nH]2)[C@H]2CC[C@@H]1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1C(c2ncc(-c3ccc(Br)cc3F)[nH]2)[C@H]2CC[C@@H]1C2)[C@@H](C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(1R,4S)-tert-butyl 3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate was dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL). After 1 h, the reaction mixture was concentrated. The residue was treated (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (76 mg, 0.406 mmol), HATU (154 mg, 0.406 mmol) and DMF (4 mL). The stirred reaction mixture was cooled to 0° C., DIPEA (0.35 mL, 2.03 mmol) was added dropwise and the reaction mixture was warmed to RT. After 20 min, it was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford the title compound (162 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: N#CCCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4cccc(CCC#N)c4)n3)cc21

Procedure:
3-{3-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-propionitrile was prepared from 3-[3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-propionitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one) in an analogous manner to Example 1d. Title compound isolated as a white foam. Purity 99% (HPLC). LCMS: 462.50 (M+H). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.96 (bs, 1H), 7.66 (bs, 1H), 7.62 (s, 1H), 7.28-7.26 (m, 2H), 7.25-7.23 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.98 (d, J=7.3 Hz, 1H), 4.00-3.55 (m, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.67-2.64 (m, 2H), 2.30-2.27 (m, 2H), 2.18-2.08 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:47][C:48](=[O:51])[CH2:49]Br)(C)(C)C.C(O)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C.O>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:49][C:48]([OH:51])=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: CCOCOCC
Solvent: O
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture that consists of 500.0 g (924.2 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose and 50.00 g (147.1 mmol) of tetrabutylammonium hydrogen sulfate in 2500 ml of diethoxymethane is cooled to a temperature of 0° C. 121.77 g (217.0 mmol) of fine-powder potassium hydroxide is then added thereto, and it is stirred for 10 more minutes. At a temperature of between 0° C. and 5° C., 180.39 g (1608 mmol) of bromoacetic acid tert-butyl ester is added in drops within 30 minutes while being stirred vigorously. Stirring is continued for two hours at 0° C. It is then allowed to reach room temperature within two hours, 500 ml of absolute ethanol (denaturized with cyclohexane) is added thereto, and the solvent is largely distilled off at a bath temperature of 105° C. 1000 ml of ethanol (absolute, denaturized with cyclohexane) is now added thereto, and the solvent is largely distilled off again at a bath temperature of 105° C. 1000 ml of ethanol (absolute, denaturized with cyclohexane) is again added thereto, as well as 60.89 g (1085 mmol) of potassium hydroxide (as a powder) as well as 1000 ml of completely demineralized water. It is refluxed for 7 hours and then concentrated by evaporation to an oil that can still be stirred. After cooling to room temperature, the residue is extracted 3 times with 500 ml each of hexane. The aqueous phase is mixed with 500 ml of MTB and set at a pH of 2 while being stirred vigorously with 37% hydrochloric acid. The aqueous phase is then extracted twice with 1000 ml each of MTB. The organic phases are combined, dried and evaporated to the dry state in a rotary evaporator at a bath temperature of 50° C. and a pressure of 70 mbar. The residue is chromatographed on 1000 g of silica gel 60 (grain size 40-63 μm). As an eluant, 2700 ml of nhexane, 5400 ml of dichloromethane as well as 1500 ml of methanol are used. The product-containing fractions are combined and evaporated to the dry state in a vacuum.
Reaction SMILES: CC(C)=O.[C:5]1([C@@H:11]([NH2:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1([C@H:11]([NH2:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](N)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](N)c1ccccc1
Yield: 234 %

Procedure:
The above two crystals were combined (0.89 g), 13 ml of a mixed solution of acetone:water=8:5 was added, and stirring was carried out at 55° C. 0.47 g of (S)-(−)-1-phenylethylamine was added to this solution, and it was stirred at room temperature for 15 hours. The resulting crystals were filtered, yielding 1.10 g of (R)-(−)-1-phenylethylamine salt.
Reaction SMILES: O.[CH3:2][O:3][C:4](=[O:15])[C:5](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:6]([CH2:8]Cl)=O.[NH2:16][C:17]([NH2:19])=[S:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4](=[O:15])/[C:5](/[C:6]1[N:16]=[C:17]([NH2:19])[S:18][CH:8]=1)=[N:10]\[O:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(N)=S
Reactant: CCCON=C(C(=O)CCl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCO/N=C(\C(=O)OC)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture solution of 20 ml of water and 25 ml of ethanol are added 7.0 g of 4-chloro-2-(n-propoxyimino)acetoacetic acid methyl ester, 2.4 g of thiourea and 4.3 g of sodium acetate(trihydrate). The mixture is stirred for one hour at 40° C. The reaction mixture is, under cooling, adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate, followed by stirring for 30 minutes. The resulting crystals are collected by filtration, washed with water and isopropyl ether in this order, and dried to yield 2-(2-amino-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester as crystals, m.p. 115°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[Cl:18][CH2:19][CH2:20]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Cl:18][CH2:19][CH2:20][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: OCCCl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(CCCl)C2=O)cc1

Procedure:
The title compound 28f was prepared from compound 2 (249 mg, 1.00 mmol), 2-chloroethanol (100 μL, 1.50 mmol), triphenylphosphine (393 mg, 1.50 mmmol) and DIAD (295 μL, 1.50 mmol) in a manner similar to that described for 9 in 88.5% (276 mg) yield as a light-yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-nitrobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(Cl)ccc2c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate (0.9705 g, 2.77 mmol) in anhydrous acetonitrile (20 mL) at 0° C. was added SelectFluor (1.078 g, 3.04 mmol) in one portion. The reaction mixture was stirred for 4 hours at 0° C., then 1 hour at room temperature. The reaction mixture was quenched with saturated Na2HPO4 solution and stirred for 20 minutes. The mixture was extracted with ethyl acetate (2×), dried (MgSO4), filtered, concentrated and stored overnight in a freezer. The residue was purified by flash column chromatography (silica gel, 0 to 15% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H21ClFO4: 367.8. Found: 366.9, 368.9.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:8]2)[O:4][NH:3]1.Br>>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C@H:9]1[CH2:8][C@@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccccc3C(F)(F)F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (597 mg, 1.55 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (358 mg, 71%). 1H NMR (600 MHz, cd3od) δ 1.68 (q, 1H), 1.84 (qd, 1H), 2.11 (d, 1H), 2.22 (d, 1H), 3.02-3.20 (m, 3H), 3.21-3.32 (m, 1H), 3.51 (d, 1H), 3.57-3.67 (m, 1H), 5.74 (s, 1H), 7.44-7.56 (m, 2H), 7.64 (t, 1H), 7.74 (d, 1H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1328
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:29][N:30]([CH3:33])[CH:31]=[S:32]>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:25]([OH:26])[C:31]([N:30]([CH3:33])[CH3:29])=[S:32])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=S
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)C(=S)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
To a solution of distilled diisopropylamine (22.9 mL, 175 mmol) in 400 mL of anhydrous THF at −78° C. was added 1.6 M n-butyllithium in hexanes (100 mL, 160 mmol) over a period of 45 min. The mixture was stirred at −78° C. for 1.5 h. To the solution was cannulated over a period of 1 h a solution of 4-benzyloxybenzaldehyde (30.9 g, 146 mmol) and N,N-dimethylthioformamide (13.7 mL, 160 mmol) in 100 mL of distilled THF. The reaction mixture was stirred at −78° C. for 16 h. The reaction was then quenched with 500 mL of saturated NH4Cl solution. The mixture was extracted with EtOAc (3×1 L), and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was then recrystallyzed from EtOAc/hexanes to afford 20.0 g (66.5 mmol, 46%) of an off-white solid.
Reaction SMILES: [NH:1]1[C:55](=[O:56])[C@@H:51]([CH:52]([CH3:54])[CH3:53])[NH:50][C:48](=[O:49])[C@H:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][C:37](=[O:38])[C@H:32]([CH2:33][C:34](=[O:36])[OH:35])[NH:31][C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O>C(O)(C(F)(F)F)=O.ClCCl.C1(S)C=CC=CC=1>[NH:1]1[C:55](=[O:56])[C@@H:51]([CH:52]([CH3:54])[CH3:53])[NH:50][C:48](=[O:49])[C@H:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][C:37](=[O:38])[C@H:32]([CH2:33][C:34](=[O:35])[OH:36])[NH:31][C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:23]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@@H](C(C)C)NC(=O)[C@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CCNC2=O)c(C)c1C
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CCNC(=O)[C@H](CCCNC(=N)N)NC1=O
Reaction time: 4 h

Procedure:
A solution of 0.28 g of cyclo-(Arg(Mtr)-β-Ala-Asp-Phe-D-Val) [obtainable by cyclization according to Ex. 1] in 8.4 ml of TFA, 1.7 ml of dichloromethane and 0.9 ml of thiophenol is allowed to stand at room temperature for 4 hours, then concentrated and, after diluting with water, freeze-dried. Gel filtration on Sephadex G 10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under the conditions indicated give cyclo-(Arg-β-Ala-Asp-Phe-D-Val); RT=17.0; M+ 589.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[F:23][C:20]1[CH:19]=[C:18]([F:24])[CH:17]=[CH:22][C:21]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OC)cc(C=Cc2ccc(F)cc2F)cc1OC
Temperature: 140 °C

Procedure:
A mixture of (3,5-dimethoxy-4-1-propylphenyl)ethene (0.649 g, 3.15 mmol), 1-bromo-2,4-difluorobenzene (1.23 g, 6.37 mmol), dihydrogen di-μ-chlorotetrkis(di-tert-butylphosphinito-KP)dipalladate (0.1409 g, 0.151 mmol), Bu4NI (0.582 g, 1.58 mmol) and K2CO3 (1.45 g, 10.5 mmol) in DMF (10 mL) was heated at 140° C. under argon. After the reaction was complete (6 h), the reaction mixture was poured into water (10 ml). The aqueous was acidified with 2NHCl and extracted with ether (2×50 mL). The extract was washed with saturated sodium chloride and then dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 2% ethyl acetate in hexane afforded 1-(2,4-difluorophenyl)-2-(3,5-d-imethoxy-4-1-propylphenyl)ethene (31) quantitatively as a yellowish crystal. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 (d, J=17 Hz, 1H), 7.27 (d, J=17 Hz, 1H), 7.63 (d, J=8 Hz, 2H), 8.13 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[NH2:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[C:2]1([C:1]2[NH:9][CH2:10][C:11]3[C:12](=[CH:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)[N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)CNC(c1ccccc1)=N2

Procedure:
N-Benzoyl-2-amino-5-nitrobenzylamine (33 g, 0.12 mol) and phosphoryl chloride (150 ml) are refluxed for 3 hours. The mixture is concentrated and water is added, followed by addition of aqueous ammonia (pH>10). The product is filtered off and recrystallized from water, and then from 2/1 isopropyl ether/hexane. Yield: 27.6 g (89%); IR (KBr): 3387, 3198, 1599, 1512, 1341 cm−1; 1H-NMR (d6-DMSO) 7.95 (m, 4H); 7.30 (m, 4H); 7.01 (m, 1H); 4.71 (s, 2H).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:25])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>COCCO>[CH:20]1([CH2:19][CH2:18][CH2:17][O:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:6](=[O:25])[O:7]3)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1c(O)c2c(OCCCC3CCCC3)cccc2oc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2c(OCCCC3CCCC3)cccc2oc1=O)C(=O)O
Yield: 77 %

Procedure:
A mixture of 5-(3-cyclopentyl-propoxy)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (110 mg, 0.32 mmol) and L-alanine (424 mg, 4.76 mmol) in 2-methoxyethanol (9 mL) was added sodium methoxide (207 mg, 3.84 mmol). Resulting mixture was refluxed overnight and concentrated. Residue was dissolved in water (75 mL) and extracted with (1/1) EtOAc/hexanes which was discarded. The aqueous layer was acidified using 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to provide the title compound (99.4 mg). MS ESI(−) m/e: 402.10 (M−1).
Reaction SMILES: O1CCOCC1.Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH2:8]([N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:19][CH2:20]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 M dioxane solution of HCl was added to a methanol (80 mL) solution of 1-benzyl-4-[N-(tert-butoxycarbonyl)glycyl]aminopiperidine (6.59 g). The resulting solution was stirred at room temperature for 2 hours and concentrated. A 2 M aqueous solution of NaOH (20 mL) was then added to the solution. The resulting mixture was extracted with dichloromethane (40 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (SiO2, ethyl acetate/methanol/triethylamine=85:12:3) to thereby provide 1-benzyl-4-(glycylamino)piperidine (3.91 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 1.47-1.59 (m, 2H), 1.59 (br, 2H), 1.76-1.96 (m, 2H), 2.10-2.19 (m, 2H), 2.75-2.87 (m, 2H), 3.29 (s, 2H), 3.50 (s, 2H), 3.65-3.89 (m, 1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C@@H:12]([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[OH:14][CH2:13][C@@H:12]([N:11]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)C(=O)O)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)CO)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)propanoic acid [439589-23-8] (16 g, 41.9 mmol) in THF (150 mL) was slowly added under argon borane dimethylsulfide (8.4 mL, 84 mmol) at 0-5° C. The reaction mixture was stirred for 1 h at 0-5° C. followed by 3 h at 40-45° C. Excess borane was destroyed by careful addition of MeOH and the reaction mixture was evaporated 3× with 200 mL MeOH and 2× with CHCl3. The title compound was obtained after drying as a colorless oil (13.7 g, 99%): TLC (hexane/EtOAc 1:1) Rf=0.22; tR=1.06 min (UPLC 1), tR, 1.02 min (LC-MS 3); ESI-MS: 330 [M+H]+ (LC-MS 3).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:8][CH:9]=3)=[O:22])[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(C(=O)N2CCN(Cc3ccccc3)CC2)cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.6 %

Procedure:
To a solution of [1-methyl-5-(5-nitropyridin-2-yloxy)-1H-indol-2-yl]piperazin-1-ylmethanone (2.09 g, 5.5 mmol) in 1,2-dichloroethane (45 mL) were added benzaldehyde (1.16 g, 10 mmol), sodium triacetoxyborohydride (2.33 g, 11 mmol) and acetic acid (0.7 mL, 11 mmol) under ice cooling. The reaction mixture was stirred for 14 hours at room temperature under a nitrogen atomoshere. The solvent was removed under reduced pressure, and to the residue was added water. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=60:1) to give 2.66 g of the title compound as a pale brown oil.