Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH3:8].[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([C@@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])[CH3:8])=[CH:17][CH:16]=4)=[O:15])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: C[C@@H](c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc([C@H](C)N3CCCS3(=O)=O)cc2)CC1
Yield: 73.4 %

Procedure:
Using (S)-4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 44 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (143 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (207 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[N:32]([CH3:34])[CH3:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:33][N:32]([CH3:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[NH:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CN(C)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1ccccc1Nc1cc(CCc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenethylbenzoate 0.12 g and cesium carbonate 0.33 g were added 2-bromo-N,N-dimethylaniline 0.16 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg and palladium acetate 1.8 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 21 hours. Cesium carbonate 66 mg, 2-bromo-N,N-dimethylaniline 40 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((2-(dimethylamino)phenyl)amino)-4-phenethylbenzoate.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH3:10][N:11]1[C:17]2[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=2[NH:15][C:14](=[O:24])[C:13]2=[CH:25][S:26][CH:27]=[C:12]12>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:11]([CH3:10])[C:12]2=[CH:27][S:26][CH:25]=[C:13]2[C:14]1=[O:24]
Reactant: CN(C)CCCl
Reactant: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2CCN(C)C
Reaction time: 18 h

Procedure:
A mixture of 0.36 g. of 55% sodium hydride-mineral oil dispersion and 0.58 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.52 g. of 4,9-dihydro-4,6,7-trimethyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 119°-120°C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:24]=[N:25]/[O:26][CH3:27])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11](/[CH:24]=[N:25]/[O:26][CH3:27])=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C=N/OC)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(/C=N/OC)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-1-(5-(benzyloxy)-7-((methoxyimino)methyl)benzo[d]thiazol-2-yl)-3-ethylurea (325 mg, 0.85 mmol) was stirred in DCM (17 ml) and methanesulfonic acid (2.8 ml) was added. The reaction was allowed to stir at rt for 1 h in a round bottomed flask equipped with a drying tube. LCMS showed a mixture of product and starting material and the reaction was stirred for a further 1 h and LCMS showed no further reaction. Methanesulfonic acid (0.5 ml) was added and the reaction stirred for 18 h, diluted with DCM (30 ml) and extracted with water (2×25 ml). The DCM layer contained mainly starting material and impurities by LCMS. The aqueous portions were combined, and solid sodium hydrogen carbonate was used to adjust the pH to ˜10 and then extracted with a 1:1 mixture of DCM-Et2O. The combined organic extracts were washed with water, dried (MgSO4) and concentrated to afford a yellow solid (100 mg, 80% purity by LC-MS) (40%) which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24]([C:27]4[N:28]=[C:29]([C:32]([OH:35])([CH3:34])[CH3:33])[S:30][CH:31]=4)[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:36])[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]Br>C1COCC1>[Cl:36][C:6]1[CH:5]=[C:4]([C:1]([OH:3])([CH3:37])[CH3:2])[CH:9]=[C:8]([Cl:10])[C:7]=1[NH:11][C:12]1[C:21]2[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=2[C:15]2[CH:23]=[C:24]([C:27]3[N:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[S:30][CH:31]=3)[CH:25]=[CH:26][C:14]=2[N:13]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccc(-c4csc(C(C)(C)O)n4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccc(-c4csc(C(C)(C)O)n4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 5-[(4-acetyl-2,6-dichlorophenyl)amino]-9-[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-4-yl]benzo[c]-2,6-naphthyridin-1(2H)-one (75 mg, 0.14 mmol) in THF (2 mL) was cooled to −10° C. and methyl magnesium bromide (0.79 mL, 1.11 mmol, 1.4 M in toluene/THF) was added. The reaction was stirred rapidly keeping the temperature between −5 & 0° C. for 1 h. After warming to room temperature, the reaction was quenched with water, diluted with ethyl acetate/THF (1:3), and extracted with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane followed by reverse phase HPLC to afford the title compound.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:19]=[N:20][CH:21]=1.C=O>CO>[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:1])[CH2:25][C@@H:24]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: Fc1ccc([C@H]2CNCCN2Cc2cncc(Br)c2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2cncc(Br)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
Sodium triacetoxyborohydride (1.5 g, 7 mmol) was added to a mixture of (S)-1-(5-bromo-pyridin-3-ylmethyl)-2-(4-fluoro-phenyl)-piperazine (as tris(trifluoroacetate) salt) (820 mg, 1.2 mmol) and formaldehyde (37% aqueous solution, 3 mL, 36.9 mmol) in 20 mL of methanol. The mixture was stirred at ambient temperature overnight, and then the volatiles were removed in vacuo and the residue dissolved in water and the pH was adjusted to 11 by the addition of 10 M sodium hydroxide solution. The product was extracted into dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to leave 431 mg of product. LC/MS: Retention time, 2.15 min; (M+H)=366.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C.O>CO>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:16][CH3:14])=[N:7][CH:6]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(F)nc1C#N
Temperature: 0 °C

Procedure:
In 25 mL of methanol was dissolved 2.5 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then, 2.4 g of 28% methanolic solution of sodium methoxide was dropwise added at 5-15° C., and the mixture thus formed was stirred at an ice-cooled temperature for 2 hours. The reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 50 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.45 g of 6-fluoro-3-methoxy-2-pyrazinecarbonitrile as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:4][CH:3]=1>C(O)CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccnc1NCc1ccccn1)c1ccc(Cl)cc1
Solvent: OCCO
Product: Clc1ccc(-c2nc3cccnc3n2Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A solution of 4-chloro-N-[2-[(2-pyridinylmethyl)amino]-3-pyridinyl]benzamide (14.65 g, 0.0433 mol) prepared in the previous paragraph and ethylene glycol (145 mL) were heated at reflux for 1.5 hr and then stirred at room temperature overnight. The resulting solid was collected by filtration, rinsed several times with water, recrystallized from isopropanol/water and dried under high vacuum at 70° C. to give 10.36 g (74% yield) of the title compound, mp 144°-146° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cc2ccccc2nc1Cl
Temperature: 110 °C
Yield: 95.1 %

Procedure:
3-Nitroquinolin-2(1H)-one (1.40 g, 7.36 mmol) obtained in Step 1 was dissolved in phosphorus oxychloride (3.50 mL, 36.8 mmol) and the mixture was stirred with heat at 110° C. for 4 hours. The reaction mixture was poured into an ice bath and thereby the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 50/1) to give 2-chloro-3-nitroquinoline (1.46 g, yield: 95%).
Reaction SMILES: [NH:1]([C:3](=[O:21])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:2].C[C:23]1([CH2:30][C:31](O)=O)[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:30][C:31]2[O:21][C:3]([CH2:4][C:5]3[S:6][C:7]4[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:11]=[CH:10][C:8]=4[N:9]=3)=[N:1][N:2]=2)[S:27]1
Reactant: CC1(CC(=O)O)SC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)c1ccc2nc(CC(=O)NN)sc2c1
Product: CC(C)(C)OC(=O)c1ccc2nc(Cc3nnc(CC4SC(=O)NC4=O)o3)sc2c1
Yield: 38 %

Procedure:
Compound 188d was prepared from Compound 188c in 38% yield as a white solid using the general procedure given for Compound 1a. LCMS=1.88 min using analytical method (B), 447.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.1 Hz, 1H), 8.14 (dd, J=8.6, 1.5 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 4.82 (dd, J=9.2, 4.2 Hz, 1H), 4.76 (s, 2H), 3.82-3.76 (m, 1H), 3.49 (m, 1H), 1.64 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1C1C=C(Cl)C=CC=1O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].BrCC(OCC)=O>CC(C)=O.O>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1c1cc(Cl)ccc1O
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (7.47 g, 21.6 mmol, 1.0 eq.) and potassium carbonate anhydrous (4.48 g, 32.4 mmol, 1.5 eq.) in acetone (400 mL), ethyl bromoacetate (2.63 mL, 23.8 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in water (150 mL). The mixture was extracted with AcOEt (2×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 340 g, flow: 90 mL/min, Heptane to Heptane+50% EtOAc) to yield the title product as an yellow oil.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1>C(O)C.C(N(CC)CC)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][Br:2])[CH2:21][CH2:20]1
Reactant: BrP(Br)Br
Reactant: COc1cc2ncnc(N3CCC(CCO)CC3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(CCBr)CC3)c2cc1OC
Reaction time: 16 h

Procedure:
Phosphorus tribromide (9.7 g) was added at room temperature to a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-(2-hydroxyethyl)piperidine (7.5 g) in ethanol free chloroform (200 cm3) and triethylamine (5.0 cm3). After stirring for 16 hours the volatile material was removed in vacuo and the residue was taken into aqueous sodium carbonate solution and extracted with chloroform (3×50 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on "Florisil" (Trade Mark, Hopkin and Williams) eluting with chloroform to afford 1-(6,7-dimethoxyquinazoline-4-yl)-4-(2-bromoethyl) piperidine 1/4 H2O as a white solid, m.p. 191° (5.6 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(O[C@H]2C[C@H]3CN(Cc4ccccc4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.3 %

Procedure:
A solution of 0.971 g (4.18 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L.; et al. J. Het. Chem., 1990, 27, 2181), 0.703 g (6.27 mmol) of 4-fluorophenol and 1.32 g (5.02 mmol) of triphenylphosphine in 20 mL of dry THF was treated with 0.79 mL (5.02 mmol) of diethyl azodicarboxylate and the solution stirred at room temperature for 21 h. Excess HCl (g) in diethyl ether was added, the precipitate was collected on a Buchner funnel, washing with ethyl acetate. The gummy residue was dissolved in a mixture of ethyl acetate and aqueous ammonium hydroxide, the layers were separated, the aqueous phase was extracted with more ethyl acetate (2×), the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC with 95:5 ethyl acetate:methanol gave 1.3 g (95%) of (7S,8aS)-7-(4-fluorophenoxy)-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine.
Reaction SMILES: C([O:8][NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[O:12])C1C=CC=CC=1>FC(F)(F)CO.[Pd]>[OH:8][NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[O:12]
Reactant: NCCCC[C@H](NC(=O)CNOCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: NCCCC[C@H](NC(=O)CNO)C(=O)O
Temperature: 25 °C
Yield: 310.5 %

Procedure:
BnO-GlyLys [α-CO-3,5-Ph(CO2Me)2] [ε-Glu] [α-Boc] [γ-CO2Me] (90 mg, 0.119 mmol) was dissolved in 2,2,2-trifluoroethanol (4 ml) and stirred at room temperature. Non-Degussa Pd/C (10%, 0.030 mmol, 32 mg) was added to the degassed solution and the system was stirred under hydrogen gas (1 atm) for 24 h. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give HO-GlyLys [α-CO-3,5-Ph(CO2Me)2] [ε-Glu] [α-Boc] [γ-CO2Me] as an orange glass (81 mg, 102%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([O:8][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCCO
Reactant: CC(C)C(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)C(C)C

Procedure:
To a stirred solution of DL-valine 34 (20 g, 170.7 mmol) in toluene (200 mL) was added 1-dodecanol 2 (28.6 g, 153 mmol) in one lot, followed by pTSA (35.7 g, 187.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature and the water was separated azeotropically. The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 35 (40 g, yield, 82%) as a liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:48][C:49]1[C:50]([F:57])=[C:51](O)[C:52]([F:55])=[CH:53][CH:54]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:51]4[C:52]([F:55])=[CH:53][CH:54]=[C:49]([Cl:48])[C:50]=4[F:57])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Reactant: Oc1c(F)ccc(Cl)c1F
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCOc4c(F)ccc(Cl)c4F)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E4 and 3-chloro-2,6-difluorophenol, according to the above-described procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([O:30][CH2:29][C:28]([F:27])([F:38])[F:39])[CH:32]=1)=[O:6]
Reactant: Nc1cccc(OCC(F)(F)F)c1
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(OCC(F)(F)F)c1)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under nitrogen, to 2-chloro-6-nitrobenzoic acid (1.27 g, 6.28 mmol, 1.00 equiv) in CH2Cl2 (20 mL) at 23° C. was added oxalyl chloride (0.585 mL, 6.91 mmol, 1.10 equiv) and DMF (16 μL, 0.19 mmol, 3.0 mol %). After stirring for 1 hr at 23° C., the reaction mixture was cooled to 0° C. and triethylamine (2.63 mL, 18.8 mmol, 3.00 equiv) and 3-(2,2,2-trifluoroethoxy)aniline (1.20 g, 6.28 mmol, 1.00 equiv) were added. After stirring for 15 min at 0° C., 3N HCl aq (50 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×3.0 mL). The combined organic phases were washed with brine (3.0 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 965 mg of the title compound (41% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[C:8]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[N:16]=[CH:15]2)[CH:9]=1.O>CN(C=O)C>[C:8]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH:18]=[C:17]([C:19]([N:3]3[CH:7]=[CH:6][CH:5]=[N:4]3)=[O:20])[N:16]=[CH:15]2)[CH:9]=1
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cn(-c2cccc(-c3ccccc3)c2)cn1)n1cccn1
Reaction time: 0.5 h

Procedure:
To a stirred, ice-cooled solution of sodium hydride (45 mg, 1.14 mmol) in anhydrous DMF (10 ml) was added pyrazole (77 mg, 1.14 mmol) and stirring was continued for 30 min. under nitrogen. A solution of compound 11a (0.27 g, 0.95 mmol) in DMF (10 ml) was added slowly and the resultant mixture was stirred at ambient conditions overnight. Water (80 ml) was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (1:1) to afford 178. (60 mg, 20%). Mp 124-127° C.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH3:25])C(OC(C)(C)C)=O)[CH3:2].[ClH:47]>C(OCC)C>[ClH:47].[ClH:47].[ClH:47].[ClH:47].[CH2:24]([NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11]/[CH:10]=[CH:9]/[CH2:8][NH:7][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])[CH3:25]
Reactant: CCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCNCCCNC/C=C/CNCCCNCC

Procedure:
1.97 g (3 mmol) of (E)-1,14-di-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 30 ml of 3N methanolic hydrochloric acid are reacted analogously to Example 1. The addition of 50 ml of diethyl ether to the reaction mixture and subsequent filtration yield the title compound, m.p. >260° C. 1H-NMR (D2O): δ1.28(t,6H); 2.04-2.15(m,4H); 3.08-3.19(m,12H); 3.76(d,4H); 6.04-6.07(m,2H).