Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:53](CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]#[N:53])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A suspension of 500 mg 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b), 111.2 mg ammonium chloride and 0.7 ml triethylamine in 5 ml tetrahydrofuran are cooled to −10° C. and 1.21 ml of a T3P® solution (50% in ethyl acetate) is added dropwise. The reaction mixture is warmed to room temperature and stirred for 8 hours. The resulting suspension is stirred at 70° C. for 2 days. During this time, the addition of 111.2 mg ammonium chloride, 0.7 ml triethylamine and 1.21 ml of a T3P® solution (50% in ethyl acetate) is repeated twice. The reaction mixture is quenched by addition of 5 ml of water and extracted with 50 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.12 (EtOAc-heptane 1:2); Rt=5.42.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:28])[F:27])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:38][CH2:39][C:40]([NH:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[O:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[OH:6][N:5]=[C:4]([NH:38][CH2:39][C:40]([NH:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[O:41])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:27])[F:28])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: NCC(=O)NCC(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=NO)NCC(=O)NCC(F)(F)F
Temperature: 75 °C
Yield: 42.6 %

Procedure:
To a solution of 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (250 mg) in DMF (8 mL) was added N-chloro succinimide (84 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto water and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-(2,2,2-trifluoro-ethyl)-acetamide (116 mg) and triethylamine (0.30 mL, 0.21 g) in THF (8 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (146 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH:28]CC4C=CC(OC)=CC=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH2:28])[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(OCc5cccc(Cl)c5)c(Cl)c4)ncnc3cn2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 91 h
Yield: 97.4 %

Procedure:
To a stirred heterogeneous mixture of compound 210 (1.46 g, 2.74 mmol) and dry DCM (27 mL) was added trifluoroacetic acid (2.1 mL, 27.4 mmol), followed by anisole (0.60 mL, 5.48 mmol), and the mixture was stirred further at room temperature for 91 h. It was poured into petroleum ether (300 mL) and stirred at room temperature for ca. 30 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). The residue left behind was dissolved in mixed solvents of acetone-water=1:1 (ca. 100 mL) and stirred with 5M NH3 (100 mL) at room temperature for 1 h. The solid was filtered and washed successively with acetone-water=1:4 (5×20 mL), petroleum ether-ethyl acetate=3:1 (5×20 mL), and dried to give N4-(3-chloro-4-(3-chlorobenzyloxy)phenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (219) (1.10 g, 97%), mp 251-254° C. (decomp); 1H NMR δ [(CD3)2SO] 9.70 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 8.04 (br s, 1H), 7.73 (br d, J=8.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.48-7.39 (m, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.12 (br s, 1H), 7.65 (br s, 2H), 5.24 (s, 2H). Anal. Calcd for C20H13Cl2N5O: C, 58.27; H, 3.67; N, 16.99. Found C, 58.33; H, 3.57; N, 17.2.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35].C(Cl)(=O)C(Cl)=O.[CH2:42](O)[C:43]#[CH:44].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([O:31][CH2:44][C:43]#[CH:42])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35]
Reactant: Cc1ccc(OC(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: C#CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCOC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A mixture of 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionic acid (0.510 g, 1.00 mmol) and oxalyl chloride (0.380 g, 3.00 mmol) in methylene chloride is stirred at room temperature for 30 minutes and concentrated in vacuo to obtain a yellow foam. The foam is diluted with methylene chloride and the resultant solution is treated with a solution of propargyl alcohol (0.110 g, 2.00 mmol) in methylene chloride, stirred at room temperature for 24 hours, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel, a hexanes/methylene chloride solution (1:1) and a 5% diethyl ether in methylene chloride solution gives the title product (0.400 g) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].ClC1C=C(C2C3C(=CC(S(OC4C(F)=C(F)C(F)=C(F)C=4F)(=O)=O)=CC=3)N=CN=2)C(OC)=CC=1C1C=CC=C(F)C=1.S1C(N)=NC=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: Nc1nncs1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Nc1ncns1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nncs3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 521, except that perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate and 1,3,4-thiadiazol-2-amine were used instead of perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate and 1,2,4-thiadiazol-5-amine to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)quinazoline-7-sulfonamide as a yellow solid. (ESI) 434.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:26])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@@H:8]([C:11]1[C:12]([F:26])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 125.9 %

Procedure:
Step 2 To a solution of {(R)-1-[4-chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propyl}-carbamic acid tert-butyl ester (16.0 g, 40.7 mmol) in DCM (300 mL) was added 4M HCl in dioxane (41 mL, 162 mmol, 4 eq) and the reaction stirred for 18 h. The mixture was concentrated and then triturated with diethyl ether (˜200 mL) and the pale green solid filtered off and dried in a vacuum oven to give [3-((R)-1-Amino-propyl)-6-chloro-2-fluoro-phenyl]-pyridin-3-yl-methanone (15.0 g) as the HCl salt. Material contains about 1.3 g dioxane (from NMR ratio), which was not removed from vacuum oven drying.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:20][NH:19][C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])[CH2:3][OH:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
Z-Ser-OH (10.0 g) and 6.2 g of t-butyl carbazate were dissolved in 150 ml of DMF and the solution was ice-cooled. HONB (8.0 g) and 9.3 g of DCC were added and the mixture was stirred for 15 hours. The formed DCU was filtered off and the filtrate was concentrated. The residue was extracted into AcOEt and the AcOEt solution was washed with 4% aqueous NaHCO3 and 10% aqueous citric acid, dried over Na2SO4 and concentrated. Ether was added and the crystals was collected by filtration. Yield 7.3 g (50.4%), mp 95°-98° C., [α]D26 -6.2° (c=0.8, DMF), Rf1 0.62.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].[P:12]([Cl:17])(Cl)(Cl)([Cl:14])[Cl:13]>>[P:12]([Cl:17])([Cl:14])([Cl:13])=[O:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(C(=O)Cl)c1
Product: O=P(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-5-methylbenzoic acid (9.4 g) and phosphorous pentachloride (11.6 g) is stirred at room temperature for 1 hour and then distilled to yield phosphorous oxychloride, b.p. 45°/85 mm and 3-chloro-5-methylbenzoyl chloride, b.p. 56°/0.1 mm (10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.[CH3:38][NH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:39]([CH3:38])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
To a mixture of 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid (250 mg) synthesized in Example A106(5), ethyl 3-(methylamino)propanoate (93.1 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title object compound (254 mg, 84%) as a pale-yellow oil.
Reaction SMILES: [OH-].[Na+].CO.[NH:5]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:6]([C:19]([NH:21][C@H:22]([C:29]([NH:31][C@@H:32]([C:43]([NH:45][C@H:46]([C:48]([O:50]C)=[O:49])[CH3:47])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O>[NH:5]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[C@H:6]([C:19]([NH:21][C@H:22]([C:29]([NH:31][C@@H:32]([C:43]([NH:45][C@H:46]([C:48]([OH:50])=[O:49])[CH3:47])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2N aqueous sodium hydroxide solution (7.5 mL, 15 mmol) was added to a methanol (500 mL) and water solution (200 mL) containing Boc-Lys(Boc)-His-D-Trp-Ala-OMe (10.35 g, 13.7 mmol). After the reaction was allowed to stir overnight at room temperature, HPLC analysis indicated that less than 3% of the starting material remained. The resulting solution was concentrated in vacuo to a volume of approximately 200 mL. Water (100 mL) was added and the pH was adjusted to approximately 12 by addition of 2N sodium hydroxide (1 mL). The resulting solution was extracted with ethyl acetate (2×500 mL). The pH of the aqueous phase was then adjusted to 5 by addition of aqueous HCl which resulted in the precipitation of an oil. The aqueous phase was decanted away from the oil and the oil was then rinsed with water (2×50 mL). This oil was converted to a solid foam upon drying to constant weight in vacuo (5.62 g, 55%). 1H NMR indicated the presence of a single isomer in high purity.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:5]=2[S:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].P(Cl)(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=O>>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:5]2[S:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([N:1]=[C:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:15]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1sc2c(c1N=C1CCCN1C)c1ccccc1c(=O)n2-c1ccccc1C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-amino-4,5-dihydro-4-(2-methylphenyl)-5-oxo-thieno[2,3-c]isoquinoline-2-carboxylate [M.P. 236°-237° C.), 510 mg] in 5 ml of N-methyl-2-pyrrolidone, which was prepared by a similar manner to that described in Example 2, was added 1.57 ml of phosphorus oxychloride at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 50 ml of water, and neutralized with a saturated sodium bicarbonate aqueous solution. Precipitates were collected by a filtration, washed with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain 583 mg of the desired product as yellow crystals.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([NH2:37])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].CN(C)[C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][C:60]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:44]1([CH2:43][O:42][C:40](=[O:41])[CH2:39][N:37]([CH2:39][C:40](=[O:41])[O:42][CH2:52][C:61]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1OCCCCCCCCCCCCCC
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(CBr)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OCCCCCCCCCCCCCC
Reaction time: 48 h
Yield: 72.8 %

Procedure:
A mixture of 2.8 g (5.4 mmol) of 3,4-bis(tetradecyloxy)benzenamine, 8.6 ml (54 mmol) of benzyl bromoacetate, 2.9 g (13.5 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.3 g of sodium iodide in 60 ml of acetonitrile and 10 ml of DMF was stirred under argon for 48 hours. The solvents were removed at reduced pressure and the residue was treated with water and extracted with ethyl acetate. The dried extract was concentrated and purified by HPLC using 10% ethyl acetate-hexane to give 3.2 g (73% yield, mp 52°-52°) of N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[O:7]=[S:8]1(=[O:32])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1.N1C=CC=CC=1>CN(C=O)C>[O:32]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][O:28][C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(N)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.5 h

Procedure:
65 μl (0.65 mmol) of ethyl chloroformate are added dropwise to a solution, cooled to 0° C., of the product obtained in Step A (244 mg, 0.65 mmol) in 1.5 ml of DMF and 59 μl (0.72 mmol) of pyridine. Stirring is carried out at 0° C. for 30 minutes and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH2:17](O)[CH3:18].S(=O)(=O)(O)O.[CH:25]1C=CC=C[CH:26]=1>>[CH2:25]([O:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:26]
Reactant: CCO
Reactant: c1ccccc1
Reactant: O=C(O)CCCCCCC1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCC1=C(OCC)CCC1=O

Procedure:
A mixture containing 26 parts of 2,5-dioxocyclopentaneheptanoic acid, 560 parts of ethanol, 440 parts of benzene and 14.7 parts of concentrated sulfuric acid is slowly distilled over a period of about 40 hours, during which time approximately 200 parts of distillate is collected. The residual mixture is cooled, diluted with approximately 350 parts of ether, then washed successively with dilute aqueous sodium hydroxide and water. The resulting neutral solution is dried over anhydrous sodium sulfate and evaporated by dryness under reduced pressure to afford, as a yellow liquid, ethyl 2-ethoxy-5-oxocyclopent-1-eneheptanoate, which substance is characterized by an ultraviolet absorption maximum at about 253.5 millimicrons.
Reaction SMILES: [N+:1]([C:4](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[C:5]([O:7][CH3:8])=[O:6])([O-:3])=[O:2].C(O)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N+:1]([C:4](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[C:5]([O:7][CH2:8][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([O-:3])=[O:2]
Reactant: OCC=Cc1ccccc1
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Product: O=C(OCC=Cc1ccccc1)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
2 was prepared as a yellow solid, m.p.: 115°-116°, from 1A and cinnamyl alcohol by the procedures described in Example 1.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:13]1[CH:44]=[CH:43][C:16]([CH2:17][C:18]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=2)(C(OCC=C)=O)[C:19]([O:21]CC=C)=[O:20])=[CH:15][CH:14]=1)#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([CH:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:44][CH:43]=1)[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=1)([OH:21])=[O:20]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CCC(Cc2ccc(C#N)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 7.5 ml (53.6 mmol) of triethylamine and 1.5 ml (40.6 mmol) of formic acid in 170 ml of dioxane is added to a solution of 7.5 g (16.25 mmol) of diallyl 2-(4-cyanobenzyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate, 0.3 g (1.14 mmol) of triphenylphosphine and 70 mg of palladium acetate in 170 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 2 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 5.48 g (89% of theory, 90% purity) of a colorless solid are obtained.